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Professor Dulcie Mulholland


Professor of Organic Chemistry
B.Sc, B.Sc(Hons), M.Sc, PhD(Natal)
+44 (0)1483 686751
02 AZ 03

Academic and research departments

Department of Chemistry.

Research

Research interests

My publications

Highlights

1. The Antiangiogenic Activity of Naturally-occurring and synthetic Homoisoflavonoids from the Hyacinthaceae (sensu APGII). SL Schwikkard, H Whitmore, RS. Sulaiman, K. Sishtla, T Shetty, H Basavarajappa, C Waller, A Alqhatani, L Frankemoelle, A Chapman, N Crouch, W Wetschnig, W Knirsch, J Andriantiana, MK Langat , TW Corson and D Mulholland, Journal of Natural Products, 2019, DOI: 10.1021/acs.jnatprod.8b00989

2. Application of Residual Dipolar Couplings and Selective Quantitative NOE to Establish the Structures of Tetranortriterpenoids from Xylocarpus rumphii (Meliaceae). W Waratchareeyakul, E. Hellemann, RR Gil, K Chantrapromma, MK Langat and DA Mulholland. 2017, Journal of Natural Products. 10.1021/acs.jnatprod.6b00906

3. Phytochemical investigations of three Rhodocodon (Hyacinthaceae sensu APG II) species. SL Schwikkard, A Alqahtani, W Knirsch, W Wetschnig, A Jaksevicius, EI Opara, MK Langat and DA Mulholland, 2017, Journal of Natural Products. DOI 10.1021/acs.jnatprod.6b00240

4. Diterpenoids from the roots of Croton dichogamus Pax. AHS Aldhaher, MK Langat. BM Ndunda, DK Chirchir, JO Midiwo, AW Njue, SL Schwikkard, M Carew, DA Mulholland. 2017, Phytochemistry, 144, 1-8.

5.Efficacy of extracts from eight economically important forestry species against downy mildew (Plasmopora viticola) and identification of active constituents. DA Mulholland*, MK Langat, EE James, DA Nawrot, L Tamm, B Thürig, Hans-Jakob Schärer, N Demidova, D Izotov, H Kleeberg, I Kleeberg, J Treutwein, S Cergel, H Hokkanen. 2017, Crop Protection, 102, 104-109.  

Publications

DA Mulholland, NR Crouch, C Koorbanally, N Moodley, T Pohl (2006)Infraspecific chemical variation in Scilla zebrina (Hyacinthaceae), In: BIOCHEMICAL SYSTEMATICS AND ECOLOGY34(3)pp. 251-255 PERGAMON-ELSEVIER SCIENCE LTD
DA Mulholland, K McFarland, M Randrianarivelojosia (2006)Sesquiterpenoid derivatives from Cipadessa boiviniana (Meliaceae), In: BIOCHEMICAL SYSTEMATICS AND ECOLOGY34(4)pp. 365-369 PERGAMON-ELSEVIER SCIENCE LTD
NR Crouch, K du Toit, DA Mulholland, SE Drewes (2006)Bufadienolides from bulbs of Urginea lydenburgensis (Hyacinthaceae : Urgineoideae), In: PHYTOCHEMISTRY67(19)pp. 2140-2145 PERGAMON-ELSEVIER SCIENCE LTD
M Randrianarivelojosia, A Langlois, DA Mulholland (2006)Investigations of the Malagasy species Tachiadenus longiflorus Grisebach (Gentianaceae): Linking chemical finding and traditional usage, In: JOURNAL OF ETHNOPHARMACOLOGY105(3)pp. 456-458 ELSEVIER IRELAND LTD
A Aldhaher, Moses Langat, B Ndunda, D Chirchir, JO Midiwo, A Njue, S Schwikkard, M Carew, Dulcie Mulholland (2017)Diterpenoids from the Roots of Croton dichogamus Pax, In: Phytochemistry144pp. 1-8 Elsevier

Four previously undescribed diterpenoids including two crotofolanes, crotodichogamoin A and B, and two halimanes, crothalimene A and B, a new sesquiterpenoid, and fifteen previously reported compounds, including the crotofolane, crotohaumanoxide, the casbane, depressin, a further seven furanohalimane diterpenoids, three patchoulane and two further cadinane sesquiterpenoids and aleuritolic acid were isolated from the root of Croton dichogamus. Crotodichogamoin B is an important biosynthetic intermediate of the crotofolane class and this is the first report of patchoulene sesquiterpenoids from the genus. Compounds were tested at one concentration, 1x10-5 M, in the NCI59 cell one-dose screen but did not show significant activity snd were also evaluated for their cytotoxicity against Caco-2 cell lines using the neutral red assay. 10-epi-Maninsigin D reduced Caco-2 cell viability at 10, 30 and 100 µM, with values of decreased viability of 28%, 48% and 43% respectively. None of the other tested compounds showed significant activity.

E Douwes, NR Crouch, TJ Edwards, DA Mulholland (2008)Regression analyses of southern African ethnomedicinal plants: informing the targeted selection of bioprospecting and pharmacological screening subjects, In: JOURNAL OF ETHNOPHARMACOLOGY119(3)pp. 356-364 ELSEVIER IRELAND LTD
C Koorbanally, NR Crouch, A Langlois, K Du Toit, DA Mulholland, SE Drewes (2006)Homoisoflavanones and spirocyclic nortriterpenoids from three Eucomis species: E comosa, E schijffii and E pallidiflora subsp pole-evansii (Hyacinthaceae), In: SOUTH AFRICAN JOURNAL OF BOTANY72(3)pp. 428-433 ELSEVIER SCIENCE BV
JJ Magadula, DA Mulholland, NR Crouch (2008)Triterpenoids from Anthocleista grandiflora (Gentianaceae), In: NATURAL PRODUCT COMMUNICATIONS3(6)pp. 885-889 NATURAL PRODUCTS INC
DA Mulholland, A Langlois, M Randrianarivelojosia, E Derat, JM Nuzillard (2006)The structural elucidation of a novel iridoid derivative from Tachiadenus longiflorus (Gentianaceae) using the LSD programme and quantum chemical computations, In: PHYTOCHEMICAL ANALYSIS17(2)pp. 87-90 JOHN WILEY & SONS LTD
MK Langat, NR Crouch, PJ Smith, DA Mulholland (2011)Cembranolides from the Leaves of Croton gratissimus., In: J Nat Prod74(11)pp. 2349-2355 American Chemical Society

Ten new cembranolides, (-)-(1R*,4R*,10R*)-4-methoxycembra-2E,7E,11Z-trien-20,10-olide (1), (-)-(1S*,4R*,10R*)-1-hydroxy-4-methoxycembra-2E,7E,11Z-trien-20,10-olide (2), (-)-(1S*,4S*,10R*)-1,4-dihydroxycembra-2E,7E,11Z-trien-20,10-olide (3), (-)-(1S*,4S*,10R*)-1,4-dihydroxycembra-2E,7E,11Z-trien-20,10-olide (4), (+)-(10R*)-cembra-1E,3E,7E,11Z,16-pentaen-20,10-olide (5), (+)-(10R*)-cembra-1Z,3Z,7E,11Z,15-pentaen-20,10-olide (6), (+)-(5R*,10R*)-5-methoxycembra-1E,3E,7E,11Z,15-pentaen-20,10-olide (7), (+)-(1S*,4S*,7R*,10R*)-1,4,7-trihydroxycembra-2E,8(19),11Z-trien-20,10-olide (8), (-)-(1S*,4S*,7S*,10R*)-1,4,7-trihydroxycembra-2E,8(19),11Z-trien-20,10-olide (9), and (+)-(1S*,4R*,8S*,10R*)-1,4,8-trihydroxycembra-2E,6E,11Z-trien-20,10-olide (10), together with six known compounds, lupeol, 4(15)-eudesmene-1β,6α-diol, α-glutinol, 24-ethylcholesta-4,22-dien-3-one, (+)-(1R*,10R*)-cembra-2E,4E,7E,11Z-tetraen-20,10-olide, and (+)-(1R*,4S*,10R*)-4-hydroxycembra-2E,7E,11Z-trien-20,10-olide (4a), have been isolated from the leaves of Croton gratissimus. The acetyl derivatives of 8 and 4a were evaluated against a chloroquine-sensitive strain of Plasmodium falciparum (D10).

C Koorbanally, DA Mulholland, NR Crouch (2006)Norlignans and homoisoflavanones from two south African Drimiopsis species (Hyacinthaceae : Hyacinthoideae), In: BIOCHEMICAL SYSTEMATICS AND ECOLOGY34(7)pp. 588-592 PERGAMON-ELSEVIER SCIENCE LTD
DA Nawrot, M Randrianarivelojosia, MK Langat, DA Mulholland (2013)Coumarins from the Malagasy Cedrelopsis rakotozafyi Cheek and Lescot (Rutaceae), In: BIOCHEMICAL SYSTEMATICS AND ECOLOGY50pp. 452-454 PERGAMON-ELSEVIER SCIENCE LTD
Dieudonné M. Takou, Alain F. Kamdem Waffo, Moses K. Langat, Jean D. Wansi, Lauren E. Mulcahy-Ryan, Sianne L. Schwikkard, Elizabeth I. Opara, Eduard Mas-Claret, Dulcie Mulholland (2019)Melanin Production Inhibitors from the West African Cassipourea congoensis, In: Planta Medica International Open6(02)pp. e50-e56 Thieme Open

Cassipourea congoensis (syn. Cassipourea malosana) is used in African countries as a skin-lightening agent. Two previously unreported cycloartane triterpenoids, 26-hydroxy-3-keto-24-methy lenecycloartan-30-oic acid 1 and 24-methylene-cycloartan-3β,26,30-triol 2 along with the known mahuannin B 3, 7-methoxymahuannin B 4, 7-methoxygeranin A 5, methyl-3-(4-hydroxy-3-methoxyphenyl)-2E-propenoate, glycerol-1-alkanoate, (E)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enal 6, (-)-syringaresinol 7, and stigmast-5-en-3-O-β-D-glucoside, were isolated from the roots of C. congoensis. The crude extract and compounds 1 and 5 were found to inhibit the production of melanin at 10 μM with low cytotoxicity validating the ethno-medicinal use of this plant

MC Kapingu, JJ Magadula, ZH Mbwambo, DA Mulholland (2008)Puguflavanones A and B; Prenylated flavanones from Baphia puguensis, In: NATURAL PRODUCT COMMUNICATIONS3(5)pp. 749-753 NATURAL PRODUCTS INC
PH Coombes, DA Mulholland, M Randrianarivelojosia (2008)Vilasinin limonoids from Malleastrum antsingyense J.F. Leroy (Meliodeae : Meliaceae), In: BIOCHEMICAL SYSTEMATICS AND ECOLOGY36(1)pp. 74-76 PERGAMON-ELSEVIER SCIENCE LTD
Moses K. Langat, Ncoza C. Dlova, Lauren E. Mulcahy-Ryan, Sianne L. Schwikkard, Elizabeth I. Opara, Neil R. Crouch, Jacob D. Hiles, Dulcie Mulholland (2020)The effect of isolates from Cassipourea flanaganii (Schinz) Alston, a plant used as a skin lightening agent, on melanin production and tyrosinase inhibition, In: Journal of Ethnopharmacology113272 Elsevier

Ethnopharmacological relevance: The Zulu and Xhosa people of South Africa use the stem bark of Cassipourea flanaganii as a skin-lightening cosmetic. Aim of the study: To isolate and identify compounds responsible for the skin lightening properties from the stem bark of Cassipourea flanaganii and to evaluate their cytotoxicity towards skin cells, and potential to treat hyperpigmentation. Materials and methods: Extracts from the stem bark of Cassipourea flanaganii were isolated using chromatographic methods and structures were determined using NMR, IR and MS analysis. The tyrosinase inhibitory activity and the ability to inhibit the production of melanin were determined using human primary epidermal melanocyte cells. Cytoxicity was established using the same melanocytes and a neutral red assay. Results: One previously undescribed compound, ent-atis-16-en-19-al (1) along with the known ent-atis-16-en-19-oic acid (2), ent-atis-16-en-19-ol (3), ent-kaur-16-en-19-oic acid (4), ent-kaur-16-en-19-al (5), ent-manoyl oxide (6), guinesine A (7), guinesine B (8), guinesine C (9), lichenxanthone (10), 2,4-dihydroxy-3,6-dimethyl benzoic acid methyl ester (11), lynoside (12), lupeol (13), β-amyrin (14), docosyl ferulate (15), stigmasterol, sitosterol and sitosterol-O-glucoside were isolated in this investigation. An impure fraction containing compound 3 was acetylated to obtain 19-acetoxy-ent-atis-16-ene (3a). Compounds 10 and 11 are usually isolated from lichen, hence they are possible contaminants of lichen harvested with the bark. Compounds 1, 3a, 5-14 were not significantly cytotoxic to the primary epidermal melanocyte cells (P > 0.05) when compared to the negative and positive controls (DMSO, 0.1% and hydrogen peroxide, 30 wt% in water). Inhibition of tyrosinase was significantly greater with respect to the negative control (P < 0.001) for compounds 3a, 5-8 and 9-10 at 10 M and for compounds 5-8 and 9-10 at 100 M. Compared to hydroquinone (the positive control) at 10µM, the level of inhibition was comparable or to that of compounds 3a, 5, 6, and 8-10 at 10µM, with 9 and 10 showing a greater level of inhibition. Inhibition of melanin was both concentration and time dependent for all compounds tested with higher melanin content at 24 hours compared to 48hrs and at 10mM compared to100 mM at both time points; melanin content was significantly lower for hydroquinone at both time points and concentrations. Conclusions: Compounds 1, 5-14, isolated from Cassipourea flanaganii and the derivative 3a showed low cytotoxicity. All compounds had a clear time and concentration dependent effect on melanin content which did not appear to be dependent on their inhibition of tyrosinase.

A Tsamo, MK Langat, P Nkounga, AFK Waffo, AE Nkengfack, DA Mulholland (2013)Limonoids from the West African Trichilia welwitschii (Meliaceae), In: BIOCHEMICAL SYSTEMATICS AND ECOLOGY50pp. 368-370 PERGAMON-ELSEVIER SCIENCE LTD
AF Kamdem Waffo, PH Coombes, NR Crouch, DA Mulholland, SMM El Amin, PJ Smith (2007)Acridone and furoquinoline alkaloids from Teclea gerrardii (Rutaceae : Toddalioideae) of southern Africa, In: PHYTOCHEMISTRY68(5)pp. 663-667 PERGAMON-ELSEVIER SCIENCE LTD
K Du Toit, EE Elgorashi, SF Malan, DA Mulholland, SE Drewes, J Van Staden (2007)Antibacterial activity and QSAR of homoisoflavanones isolated from six Hyacinthaceae species, In: SOUTH AFRICAN JOURNAL OF BOTANY73(2)pp. 236-241 ELSEVIER SCIENCE BV
PH Coombes, D Naidoo, DA Mulholland, M Randrianarivelojosia (2005)Quassinoids from the leaves of the Madagascan Simaroubaceae Samadera madagascariensis, In: PHYTOCHEMISTRY66(23)pp. 2734-2739 PERGAMON-ELSEVIER SCIENCE LTD
OQ Munro, K du Toit, SE Drewes, NR Crouch, DA Mulholland (2006)Experimental and theoretical studies of a naturally occurring non-oligomeric steroidal supramolecular zipper, In: NEW JOURNAL OF CHEMISTRY30(2)pp. 197-207 ROYAL SOC CHEMISTRY
EE Elgorashi, PH Coombes, DA Mulholland, J Van Staden (2007)Isoeugenitol, a cyclooxygenase-1 inhibitor from Gethyllis ciliaris, In: South African Journal of Botany73(1)pp. 156-158

Bioassay guided fractionation of the dichloromethane extract of the underground parts of Gethyllis ciliaris, using a cyclooxygenase-1 enzyme assay, has resulted in the isolation of the dihydroxydimethylbenzopyran-4-one isoeugenitol 1 (IC50 = 262 μM). The 90% methanolic extract yielded 9Z-octadec-9-enamide 3 and the novel compound isoeugenitol glycoside 2. The structures of the isolated compounds have been assigned on the basis of spectral analysis, including 1D and 2D NMR techniques. © 2006 Elsevier B.V. All rights reserved.

C Koorbanally, S Sewjee, DA Mulholland, NR Crouch, A Dold (2007)Homoisoflavanones from Pseudoprospero firmifolium of the monotypic tribe Pseudoprospereae (Hyacinthaceae : Hyacinthoideae), In: PHYTOCHEMISTRY68(22-24)pp. 2753-2756 PERGAMON-ELSEVIER SCIENCE LTD
N Moodley, RC Neil, DA Mulholland (2007)Bufadienolides from drimia macrocentra and urginea riparia (Hyacinthaceae: urgineoideae), In: PHYTOCHEMISTRY68(19)pp. 2415-2419 PERGAMON-ELSEVIER SCIENCE LTD
L Penali, DA Mulholland, KD Tano, PK Cheplogoi, M Randrianarivelojosia (2007)Low antiplasmodial activity of alkaloids and amides from the stem bark of Zanthoxylum rubescens (Rutaceae), In: PARASITE-JOURNAL DE LA SOCIETE FRANCAISE DE PARASITOLOGIE14(2)pp. 161-164 PRINCEPS EDITIONS
NR Crouch, A Langlois, DA Mulholland (2007)Bufadienolides from the southern African Drimia depressa (Hyacinthaceae : Urgineoideae), In: PHYTOCHEMISTRY68(13)pp. 1731-1734 PERGAMON-ELSEVIER SCIENCE LTD
M Randrianarivelojosia, DA Mulholland, K Mc Farland (2005)Prenylated coumarins from Cedrelopsis longibracteata (Ptaeroxylaceae), In: Biochemical Systematics and Ecology33(3)pp. 301-304
AF Atangana, FAA Toze, Moses Langat, EN Happi, LL Meva’a Mbazea, Dulcie Mulholland, AFK Waffo, N Sewald, JD Wansi (2017)Acridone alkaloids from Vepris verdoorniana (Excell & Mendonça) Mziray (Rutaceae), In: Phytochemistry Letters19pp. 191-195 Elsevier

Two new acridone alkaloids, verdoocridone A (1) and B (4), together with fifteen known compounds were isolated from methanol extracts of the roots and leaves of Vepris verdoorniana. The structures of all compounds were determined by comprehensive spectroscopic analyses (1D and 2D NMR, EI- and ESI– MS). The 13C NMR values of 1,2,3,5-tetramethoxy-N-methylacridone (2) and 5-methoxyaborinine (3) are also reported. The crude extracts and compounds (1-6) were tested for their antimicrobial activity. The test delivered moderate activities for crude extracts and compounds 1, 5 and 6 against the bacterium Staphylococcus aureus and the fungi Mucor meihei and Candida albicans with MIC values between 115 and 180mg/mL for extracts and between 21.3 and 29.4mM for compounds, compared to gentamycin with 0.2mM and nystatin with 5.2mM against both fungi. The determination of the radical scanvenging activity using 1,1-dephenyl-2-picrylhydrazyl (DPPH) assay gave moderate antioxidant values for all tested compounds, with IC50 between 0.29 and 0.41mM, compared to the standard 3-t-butyl-4- hydroxyanisole (BHA) displaying 0.03mM.

VJ Ndlebe, NR Crouch, DA Mulholland (2008)Triterpenoids from the African tree Phyllanthus polyanthus, In: PHYTOCHEMISTRY LETTERS1(1)pp. 11-17 ELSEVIER SCIENCE BV
NR Crouch, DA Mulholland, J Chetty (2005)Lupane triterpenoid and alkaloid isolates from Cyrtanthus breviflorus (Amaryllidaceae), In: South African Journal of Botany71(1)pp. 104-106

Cyrtanthus breviflorus Harv. is a highly variable bulbous taxon from both moist and dry grasslands of the eastern seaboard region of southern Africa. Amongst at least 42 ethnomedicinal regional amaryllids it is the only species reported to treat intestinal worms. The current investigation, the first to phytochemically profile C. breviflorus, has determined the presence in ethanolic bulb extracts of the four known isoquinoline alkaloids: haemanthamine, crinamine hydrochloride, lycorine and tazettine. From the hexane bulb extract five known lupane triterpenoids were isolated: lupeol, lupenone, glochidone, 3β, 27-dihydroxylup-20(29)-ene and betulinaldehyde. Copyright © NISC Pty Ltd.

Hannah Whitmore, Kamakshi Sishtla, Walter Knirsch, Jacky L. Andriantiana, Sianne Schwikkard, Eduard Mas-Claret, Sarah M. Nassief, Sani M. Isyaka, Timothy W. Corson, Dulcie A. Mulholland (2020)Bufadienolides and anti-angiogenic homoisoflavonoids from Rhodocodon cryptopodus, Rhodocodon rotundus and Rhodocodon cyathiformis, In: Fitoterapia141104479 Elsevier

Background Homoisoflavonoids have been shown to have potent anti-proliferative activities in endothelial cells over other cell types and have demonstrated a strong antiangiogenic potential in vitro and in vivo in animal models of ocular neovascularization. Three species of Rhodocodon (Scilloideaea subfamily of the Asparagaceae family), endemic to Madagascar, R. cryptopodus, R. rotundus and R. cyathiformis, were investigated. Purpose To isolate and test homoisoflavonoids for their antiangiogenic activity against human retinal microvascular endothelial cells (HRECs), as well as specificity against other ocular cell lines. Methods Plant material was extracted at room temperature with EtOH. Compounds were isolated using flash column chromatography and were identified using NMR and CD spectroscopy and HRESIMS. Compounds were tested for antiproliferative effects on primary human microvascular retinal endothelial cells (HRECs), ARPE19 retinal pigment epithelial cells, 92–1 uveal melanoma cells, and Y79 retinoblastoma cells. HRECs exposed to compounds were also tested for migration and tube formation ability. Results Two homoisoflavonoids, 3S-5,7-dihydroxy-(3′-hydroxy-4′-methoxybenzyl)-4-chromanone (1) and 3S-5,7-dihydroxy-(4′-hydroxy-3′-methoxybenzyl)-4-chromanone (2), were isolated along with four bufadienolides. Compound 1 was found to be non-specifically antiproliferative, with GI50 values ranging from 0.21–0.85 μM across the four cell types, while compound 2 showed at least 100-fold specificity for HRECs over the other tested cell lines. Compound 1, with a 3S configuration, was 700 times more potent that the corresponding 3R enantiomer recently isolated from a Massonia species. Conclusion Select homoisoflavonoids have promise as antiangiogenic agents that are not generally cytotoxic.

NR Crouch, TL Pohl, DA Mulholland, E Ndlovu (2005)Alkaloids from three ethnomedicinal Haemanthus species: H. albiflos, H. deformis and H. pauculifolius (Amaryllidaceae), In: South African Journal of Botany71(1)pp. 49-52

Three closely-allied ethnomedicinal Haemanthus (Amaryllidaceae) species from the summer-rainfall region of South Africa have been phytochemically investigated and have yielded a range of isoquinoline alkaloids. H. albiflos yielded homolycorine, albomaculine and the O-methyl-lycorenium salt. From H. pauculifolius, homolycorine, the novel paucamine present as a salt, and the quaternary salts of homolycorine, montanine and manthidine were isolated. H. deformis yielded coccinine, montanine and the quaternary salt of manthidine. Copyright © NISC Pty Ltd.

N. Moodley, N.R. Crouch Crouch, J. Bastida, E. Mas-Claret, P. Houghton, D.A. Mulholland (2020)Organ-specific production of alkaloids from bulbs and seeds of Crinum stuhlmannii subsp. delagoense (Amaryllidaceae), In: South African Journal of Botany Elsevier

The phytochemistry of both bulbs and seeds of the ethnomedicinal Crinum stuhlmannii subsp. delagoense (Amaryllidaceae) was studied, sourced from a single location simultaneously. Eight alkaloids, including two previously unreported ones, N-methyl-haemanthamide (nivanine), and N-methyl-ent-delagoenine, were isolated along with lycorine, 8,9-methylenedioxophenanthridine, 6-hydroxycrinamine, 6-ethoxycrinamine, haemanthamine and hamayne. Compounds isolated were tested for acetylcholinesterase inhibition.

SL Schwikkard, DA Mulholland (2014)Useful Methods for Targeted Plant Selection in the Discovery of Potential New Drug Candidates, In: PLANTA MEDICA80(14)pp. 1154-1160 GEORG THIEME VERLAG KG
Alice W. Njue, Josiah O. Omolo, Peter K. Cheplogoi, Moses K. Langat, Dulcie Mulholland (2017)Cytotoxic Ergostane Derivatives from the Edible Mushroom Termitomyces microcarpus (Lyophyllaceae), In: Biochemical Systematics and Ecology76pp. 12-14 Elsevier

Five ergostanes, dimethylincisterol (1), 5α,8α–epidioxy-(22E,24R)-ergosta-6,9(11),22-trien-3β-ol (2), 5α,8α–epidioxy-(22E,24R)-ergosta-6,22-dien-3β-ol (3), 5α,6α-epoxy-(22E,24R)-ergosta-8(14),22-diene-3β,7α-diol (4), (22E,24R)-ergosta-7,22-diene-3β,5α,6β-triol (5) and betulinic acid (6) were isolated from the fresh fruiting bodies of the edible mushroom, Termitomyces microcarpus. The cytotoxicity of the compounds isolated was evaluated against the NCI 60 human cancer cell line panel. The degraded sterol dimethylincisterol (1) and 5α,8α–epidioxyergosta-6,22-dien-3β-ol (3) possessed cytotoxic activity at the 1 µM level.

Joan J.E. Munissi, Sani M. Isyaka, Eduard Mas-Claret, Molly Brabner, Moses K. Langat, Stephen S. Nyandoro, Dulcie A. Mulholland (2020)Ent-clerodane and ent-trachylobane diterpenoids from Croton dictyophlebodes, In: Phytochemistry179112487 Elsevier

The stem bark and root bark extracts of Croton dictyophlebodes (Euphorbiaceae) yielded seven undescribed ent-clerodanes: 15,16-epoxy-17,12(S)-olide-ent-cleroda-1,3,13(16),14-tetraen-18-oic acid methyl ester (crotodictyo A), 3β,4β:15,16-diepoxy-ent-cleroda-13(16),14-dien-20-al (crotodictyo B), 3β,4β:15,16-diepoxy-ent-cleroda-13(16),14-dien-19,20-dioic acid (crotodictyo C), 3β,4β:15,16-diepoxy-ent-cleroda-13(16),14-dien-20,19-olide (crotodictyo D), 3β,4β:15,16-diepoxy-20,12(R)-olide ent-cleroda-13(16),14-dien-19-oic acid methyl ester (crotodictyo E), 15,16-epoxy-ent-cleroda-3,13(16),14-trien-12-oxo-18-oic acid (crotodictyo F) and 15,16-epoxy-ent-cleroda-1,3,13(16),14-tetraen-12-oxo-18-oic acid (crotodictyo G), in addition to 15,16-epoxy- ent-cleroda-3,13(16),14-trien-12-oxo-18-oic acid methyl ester (crotodictyo H), reported previously as a synthetic derivative, and acetyl aleuritolic acid. The root extract yielded two ent-trachylobanes, ent-trachylobane-18,19-diol, the undescribed ent-trachylobane-2α,19-diol, along with ent-kaur-16-en-19-oic acid and 2-methoxybenzyl benzoate. Compounds were evaluated against the NCI 60 panel of human tumour cell lines at a single dose of 10−5 M, but showed no significant activity.

Moses K. Langat, Beth M. Ndunda, Caitlin Salter, Babatope O. Odusina, Sani M. Isyaka, Eduard Mas-Claret, Patricia A. Onocha, Jacob O. Midiwo, Jean-Marc Nuzillard, Dulcie A. Mulholland (2020)Diterpenoids from the stem bark of Croton megalocarpoides Friis & M. G. Gilbert, In: Phytochemistry Letters39pp. 1-7 Elsevier

Five previously undescribed compounds, megalocarpoidolide I (1), megalocarpoidolide J (3), 12-epi-crotonzambefuran A (4), megalocarpoidolide K (5), 1-trans-p-hydroxycoumaroyl–geranylgerani-1-ol (6) were isolated from the stem bark of Croton megalocarpoides Friis & M. G. Gilbert. The known ent-trachyloban-18-ol, megalocarpoidolide B, megalocarpoidolide C (2), megalocarpoidolide H, crotocorylifuran, 7,8-dehydrocrotocorylifuran, 1,2-dehydrocrotocorylifuran-2-one, acetyl aleuritolic acid, lupeol, N-trans-p-coumaroyl-3′,4′-dihydroxyphenylethylamine, dodecyl trans-ferulate and lignoceryl trans-ferulate were also isolated. The structures of the compounds were determined using NMR, IR spectroscopy and HRMS. The structure of compound 1 was determined using Logic for Structural Determination (LSD). Compounds 1, 2 and 3 that were selected for screening based on their ability to add diversity to the NCI small molecule compound collection, were evaluated against the NCI60 panel of human tumour cell lines at 10μM level but found to be inactive.

N. Moodley, N.R. Crouch, J. Bastida, D.A. Mulholland (2020)Novel alkaloids and a ceramide from Brunsvigia natalensis (Amaryllidaceae) and their anti-neoplastic activity, In: South African Journal of Botany Elsevier

Two new 5,10b-ethanophenanthridine bridge alkaloids, 3-O-methyl–epi–vittatine, 1, and crouchinine, 2, (2R)-7-hydroxyflavan, 3, and a novel ceramide, brunsceramide, were isolated from the bulbs of Brunsvigia natalensis. (2R)-7-Hydroxyflavan showed total growth inhibition in the 55–60 ppm range against the melanoma (UACC62), breast (MCF7) and renal (TK10) cancer cell lines. 3-O-Methyl–epi–vittatine, 1, and bruns-ceramide, 4, were inactive against the cell lines tested.

Dulcie Mulholland, B Thuerig, Moses Langat, L Tamm, DA Nawrot, Emily James, M Qayyum, D Shen, K Ennis, A Jones, H Hokkanen, N Demidova, D Izotove, H-J Schärer (2017)Efficacy of extracts from eight economically important forestry species against grapevine downy mildew (Plasmopara viticola) and identification of active constituents., In: Crop Protection102pp. 104-109 Elsevier

Downy mildew caused by the oomycete Plasmopara viticola is the most devastating pathogen of grapevine. In this study, extracts of the bark of eight important northern forestry species were screened to find extracts showing activity against this pathogen and to identify the active compounds. Extracts from all eight species showed activity against P. viticola, the most promising, dichloromethane extracts of three Larix species, almost completely protecting grapevine from downy mildew under semi-controlled conditions. Five promising lead compounds were isolated: larixol, larixyl acetate, lariciresinol and lariciresinol acetate from Larix species and 7α,15-dihydroxydehydroabietic acid from Pinus sylvestris. These compounds showed 90%-100% efficacy. Larixol and larixyl acetate or 7α,15-dihydroxydehydroabietic acid are present in significant amounts in Larix or P. sylvestris bark extracts, respectively. The identified active compounds are gained from a renewable resource potentially available in large quantities at relatively low prices, making them interesting candidates for the development of a plant-derived fungicide active against a key pathogen in agriculture, providing an opportunity to the forest industry to transform low value by-products into high value-added, bioactive extracts.

DA Mulholland, AMA Mohammed, PH Coombes, S Haque, LL Pohjala, PSM Tammela, NR Crouch (2011)Triterpenoid Acids and Lactones from the Leaves of Fadogia tetraquetra var. tetraquetra (Rubiaceae), In: NATURAL PRODUCT COMMUNICATIONS6(11)pp. 1573-1576
AFK Waffo, D Mulholland, JD Wansi, LM Mbaze, R Powo, TN Mpondo, ZT Fomum, W Konig, AE Nkengfack (2006)Afzeliixanthones A and B, two new prenylated xanthones from Garcinia afzelii ENGL. (Guttiferae), In: CHEMICAL & PHARMACEUTICAL BULLETIN54(4)pp. 448-451 PHARMACEUTICAL SOC JAPAN
Sani M. Isyaka, Eduard Mas-Claret, Moses K. Langat, Thomas Hodges, Bethany Selway, Blaise M. Mbala, Bienvenu K. Mvingu, Dulcie Mulholland (2020)Cytotoxic diterpenoids from the leaves and stem bark of Croton haumanianus (Euphorbiaceae), In: Phytochemistry178112455 Elsevier

The leaf extract of Croton haumanianus J. Léonard (Euphorbiaceae) yielded twenty-six compounds, including eight previously reported ent-kauranes and an ent-labdane and eight undescribed ent-kauranes, ent-16R-kauran-17-al, ent-3β-hydroxy-16R-kauran-17-al, ent-16S,17-epoxykauran-19-ol, ent-16S,17-epoxykauran-3β-ol, ent-17-palmityloxykaurane-3β,16β-diol, ent-17-palmityloxykauran-16β-ol, ent-3α,18-cyclokaurane-16β,17-diol and 19-nor-16α,17-dihydroxy-ent-kaur-4(18)-ene and three undescribed ent-clerodanes, dimethyl ent-15,16-epoxy-6β-hydroxy-1,3,13(16),14-clerodatetraen-20,12S-olide-18,19-dioate (saniolide A), dimethyl ent-15,16-epoxy-6β-hydroxy-1,3,13(16),14-clerodatetraen-20,12R-olide-18,19-dioate (12-epi-saniolide A), methyl ent-15,16-epoxy-1,3,13(16),14-clerodatetraen-18,6R:20,12S-diolide-19-oate (saniolide B) . The stem bark extract yielded the ent-clerodane crotocorylifuran, and five undescribed ent-isopimaranesent-isopimara-8(14),15-dien-18-al, ent-18-hydroxyisopimara-8(14),15-dien-7-one, ent-isopimara-7,15-dien-18-oic acid, ent-isopimara-7,15-dien-18-ol and ent-isopimara-8,15-dien-7-oxo-18-oic acid. Three compounds, ent-kaurane-3β,16β,17-triol, ent-17-palmityloxykaurane-3β,16β-diol and ent-17-palmityloxykauran-16β-ol, showed selective activity against three of the NCI 60 cancer cell lines, the colon (HCT-116), the melanoma (M14) and the renal (786-0) cancer cell lines at a concentration of 10-5 M.

AB Essop, RL van Zyl, SF van Vuuren, D Mulholland, AM Viljoen (2008)The in vitro pharmacological activities of 12 South African Hermannia species, In: JOURNAL OF ETHNOPHARMACOLOGY119(3)pp. 615-619 ELSEVIER IRELAND LTD
DA Nawrot, MK Langat, DA Mulholland (2012)CHEMICAL CONSTITUENTS OF EAST EUROPEAN FOREST SPECIES, In: PHARMACEUTICAL BIOLOGY50(5)pp. 588-588
VJ Tembu, MK Langat, NR Crouch, DA Mulholland (2014)Use of Circular Dichroism to Determine the Absolute Configuration of a Pimarane Diterpenoid from the Southern African Sclerocroton integerrimus (Euphorbiaceae), In: NATURAL PRODUCT COMMUNICATIONS9(8)pp. 1131-1133 NATURAL PRODUCTS INC
Watcharee Waratchareeyakul, Fabio Fusi, Miriam Durante, Amer Ahmed, Walter Knirsch, Eduard Mas-Claret, Dulcie A. Mulholland (2020)Vasorelaxing Activity of Stilbenoid and Phenanthrene Derivatives from Brasiliorchis porphyrostele: Involvement of Smooth Muscle CaV1.2 Channels, In: Planta Medica86(09)pp. 631-642 Thieme Gruppe

Five compounds, 3,4’-dihydroxy-3’,5,5’-trimethoxydihydrostilbene, 1, 3,4'-dihydroxy-3',5'-dimethoxydihydrostilbene, 2, 3,4'-dihydroxy-5,5'-dimethoxydihydrostilbene, 3, 9,10-dihydro-2,7-dihydroxy-4,6-dimethoxyphenanthrene, 4, and the previously unreported 1,2,6,7-tetrahydroxy-4-methoxyphenanthrene, 5, were isolated from the South American orchid, Brasiliorchis porphyrostele. An in depth analysis of their vascular effects was performed on in vitro rat aorta rings and tail main artery myocytes. Compounds 1-4 were shown to possess vasorelaxant activity on rings pre-contracted by the α1 receptor agonist phenylephrine, the CaV1.2 stimulator (S)-(-)-Bay K 8644, or depolarised with high K+ concentrations. However, compound 5 was active solely on rings stimulated by 25 mM but not 60 mM K+. The spasmolytic activity of compounds 1 and 4 was significantly affected by the presence of an intact endothelium. The KATP channel blocker glibenclamide and the KV channel blocker 4-aminopyridine significantly antagonised the vasorelaxant activity of compounds 4 and 1, respectively. In patch-clamp experiments, compounds 1-4 inhibited Ba2+ current through CaV1.2 channels in a concentration-dependent manner, whereas neither compound 4 nor compound 1 affected K+ currents through KATP and KV channels, respectively. The present in vitro, comprehensive study demonstrates that Brasiliorchis porphyrostele may represent a source of vasoactive agents potentially useful for the development of novel antihypertensive agents that has now to be validated in vivo in animal models of hypertension.

JK Sihra, AE Thumser, MK Langat, NR Crouch, DA Mulholland (2015)Constituents of Bulbs of three Species of the Hyacinthaceae (Hyacinthoideae): Eucomis vandermerwei, E. zambesiaca and Resnova humifusa, In: NATURAL PRODUCT COMMUNICATIONS10(7)pp. 1207-1209 NATURAL PRODUCTS INC
B Ndunda, Moses Langat, Dulcie Mulholland, H Eastman, MR Jacob, S Khan, L Walker, I Muhammad, LO Kerubo, JO Midiwo (2016)New ent-clerodane and abietane diterpenoids from the roots of Kenyan Croton megalocarpoides, In: Planta Medica82(11-12)pp. 1079-1086 Georg Thieme Verlag

The roots of the endangered medicinal plant Croton megalocarpoides (Euphorbiaceae) collected in Kenya has been investigated. Twenty two compounds has been isolated. Among them twelve new ¬ent-clerodane (1-12) and a new abietane (13) diterpenoid alongside the known crotocorylifuran (4a), two known abietane and four known ent-trachylobane diterpenoids, and the triterpenoids, lupeol and acetyl aleurotolic acid. The structures of the compounds were determined using NMR, HRMS and ECD. The isolated compounds have been evaluated against a series of microorganisms (fungal and bacteria) and also against Plasmodium falciparum, however no activity was observed.

AMA Mohammed, PH Coombes, NR Crouch, DA Mulholland (2012)Garjasmine unequivocally isolated from the Rubiaceae, In: BIOCHEMICAL SYSTEMATICS AND ECOLOGY44pp. 109-111 PERGAMON-ELSEVIER SCIENCE LTD
Sani M. Isyaka, Moses K. Langat, Eduard Mas-Clare, Blaise M. Mbala, Bienvenu K. Mvingu, Dulcie A. Mulholland (2019)Ent-abietane and ent-pimarane diterpenoids from Croton mubango (Euphorbiaceae), In: Phytochemistry170112217 Elsevier

Twelve ent-abietane and two ent-pimarane diterpenoids were isolated from the leaves of Croton mubango Müll. Arg. (Euphorbiaceae) collected in the Democratic Republic of the Congo. 2β-Hydroxy-ent-abieta-7,13-dien-3-one, 15-hydroxy-ent-abieta-7,13-dien-3-one, 13α,15-dihydroxy-ent-abieta-8(14)-en-3-one, 2β,9,13-trihydroxy-ent-abieta-7-en-3-one, 2β,7β-dihydroxy-ent-abieta-8,11,13-trien-3-one, 15-hydroxy-ent-abieta-8,11,13-trien-3-one and ent-pimara-8(14),15-dien-3-one and the ent-forms of the previously reported normal series diterpenoids, ent-abieta-8,11,13-trien-3-one, 7β-hydroxy-ent-abieta-8,11,13-trien-3-one, 3α-hydroxy-ent-abieta-8,11,13-triene, 15-hydroxy-ent-abieta-8,11,13-triene and 6β-hydroxy-ent-abieta-8,11,13-triene are reported here for the first time. Structures were established using HRESIMS, FTIR, NMR, DP4+ probability calculations and by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Ent-pimara-8(14), 15-dien-3-one, showed antiproliferative activity against melanoma (MALME-3M), renal (UO-31) and ovarian cancer cell lines (IGROV1) at a concentration of 10−5 M in the NCI 60 screen.

W Waratchareeyakul, E Hellemann, RR Gil, K Chantrapromma, Moses Langat, Dulcie Mulholland (2017)Application of Residual Dipolar Couplings and Selective Quantitative NOE to Establish the Structures of Tetranortriterpenoids from Xylocarpus rumphii, In: Journal of Natural Products80(2)pp. 391-402 American Chemical Society

Nine triterpenoid derivatives were isolated from the heartwood of X. rumphii and were identified as xylorumphiins E (1), C (2), L (3), and M-R (4-9). Compounds 4-9 have a hemiacetal group in the triterpenoid sidechain making them impossible to purify. Purification was achieved after acetylation and subsequent separation of the epimeric mixtures of acetates, however differentiaition of the R and S epimers was not possible using standard NMR techniques. In one case, the relative configuration of a remotely located stereocenter with respect to the stereocenters in the main skeleton was unambiguously determined using residual dipolar couplings (RDCs). Dipolar couplings were collected from the sample oriented in compressed poly (methyl methacrylate) (PMMA) gels swollen in CDCl3. In another case, the relative configuration was determined using 1D selective quantitative NOE experiments. Xylorumphiin K (10), xyloccensin E, taraxer-14-en-3-ol, (22S)-hydroxytirucalla-7,24-diene-3,23-dione and 25-hydroxy-(20S,24S)-epoxydammaran-3-one were isolated from the bark of the same plant. Compounds 3-10 are new compounds. Compounds 1-6 and xyloccensin E were tested at one concentration, 1 x 10-5 M, in the NCI59 cell one-dose screen but did not show significant activity.

Moses Langat, Neil R. Crouch, Jean-Marc Nuzillard, Dulcie Mulholland (2017)Pseudopulchellol: A unique sesquiterpene-monoterpene derived C-25 terpenoid from the leaves of Croton pseudopulchellus Pax (Euphorbiaceae), In: Phytochemistry Letters23pp. 38-40 Elsevier

A C-25 terpenoid, pseudopulchellol, a rare example of a compound formed by the combination of a monoterpenoid and a sesquiterpenoid unit, was isolated along with eudesm-4(15)-en-1β,6α-diol, its likely precursor, and nine known compounds, including six ent-kaurenoic acids, from the leaves of Croton pseudopulchellus. The Logic for Structure Determination (LSD) protocol was used to determine that pseudopelchellol consisted of the sesquiterpene, eudesm-4(15)-ene-6α-ol, attached at the C-1β position to C10 of the monoterpene, α-pinene. The Electronic circular dichroism (ECD) studies were used to assign the absolute configuration of pseudopulchellol.

S Schwikkard, A Alqahtani, W Knirsch, W Wetschnig, A Jaksevicius, EI Opara, Moses Langat, JL Andriantiana, Dulcie Mulholland (2017)Phytochemical Investigations of Three Rhodocodon (Hyacinthaceae Sensu APG II) Species, In: Journal of Natural Products80(1)pp. 30-37 American Chemical Society

The genus Rhodocodon (Hyacinthaceae sensu APG II) is endemic to Madagascar and its phytochemistry has not been described previously. The phytochemistry of three species in this genus has been investigated and eight compounds, including three bufadienolides (compounds 1, 4, and 5), a norlignan (2), and four homoisoflavonoids (compounds 3 and 6-8) have been isolated and identified. Compounds 1-3 and 6-8 have not been described previously. The COX-2 inhibitory activity of compound 6 and compound 7 acetate (compound 7A) were investigated on isolated colorectal cancer cells. Compounds 6 and 7A inhibited COX-2 by 10% and 8%, respectively, at a concentration of 12.5 M compared to 12% for 1 mM aspirin (the positive control).

PH Coombes, EM Mwangi, BK Peters, NR Crouch, DA Mulholland (2009)The cyclobuta[b]quinoline alkaloid cyclomegistine from Teclea gerrardii I.Verd. (Toddalioideae: Rutaceae), In: BIOCHEMICAL SYSTEMATICS AND ECOLOGY37(4)pp. 494-496 PERGAMON-ELSEVIER SCIENCE LTD
DULCIE ADA MULHOLLAND (2021)Antiproliferative bufadienolides from the bulbs of Drimia altissima, In: Journal of natural products American Chemical Society

The bulbs of the South African Drimia altissima (Asparagaceae or Hyacinthaceae sensu APGII) have yielded a range of previously undescribed bufadienolides, drimianins A–G (1–7), the known bufadienolides bovogenin A (8), 3β-O-β-d-glucopyranosylbovogenin A (9), scillaren F (10), and altoside (11), the known homoisoflavonoid (3S)-3-(4′-methoxybenzyl)-5,6,7-trimethoxychroman-4-one (urgineanin C), the sesquiterpenoids 1β,6α-dihydroxy-4(15)-eudesmene and 6α-hydroxy-4(15)-eudesmen-1-one, polybotrin, adenosine, and 9R-hydroxy-(10E,12Z)-octadecadienoic acid ethyl ester. The bufadienolides isolated were tested at 10 μM in the NCI-60 cancer cell screen, and nine of these were selected for further screening at five concentrations. Drimianins C (3) and E (5) showed activity at the nanomolar level against a number of human cancer cell lines in the NCI-60 screen.

DA Mulholland, MK Langat, NR Crouch, HM Coley, EM Mutambi, J-M Nuzillard (2010)Cembranolides from the stem bark of the southern African medicinal plant, Croton gratissimus (Euphorbiaceae), In: PHYTOCHEMISTRY71(11-12)pp. 1381-1386 PERGAMON-ELSEVIER SCIENCE LTD
DA Mulholland, SL Schwikkard, NR Crouch (2013)The chemistry and biological activity of the Hyacinthaceae., In: Nat Prod Rep30(9)pp. 1165-1210 Royal Society of Chemistry

Covering: 1914 to 2012The Hyacinthaceae (sensu APGII), with approximately 900 species in about 70 genera, can be divided into three main subfamilies, the Hyacinthoideae, the Urgineoideae and the Ornithogaloideae, with a small fourth subfamily the Oziroëoideae, restricted to South America. The plants included in this family have long been used in traditional medicine for a wide range of medicinal applications. This, together with some significant toxicity to livestock has led to the chemical composition of many of the species being investigated. The compounds found are, for the most part, subfamily-restricted, with homoisoflavanones and spirocyclic nortriterpenoids characterising the Hyacinthoideae, bufadienolides characterising the Urgineoideae, and cardenolides and steroidal glycosides characterising the Ornithogaloideae. The phytochemical profiles of 38 genera of the Hyacinthaceae will be discussed as well as any biological activity associated with both crude extracts and compounds isolated. The Hyacinthaceae of southern Africa were last reviewed in 2000 (T. S. Pohl, N. R. Crouch and D. A. Mulholland, Curr. Org. Chem., 2000, 4, 1287-1324; ); the current contribution considers the family at a global level.

B Moodley, HC Brookes, DA Mulholland (2011)The electro-oxidation of lignin in Sappi Saiccor dissolving pulp effluent., In: Water SA37(1)pp. 33-? Water Research Commission, SA

Electro-oxidation reactions using a nickel anode were carried out on the calcium-spent liquor effluent obtained from Sappi Saiccor (formerly South African Industrial Cellulose Corporation) dissolving pulp mill as well as on lignin- and lignan-type compounds previously identified in the effluent. Voltammograms were obtained for each solution in order to identify the oxidation potentials of the compounds to be electro-oxidised. Value-added products such as vanillin and syringaldehyde were identified in the electro-oxidised reaction mixtures using gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC). Profiles of the changes in concentration of these compounds were determined as a function of time with maximum concentrations reached within the first half hour. These findings are significant in that few electro-oxidation reactions have been carried out on the effluent of a pulp mill which uses the acid bisulphite pulping process and no results have previously been reported on the electro-oxidation of syringaldehyde. This study contributes to a further understanding of the electro-oxidation of lignin and is of value to the paper and pulp industry at large. Reduction of the organic content of the effluent by electro-oxidation was shown to be possible.

Moses Langat, A Helfenstein, C Horner, P Tammel, H Hokkanen, D Izotov, Dulcie Mulholland (2018)Pumilol, a Diterpenoid with a Rare Strobane Skeleton from Pinus pumila (Pinaceae), In: Chemistry and Biodiversity15(10)e1800056 Wiley

Pumilol (1), a strobane diterpenoid, reported herein for the first time was isolated from the bark of Pinus pumila (Pall.) Regel (Siberian Dwarf Pine or Japanese Stone Pine), along with seventeen known compounds including serratane triterpenoids, not previously reported from this species, and four ferulate derivatives. The stereostructure of pumilol was established using HRESIMS, NMR, the DP4+ probabilities and by comparison of the experimental and calculated electronic circular dichroim (ECD) spectra. Labda-8(17),13-dien-15-oic acid (4), bornyl trans-4-hydroxycinnamate (14) and E-bornyl ferulate (15) showed activity against S. aureus and/or E. faecalis with MIC90 values 12.5-50 µM.

PK Cheplogoi, DA Mulholland, PH Coombes, M Randrianarivelojosia (2008)An azole, an amide and a limonoid from Vepris uguenensis (Rutaceae), In: PHYTOCHEMISTRY69(6)pp. 1384-1388 PERGAMON-ELSEVIER SCIENCE LTD
Georges Bellier Tabekoueng, Carine Mvot Akak, Moses K. Langat, Anatole Guy Blaise Azebaze, Alain Francois Kamdem Waffo, Dulcie A. Mulholland, Juliette Catherine Vardamides (2019)The chemical constituents of Penianthus longifolius Miers, In: Phytochemistry Letters30pp. 103-106 Elsevier

Fourteen compounds were isolated from the roots, leaves and twigs of Penianthus longifolius Miers (Menispermaceae), including two previously unreported neo-clerodane diterpenoids, penianthin (1), its C-8 epimer (2). In addition, the previously reported O-methylmoschatoline (3), taraxerol (4), taraxerone (5), rubrosterone, (6), panuosterone (7), 22-epi-20-hydroxyecdysone (8), ergosterol peroxide (9), stigmast-5-ene-3,7-dione (10), stigmasterol (11), β-sitosterol (12), stigmasterol glucoside (13) and β-sitosterol glucoside (14) were isolated. The structures of the compounds were determined by means of NMR spectroscopic and mass spectrometric analysis. The absolute configurations of 1 and 2 were determined by circular dichroism analysis. Compounds 1 and 2 were screened against the NCI60 cancer cell panel but showed no significant activity at 10 μM.

IM Eldeen, EE Elgorashi, DA Mulholland, J van Staden (2006)Anolignan B: a bioactive compound from the roots of Terminalia sericea., In: J Ethnopharmacol103(1)pp. 135-138

Antibacterial bioassay-guided fractionation of an ethyl acetate root extract of Terminalia sericea led to the isolation of anolignan B. The isolated compound was further tested for anti-inflammatory activity using the cyclooxygenase enzyme assays (COX-1 and COX-2) and for potential mutagenic effects using the Ames test. In the antibacterial test, anolignan B showed activity against both Gram-positive and Gram-negative bacteria. The minimum inhibitory concentration values obtained (MIC) ranged from 3.8 microg/ml against Bacillus subtilis (Gram-positive) to 31 microg/ml against Escherichia coli (Gram-negative). In the anti-inflammatory assays, anolignan B showed activity against both COX-1 (IC(50) = 1.5 mM) and COX-2 (IC(50) = 7.5 mM) enzymes. No potential mutagenic effects were observed in the Salmonella microsome assay (TA98). Isolation of anolignan B from Terminalia sericea as well as the antibacterial and anti-inflammatory activities observed in this study has not been reported previously.

Barbara Thueriga, Emily James, Hans-Jakob Schärer, Moses Langat, Dulcie Mulholland, Jonas Treutwein, Ina Kleeberg, Mathias Ludwig, Praveen Jayarajah, Oscar Giovannini, Emilia Markellou, Lucius Tamm (2017)Reducing copper use in the environment: The use of larixol and larixyl acetate to treat downy mildew caused by Plasmopara viticola in viticulture, In: Pest Management Science74(2)pp. 477-488 Wiley

BACKGROUND: Plant extracts might provide sustainable alternatives to copper fungicides, which are still widely used despite their unfavourable ecotoxicological profile. Larch bark extract and its constituents, larixyl acetate and larixol, have been shown to be effective against grapevine downy mildew (Plasmopara viticola) under semi-controlled conditions. The aim of this study was to reduce the gap between innovation and the registration of a marketable product, namely to develop scalable extraction processes and to evaluate and optimize performance of larch extracts under different conditions. RESULTS: Toxicologically and technically acceptable solvents like ethanol were used to extract the active compounds larixyl acetate and larixol from bark in sufficient amounts and their combined concentration could be increased up to 39% by purification steps. The combined concentration of larixyl acetate and larixol from larch turpentine could be increased up to 66%. MIC100 against P. viticola in vitro (6-23 g mL-1) and EC50 in planta under semi-controlled conditions (0.2-0.4 mg mL-1) were promising compared to other plant extracts. In vineyards, efficacies of larch extracts reached up to 68% in a stand-alone strategy and 84% in low-copper strategies. CONCLUSIONS: Larch extracts represent valid candidates for copper reduction in organic vineyards, and their development into a sustainable plant protection product might be feasible

A Langlois, DA Mulholland, GD Duncan, NR Crouch, TJ Edwards (2005)A novel 3-benzylchromone from the South African Lachenalia rubida (Hyacinthaceae), In: Biochemical Systematics and Ecology33(9)pp. 961-966
C Koorbanally, DA Mulholland, NR Crouch (2005)A novel homoisoflavonoid from Drimia delagoensis (Urgineoideae: Hyacinthaceae), In: Biochemical Systematics and Ecology33(7)pp. 743-748
JC Chukwujekwu, P Smith, PH Coombes, DA Mulholland, J van Staden (2005)Antiplasmodial diterpenoid from the leaves of Hyptis suaveolens., In: J Ethnopharmacol102(2)pp. 295-297

Bioactivity-guided fractionation of the petroleum ether extract of the leaves of Hyptis suaveolens, widely used in Traditional Medicine, has led to the isolation of an abietane-type diterpenoid endoperoxide, 13 alpha-epi-dioxiabiet-8(14)-en-18-ol, displaying high antiplasmodial activity (IC(50) 0.1 microg/ml).

JK Sihra, DA Mulholland, MK Langat, NR Crouch, J-M Nuzillard, AE Thumser (2012)NOVEL TRITERPENOID DERIVATIVES FROM EUCOMIS BICOLOR (HYACINTHACEAE: HYACINTHOIDEAE), In: PHARMACEUTICAL BIOLOGY50(5)pp. 645-645
NR Crouch, A Langlois, DA Mulholland, JJ Nair (2005)A novel alkylamide from the leaves of Acmella caulirhiza (Asteraceae), a traditional surface analgesic, In: South African Journal of Botany71(2)pp. 228-230

Dried leaves of the widespread African ethnomedicinal herb Acmella caulirhiza (Asteraceae) have been phytochemically characterised. The hexane extract yielded two unsaturated alkylamides, spilanthol and a novel compound tentatively identified as N-isobutylnona-2E, 4E-dien-8-ynamide based on 1H, 13C, COSY and HETCOR spectra. The occurrence of these amides supports the validation of documented traditional usage patterns. Copyright © NISC Pty Ltd.

NA Koorbanally, NR Crouch, A Harilal, B Pillay, DA Mulholland (2006)Coincident isolation of a novel homoisoflavonoid from Resnova humifusa and Eucomis montana (Hyacinthoideae: Hyacinthaceae), In: Biochemical Systematics and Ecology34(2)pp. 114-118

We report on the first phytochemical investigation of a member of the African genus Resnova (Hyacinthoideae: Hyacinthaceae). From the dichloromethane extract of the bulbs of both Resnova humifusa and Eucomis montana (Hyacinthoideae: Hyacinthaceae) a novel 3-benzyl-4-chromanone homoisoflavonoid, 5,6-dimethoxy-7-hydroxy-3-(4′-hydroxybenzyl)-4-chromanone, was isolated. A further 11 known homoisoflavonoids were also identified, the 12 in total presenting a clear biosynthetic sequence. Eight of the 12 compounds found were common to both species. © 2005 Elsevier Ltd. All rights reserved.

Jaspreet Sihra, Moses Langat, NR Crouch, J-M Nuzillard, B Plainchont, Dulcie Mulholland (2017)Novel triterpenoid derivatives from Eucomis bicolor Bak. (Hyacinthaceae: Hyacinthoideae), In: RSC Advances7pp. 15416-15427 Royal Society of Chemistry

The bulbs of Eucomis bicolor (Hyacinthoideae) yielded fourteen novel natural compounds, including (17S)-3-oxo-24,25,26,27,28-pentanorlanost-8-en-23,17α-olide, whose structure was determined using the Logic for Structure Determination Program, and nine novel lanosterol glycosides. Compounds were screened against the NCI-59 cancer cell panel but showed limited activity.

C Koorbanally, DA Mulholland, NR Crouch (2005)A novel 3-hydroxy-3-benzyl-4-chromanone-type homoisoflavonoid from Albuca fastigiata (Ornithogaloideae: Hyacinthaceae), In: Biochemical Systematics and Ecology33(5)pp. 545-549
Mina Kalantarzadeh, Dulcie Mulholland, Frans De Leij, Joan F. Webber (2019)Induced antimicrobial activity in heat-treated woodchips inhibits the activity of the invasive plant pathogen Phytophthora ramorum, In: Plant Pathology68(5)pp. 889-900 Wiley

We investigated the antimicrobial activity of heat‐treated woodchips of three woody host species against the invasive oomycete plant pathogen Phytophthora ramorum to assess the potential of heated woodchips for disease suppression. Results demonstrated that heat‐treated pine (Pinus sylvestris), Japanese larch (Larix kaempferi) and rhododendron (Rhododendron ponticum) woodchips inhibited the recovery of P. ramorum spores and mycelium compared with similar material that had only been air‐dried. Effects were most evident with pine and larch; inhibition was maintained even when larch woodchips were diluted with soil. In vitro assays using methanol crude extracts from woodchips of the three species showed they all had an inhibitory effect on P. ramorum zoospores and reduced chlamydospore germination compared with air‐dried wood extracts. Chemical analysis of the extracts revealed several induced compounds were present but in different concentrations for each species. Coniferaldehyde was the most active inhibitory against spores and mycelium, whilst the dominant resin acids, dehydroabietic and abietic acid, decreased the minimum inhibitory concentration of phenolic compounds tested against P. ramorum but were ineffective when used alone. An array of compounds, including dehydroabietic acid, methyl abietate, α‐pinene and 3‐carene, occurred at elevated levels in the living tissue of Japanese larch bark attacked by P. ramorum. These compounds may be part of the induced resistance response of larch to P. ramorum. Results of a field trial using heat‐treated and air‐dried woodchips were consistent with the crude extract bioassay results, suggesting that heat‐treated woody materials have potential to reduce the survival of P. ramorum under natural conditions.

KA Reid, J Maes, A Maes, J van Staden, N De Kimpe, DA Mulholland, L Verschaeve (2006)Evaluation of the mutagenic and antimutagenic effects of South African plants., In: J Ethnopharmacol106(1)pp. 44-50

Dichloromethane and 90% methanol extracts of 42 South African plants were screened for mutagenicity and antimutagenicity using the Salmonella/microsome mutagenicity assay (Ames) against Salmonella typhimurium TA98 and TA100 bacterial strains in the presence and absence of metabolic activator S9. The methanol extracts from whole plants of Helichrysum simillimum, Helichrysum herbaceum and Helichrysum rugulosum indicated mutagenicity. These are the first reported tests on the mutagenicity of Helichrysum species. Six species indicated antimutagenic properties, all in the presence of S9: methanol leaf extract of Bauhinia galpinii, and dichloromethane leaf extracts of Bauhinia galpinii, Clerodendrum myricoides, Datura stramonium, Buddleja saligna, Millettia sutherlandii and Sutherlandia frutescens.

F Salim, MM Zain, R Ahmad, MSM Ridzuan, MK Langat, DA Mulholland (2013)Flavan-3-ols from the leaves of Malaysian Uncaria longiflora var. pteropoda (Miq.) Ridsd, In: Phytochemistry Letters6(2)pp. 236-240 Elsevier

A novel flavonoid, (-)-2R,3R-3,5,4′-trihydoxyflavan-[6,7:5″, 6″]-2″-pyranone, named uncariechin (1), was isolated from the methanolic extract of the leaves of Uncaria longiflora var. pteropoda (Miq.) Ridsd. along with the known (-)-epiafzelechin (2) and (-)-epicatechin (3), methyl 4-hydroxybenzoate and 4-hydroxybenzaldehyde, four pentacyclic oxindole alkaloids, isopteropodine, pteropodine, uncarine F and isopteropodic acid, previously found in the stems, and two coumarins, scopoletin and 3,4-dihydroxy-7-methoxycoumarin. Structures of the compounds were elucidated by 1D and 2D NMR, FTIR, UV, MS, and experimental as well as calculated electronic circular dichroism (ECD) data. Compounds 2 and 3 were evaluated for their neurotoxic and neuroprotective properties against differentiated SH-SY5Y neuroblastoma cell lines using the MTS assay. Compounds 2 and 3 did not show any neurotoxic effects but showed strong protective potential against hydrogen peroxide-induced neurotoxicity with maximum cell viability at a concentration of 1 μM. © 2013 Phytochemical Society of Europe.

S Claessens, D Naidoo, D Mulholland, L Verschaeve, J Van Staden, N De Kimpe (2006)Synthesis of pyranonaphthoquinone antibiotics involving the phthalide annulation strategy, In: Synlett(4)pp. 621-623

The synthesis of the pyranonaphthoquinone antibiotic pentalongin was performed using the phthalide annulation strategy. Annulation of the cyanophthalide onto 6H-pyran-3-one resulted in a hongconin analogue, which upon further elaboration was converted into the natural product. © Georg Thieme Verlag Stuttgart.

C Koorbanally, DA Mulholland, NR Crouch (2005)Eudesmane-type sesquiterpenoids from Urginea epigea (Urgineoideae; Hyacinthaceae), In: Biochemical Systematics and Ecology33(3)pp. 295-299
DA Mulholland (2005)The future of ethnopharmacology: a southern African perspective., In: J Ethnopharmacol100(1-2)pp. 124-126

The traditional use of medicinal plants in southern Africa is widespread with over 80% of South African households using medicinal plants. A mushrooming of research into the study of medicinal plants in the developing world has occurred but most of Africa is lagging behind in research output despite long traditions of medicinal plant usage. A considerable investment in research infrastructure is required.

Ahmad Nazif Aziz, Nor Hadiani Ismail, Siti Nadiah Abdul Halim, Chung Yeng Loo, Anouar El Hassane, Moses K Langat, Dulcie Mulholland, Khalijah Awang (2018)Laevifins A-G, Clerodane Diterpenoids from the Bark of Croton oblongus Burm.f., In: Phytochemistry156pp. 193-200 Elsevier

A phytochemical investigation of the stem barks of the Malaysian Croton oblongus Burm.f. (Syn. Croton laevifolius Blume) (Euphorbiaceae) yielded seven previously undescribed ent-neo-clerodane diterpenoids, laevifins A - G (1, 2, 4-8) and the known crovatin (3). Structures were established by a combination of spectroscopic methods including HRESIMS, NMR spectroscopy and X-ray crystallography. The absolute configuration of crovatin and laevifins A-G was established by comparison of experimental ECD and theoretical TDDFT ECD calculated spectra. This is the first report on the occurrence of the sesquiterpenoid cryptomeridiol in a Croton species. In vitro cytotoxicity assays on laevifins A (1), B (2) and G (8) showed moderate activities against the MCF-7 cancer cell line (IC50 102, 115 and 106 μM, respectively) while β-amyrin and acetyl aleuritolic acid showed good anti-inflammatory activity on the LPS-induced NF-κB translocation inhibition in RAW 264.7 cells assay with IC50 values of 23.5 and 35.4 μg/mL, respectively.

CP Tunbridge, NR Crouch, AE Thumser, DA Mulholland (2012)COX-2 SPECIFIC INHIBITORS FROM LEDEBOURIA OVATIFOLIA AND LEDEBOURIA SOCIALIS (HYACINTHACEAE:HYACINTHOIDEAE), In: PHARMACEUTICAL BIOLOGY50(5)pp. 569-569
D Naidoo, PH Coombes, DA Mulholland, NR Crouch, AJ van den Bergh (2005)N-Substituted acridone alkaloids from Toddaliopsis bremekampii (Rutaceae: Toddalioideae) of south-central Africa., In: Phytochemistry66(14)pp. 1724-1728

Toddaliopsins A-D, four novel 1,2,3-trioxygenated acridone alkaloids, have been isolated from the leaves of Toddaliopsis bremekampii. Toddaliopsins B-D are the first reported acridone alkaloids with substituted N-methyl groups, in the light of which the chemotaxonomic relationship of Toddaliopsis and Vepris is discussed. Toddaliopsin C possesses moderate anti-inflammatory activity, which may be related to the hydroxy group present at C-1.

NC Dlova, FT Nevondo, EM Mwangi, B Summers, J Tsoka-Gwegweni, BS Martincigh, DA Mulholland (2013)Chemical analysis and in vitro UV-protection characteristics of clays traditionally used for sun protection in South Africa, In: PHOTODERMATOLOGY PHOTOIMMUNOLOGY & PHOTOMEDICINE29(3)pp. 164-169 WILEY-BLACKWELL
JC Chukwujekwu, PH Coombes, DA Mulholland, J van Staden (2006)Emodin, an antibacterial anthraquinone from the roots of Cassia occidentalis, In: South African Journal of Botany72(2)pp. 295-297

The antibacterial activity of the ethanolic root extract of Cassia occidentalis was examined. A biologically active component was isolated and identified as emodin by spectroscopic analysis. The bioactive Minimum Inhibitory Concentration (MIC) values of emodin were 7.8 × 10- 3 and 3.9 × 10- 3 mg ml- 1 against Bacillus subtilis and Staphylococcus aureus, respectively. It was not active against two Gram-negative bacteria (Klebsiella pneumoniae and Escherichia coli) at the highest concentration (5.0 × 10- 1 mg ml- 1) tested. © 2005 Elsevier B.V. All rights reserved.

CJD Obbo, B Makanga, DA Mulholland, PH Coombes, R Brun (2013)Antiprotozoal activity of Khaya anthotheca, (Welv.) CDC a plant used by chimpanzees for self-medication, In: JOURNAL OF ETHNOPHARMACOLOGY147(1)pp. 220-223 ELSEVIER IRELAND LTD
F Ismail, DA Mulholland, JJ Marsh (2005)An analysis of the water soluble components of Sappi Saiccor's effluent streams, In: Water SA31(4)pp. 569-574

Sappi Saiccor is a pulp mill that produces high-grade chemical cellulose (dissolving pulp) from predominantly hardwood timber and is currently the world's largest manufacturer of this type of pulp. Attempts to isolate pure lignosulphonates were unsuccessful; however, an acid hydrolysis of the aqueous portion of the calcium effluent stream yielded a range of organic compounds. These included lignans, lignin-type precursors as well as small quantities of vanillin and syringaldehyde. The structures of these compounds were determined using NMR spectroscopic and mass spectrometric techniques.

MK Langat, MK Langat, M Randrianavelojosia, M Randrianavelojosia, LC Langat, LC Langat, N Plant, DA Mulholland, DA Mulholland (2014)Langaside, a novel secoiridolactone glycoside derivative from Tachiadenus longiflorus Griseb. (Gentianaceae) formed by a [2+2] cycloaddition reaction, In: Phytochemistry Letters10pp. cxviii-cxxii

Langaside (1), a secoiridoid lactone glucoside possessing a novel skeleton formed by a [2 + 2] cycloaddition reaction between the secoiridolactone glucoside, 1,9-trans-9,5-cis-sweroside, and p-coumaric acid was isolated from the fruits and flowers of the Malagasy Tachiadenus longiflorus Griseb. (Gentianaceae), alongside another seven known compounds. The structure of langaside was established using HRESIMS, IR and NMR spectroscopy and comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Langaside was screened for its neuritogenic activity against SHSY-5Y cells and anticancer activity against the NCI59 human tumour cell panel but not found to be active.

Sianne Schwikkard, Hannah Whitmore, Kamakshi Sishtla, Rania S. Sulaiman, Trupti Shetty, Halesha D. Basavarajappa, Catherine Waller, Alaa Alqahtani, Lennart Frankemoelle, Andy Chapman, Neil Crouch, Wolfgang Wetschnig, Walter Knirsch, Jacky Andriantiana, Eduard Mas-Claret, Moses K. Langat, Dulcie Mulholland, Timothy W. Corson (2019)The Antiangiogenic Activity of Naturally Occurring and Synthetic Homoisoflavonoids from the Hyacinthaceae (sensu APGII), In: Journal of Natural Products American Chemical Society

Excessive blood vessel formation in the eye is implicated in wet age-related macular degeneration, proliferative diabetic retinopathy, neovascular glaucoma, and retinopathy of prematurity, which are major causes of blindness. Small molecule antiangiogenic drugs are strongly needed to supplement existing biologics. Homoisoflavonoids have been previously shown to have potent antiproliferative activities in endothelial cells over other cell types. Moreover, they demonstrated a strong antiangiogenic potential in vitro and in vivo in animal models of ocular neovascularization. Here, we tested the antiangiogenic activity of a group of naturally occurring homoisoflavonoids isolated from the family Hyacinthaceae and related synthetic compounds, chosen for synthesis based on structure–activity relationship observations. Several compounds showed interesting antiproliferative and antiangiogenic activities in vitro on retinal microvascular endothelial cells, a disease-relevant cell type, with the synthetic chromane, 46, showing the best activity (GI50 of 2.3 × 10–4 μM).

A Aldhaher, Moses Langat, W Knirsch, J Andriantiana, Dulcie Mulholland (2018)Isoquinoline alkaloids from three Madagascan Crinum (Amaryllidaceae) species., In: Biochemical Systematics and Ecology77pp. 7-9 Elsevier

The phytochemistry of two Madagascan Crinum species, Crinum hardyi Lehmiller and Crinum pronkii Lehmiller were investigated and compared to that of Crinum firmifolium Baker which has been investigated previously. In addition to hippadine, lycorine, hippeastrine, masonine and crinine from C. firmifolium, lycorine, crinine, and 6-hydroxycrinamine from Crinum hardyi and lycorine, 6-hydroxycrinamine and pseudolycorine from C. pronkii, the novel lycorine-relatediminium salt, the 6,7,11b,11c-didehydrolycorinium salt, was isolated from bulbs of both C. firmifolium and C. hardyi.

The bulbs of Ledebouria socialis (Hyacinthaceae) yielded the benzocyclobutene homoisoflavonoid, (R)-2',5-dihydroxy-3',4',7-trimethoxyspiro{2H-1-benzopyran-3-(4H)-9-bicyclo[4.2.0]octa[1,3,5]triene}-4-one, socialinone (1). Ledebouria ovatifolia yielded (2ε,3R)-2,5-dihydroxy-7-methoxyspiro[2H-1-benzopyran-3(4H), 5'(6'H)-cyclobuta[f][1,3]benzodioxol]-4-one (2) and the homoisoflavanone, (E)-3-(3',4'-dihydroxybenzylidene)-5,7-dihydroxychroman-4-one, ovatifolionone (5), the dihydrochalcone, 4,4'-dihydroxy-2',6'-dimethoxydihydrochalcone (3), and xanthone, 1,6-dihydroxy-2,3,5-trimethoxy-8-methyl-9H-xanthen-9-one (4) along with 21 known compounds. Structures were determined using spectroscopic techniques. The anti-inflammatory activities of the homoisoflavonoids and xanthones isolated were evaluated against cyclooxygenase-1 and -2 isoenzymes. (R)-3-(3',4'-Dihydroxybenzyl)-7-hydroxy-5-methoxychroman-4-one (7), (E)-3-(3',4'-dihydroxybenzylidene)-7-hydroxy-5-methoxychroman-4-one (10), 1,3,6-trihydroxy-2-methoxy-8-methylxanthen-9-one (6) and ovatifolionone acetate (5Ac) exhibited significant activity against cyclooxygenase-2 at

MK Langat, DA Mulholland, MK Langat, NR Crouch, DA Mulholland, NR Crouch, L Pohjala, P Tammela, L Pohjala, PJ Smith (2012)Ent-kauren-19-oic acid derivatives from the stem bark of Croton pseudopulchellus Pax, In: Phytochemistry Letters5(3)pp. 414-418 Elsevier

Two new ent-kauren-19-oic acid derivatives, ent-14S*-hydroxykaur-16-en-19-oic acid and ent-14S*,17-dihydroxykaur-15-en-19-oic acid together with eleven known compounds ent-kaur-16-en-19-oic acid, ent-kaur-16-en-19-al, ent-12β-hydroxykaur-16-en-19-oic acid, ent-12β-acetoxykaur-16-en-19-oic acid, 8R,13R-epoxylabd-14-ene, eudesm-4(15)-ene-1β,6α-diol, (-)-7-epivaleran-4-one, germacra-4(15), 5E,10(14)-trien-9β-ol, acetyl aleuritolic acid, β-amyrin, and stigmasterol were isolated from the stem bark of Croton pseudopulchellus (Euphorbiaceae). Structures were determined using spectroscopic techniques. Ent-14S*-hydroxykaur-16-en-19-oic acid, ent-kaur-16-en-19-oic acid, ent-12β-hydroxykaur-16-en-19-oic acid, ent-12β-acetoxykaur-16-en-19-oic acid and 8R,13R-epoxylabd-14-ene were tested for their effects on Semliki Forest virus replication and for cytotoxicity against human liver tumour cells (Huh-7 strain) but were found to be inactive. Ent-kaur-16-en-19-oic acid, the major constituent, showed weak activity against the Plasmodium falciparum (CQS) D10 strain. © 2012 Phytochemical Society of Europe.

AFK Waffo, PH Coombes, DA Mulholland, AE Nkengfack, ZT Fomum (2006)Flavones and isoflavones from the west African Fabaceae Erythrina vogelii, In: PHYTOCHEMISTRY67(5)pp. 459-463 PERGAMON-ELSEVIER SCIENCE LTD
R Vazquez, ME Riveiro, M Vermeulen, C Mondillo, PH Coombes, NR Crouch, F Ismail, DA Mulholland, A Baldi, C Shayo, C Davio (2012)Toddaculin, a natural coumarin from Toddalia asiatica, induces differentiation and apoptosis in U-937 leukemic cells, In: PHYTOMEDICINE19(8-9)pp. 737-746 ELSEVIER GMBH, URBAN & FISCHER VERLAG
S Schwikkard, Hannah Whitmore, T Corson, K Sishtla, Moses Langat, M Carew, Dulcie Mulholland (2018)Antiangiogenic Activity and Cytotoxicity of Triterpenoids and Homoisoflavonoids from Massonia pustulata and Massonia bifolia, In: Planta Medica84(09/10)pp. 638-644 Georg Thieme Verlag

The Hyacinthaceae family (sensu APGII) with approximately 900 species in around 70 genera, plays a significant role in traditional medicine in Africa as well as across Europe and the Middle and Far East. The dichloromethane extract of the bulbs of Massonia pustulata (Hyacinthaceae sensu APGII) yielded two known homoisoflavonoids, (R)-5-hydroxy-3-(4-hydroxybenzyl)-7-methoxy-4-chromanone 1 and 5-hydroxy-3-(4-hydroxybenzyl)-7-methoxy-4-chromone 2 and four spirocyclic nortriterpenoids, eucosterol 3, 28-hydroxyeucosterol 4 and two previously unreported triterpenoid derivatives, (17S,23S)-17α,23-epoxy-3β,22β,29-trihydroxylanost-8-en-27,23-olide 5 and (17S, 23S)-17α,23-epoxy-28,29-dihydroxylanost-8-en-3-on-27,23-olide 6. Compounds 1, 2, 3, and 5 were assessed for cytotoxicity against CaCo-2 cells using a neutral red uptake assay. Compounds 1, 2 and 5 reduced cell viability by 70% at concentrations of 30, 100 and 100 μM respectively. Massonia bifolia yielded three known homoisoflavonoids, (R)-(4’-hydroxy)-5-hydroxy-7-methoxy-4-chromanone 1, (R)-(4’-hydroxy)-5,7-dihydroxy-4-chromanone 7 and (R)-(3’-hydroxy-4’-methoxy)-5,7-dihydroxy-4-chromanone 9, two previously unreported homoisoflavonoids, (E)-3-benzylidene-(3’,4’-dihydroxy)-5-hydroxy-7-methoxy-4-chromanone 8 and (R)-(3’,4’-dihydroxy)-5-hydroxy-7-methoxy-4-chromanone 10, and a spirocyclic nortriterpenoid, 15-deoxoeucosterol 11. Compounds 1, 1Ac, 7, 8, 9 and 10 were screened for antiangiogenic activity against human retinal microvascular endothelial cells. Some compounds showed dose-dependent antiproliferative activity and blocked endothelial tube formation, suggestive of antiangiogenic activity.

N Moodley, NR Crouch, DA Mulholland, D Slade, D Ferreira (2006)3-Benzyl-4-chromanones (homoisoflavanones) from bulbs of the ethnomedicinal geophyte Ledebouria revoluta (Hyacinthaceae), In: SOUTH AFRICAN JOURNAL OF BOTANY72(4)pp. 517-520 ELSEVIER SCIENCE BV
Dulcie Mulholland, EM Mwangi, NC Dlova, N Plant, NR Crouch, PH Coombes (2013)Non-toxic melanin production inhibitors from Garcinia livingstonei (Clusiaceae), In: JOURNAL OF ETHNOPHARMACOLOGY149(2)pp. 570-575 ELSEVIER IRELAND LTD

Ethnopharmacological relevance The stem bark of Garcinia livingstonei is used traditionally as a skin lightening agent. Aim of the study To isolate and identify compounds responsible for the observed skin lightening activity of Garcinia livingstonei and to evaluate their cytotoxicity. Materials and methods Constituents of the stem bark and fruits of Garcinia livingstonei were isolated using chromatographic techniques and structures were determined using 1D and 2D NMR and MS analysis. MeWo cells were used to evaluate the cytotoxicity and impact on melanin levels of extracts and compounds isolated, in vitro. Results Twelve known compounds, morelloflavone (1), morelloflavone-7″-sulphate (2), guttiferone A (3), sargaol (4), isojacareubin (5), 6-deoxyisojacareubin (6) and in addition to the common triterpenoids, betulin, betulin aldehyde, lupeol, lupenone, euphol and stigmasterol were isolated in this investigation. Morelloflavone, morelloflavone-7″-sulphate and sargaol, were found to be considerably less cytotoxic and more effective as skin lightening agents than hydroquinone. Conclusions A range of compounds was isolated from the stem bark and fruit of Garcinia livingstonei. Although the bark extract contained the cytotoxic guttiferone A, it was found to be less toxic than hydroquinone, and morelloflavone, the 7″-sulphate derivative and sargaol show potential for development as depigmentation/skin lightening agents.

B Moodley, DA Mulholland, HC Brookes (2012)The chemical oxidation of lignin found in Sappi Saiccor dissolving pulp mill effluent, In: WATER SA38(1)pp. 1-7 Water Research Commission
PK Tarus, PH Coombes, NR Crouch, DA Mulholland (2006)Benzo[c]phenanthridine alkaloids from stem bark of the Forest Knobwood, Zanthoxylum davyi (Rutaceae), In: SOUTH AFRICAN JOURNAL OF BOTANY72(4)pp. 555-558 ELSEVIER SCIENCE BV
DA Mulholland, NR Crouch, M Randrianarivelojosia (2008)Phytochemistry and chemotaxonomy of the Madagascan Cedrelopsis, In: PLANTA MED74(9)pp. 914-914 GEORG THIEME VERLAG KG
JJ Magadula, MC Kapingu, ZH Mbwambo, DA Mulholland (2008)Secondary Metabolites from Teclea amanuensis (Rutaceae) from Tanzania, In: NATURAL PRODUCT COMMUNICATIONS3(10)pp. 1683-1686 NATURAL PRODUCTS INC
PH Coombes, DA Mulholland, M Randrianarivelojosia (2005)Mexicanolide limonoids from the Madagascan Meliaceae Quivisia papinae., In: Phytochemistry66(10)pp. 1100-1107

An investigation of the seeds of the Madagascan Meliaceae Quivisia papinae has yielded five mexicanolide group limonoids, together with two known mexicanolide limonoids and two known triterpenoids. Quivisianolide A 9 possesses a hitherto unreported 9alpha,11alpha-epoxide ring, quivisianolide B 10 the corresponding delta(9(11)) double bond, and quivisianone 11 is a 17-keto seco-ring D compound.

PK Tarus, PH Coombes, NR Crouch, DA Mulholland, B Moodley (2005)Furoquinoline alkaloids from the southern African Rutaceae Teclea natalensis., In: Phytochemistry66(6)pp. 703-706

The chloroform and ethyl acetate extracts of the leaves of Teclea natalensis have yielded two furoquinoline alkaloids, 6-[(2,3-epoxy-3-methylbutyl)oxy]-4,7-dimethoxyfuro[2,3-b]quinoline and 4,7-dimethoxy-6-[(3-methyl-2-butenyl)oxy]furo[2,3-b]quinoline, and the known alkaloids 4,7-dimethoxy-8-[(3-methyl-2-butenyl)oxy]furo[2,3-b]quinoline, flindersiamine and dictamnine.

AMA Mohammed, PH Coombes, NR Crouch, DA Mulholland (2009)Non-volatile isolates of two Heteropyxis species: A first chemotaxonomic assessment of subfamily Psiloxyloideae (Myrtaceae), In: BIOCHEMICAL SYSTEMATICS AND ECOLOGY37(3)pp. 241-243 PERGAMON-ELSEVIER SCIENCE LTD
L. Langat, M.K. Langat, D.A. Mulholland (2019)Homoisoflavonoids and cardenolides from cultivated Ornithogalum species: Ornithogalum dubium Houtt. and Ornithogalum ponticum ‘Sochi’, In: South African Journal of Botany Elsevier

Three new homoisoflavonoids, (3R)-3,5-dihydroxy-7-methoxy-3-(4’-hydroxybenzyl)-4-chromanone, 4, and its 5-O-β-D-glucopyranoside and 5-O-β-D-gentiobiose derivatives, 5 and 6, along with the known homoisoflavonoids, (3S)-5-hydroxy-7-methoxy-3-(4-methoxybenzyl)-4-chromanone, 1, (3R)-5-hydroxy-7-methoxy-3-(4-methoxybenzyl)-4-chromanone (2) and (3S)-5-hydroxy-7-methoxy-3-(4-hydroxybenzyl)-4-chromanone, 3, were isolated from the bulbs of Ornithogalum dubium Houtt.. In addition, three known cardenolides, 3β-(O-α-L-rhamnoside)-5β,14β-dihydroxy-19-oxocardenolide 7, 3β-(O-α-L-rhamnoside)-5β,11α,14β-trihydroxy-19-oxocardenolide, 8 and 3β-(O-α-L-rhamnoside)-5β,11α,14β,19-tetrahydroxycard-20(22)-enolide, 9, were isolated from Ornithogalum ponticum ‘Sochi’. Yields of homoisoflavonoids were low (0.0002 % - 0.0003 %) so stereospecific synthetic methodology needs further refinement to produce antiangiogenic (3R)-3-benzylchromanones and (3S)-3-hydroxyhomoisoflavonoid analogues for further evaluation. This work confirms that, apart from producing cardenolides, the absolute configuration at C-3 of homoisoflavonoids produced by Ornithogalum is 3R (H-3β) for the 3-benzylchromanones and 3S (3-OH β) for the 3-hydroxy benzylchromanones, in agreement with our earlier reports.

L Ezra, W Waratchareeyakul, K Chantrapromma, S Chantrapromma, MK Langat, SL Schwikkard, DA Mulholland (2015)Chemical constituents from Xylocarpus rumphii (Meliaceae), In: PLANTA MEDICA81(16)pp. 1462-1462
W Waratchareeyakul, A Rocco, F Fusi, SL Schwikkard, W Knirsch, DA Mulholland (2015)Vasorelaxant studies on stilbenoids and phenanthrene derivatives from Brasiliorchis porphyrostele Rchb.f. (Orchidaceae), In: PLANTA MEDICA81(16)pp. 1418-1418
S Schwikkard, EE James, DA Mulholland, W Knirsch, T Corson, E Opara, A Jaksevicius (2015)Novel, bioactive homoisoflavonoids from a Madagascan Rhodocodon species (Hyacinthaceae, sensu APG II), In: PLANTA MEDICA81(16)pp. 1451-1451
SL Schwikkard, DA Mulholland (2014)Useful methods for targeted plant selection in the discovery of potential new drug candidates, In: Planta Medica80(14)pp. 1154-1160 Georg Thieme Verlag

The efficient and effective selection of appropriate plants for investigative purposes in a drug discovery program is of crucial importance for a successful outcome. A variety of approaches have been used by researchers with varying levels of success. A variety of different approaches to plant selection are discussed, including the ethnomedicinal approach, some ecological approaches, and the use of combinatorial and computational methodologies.

L Benniou, Moses Langat, Dulcie Mulholland, F Benayache, S Benayache (2018)Oleanane Triterpenoids from the Algerian Salvia phlomoides, In: Phytochemistry Letters24pp. 136-139 Elsevier

Three previously unreported triterpenoids 2α,3β,11α-trihydroxyolean-18-ene 1, 3β-acetoxy,2α,11α- dihydroxyolean-18-ene 2 and 2α-acetoxy,3β,11α-dihydroxyolean-18-ene 3 were isolated from the chloroform extract of aerial parts (leaves and flowers) of Salvia phlomoides collected from the Constantine region in the east of Algeria. Structures were determined using NMR spectroscopy and HR-ESI mass spectrometry. Compounds 1, 2 and 3 were tested against the NCI panel of human tumour cell lines at a single dose of 10 µM. Compound 2 was the most active showing a 38 % growth inhibition against the leukemia RPMI-8226 line.

SL Schwikkard, W Waratchareeyakul, W Knirsch, DA Mulholland (2014)Chemical constituents from Maxillaria porphyrostele (Orchidaceae), In: PLANTA MEDICA80(10)pp. 803-803
KA Reid, AK Jäger, ME Light, DA Mulholland, J Van Staden (2005)Phytochemical and pharmacological screening of Sterculiaceae species and isolation of antibacterial compounds., In: J Ethnopharmacol97(2)pp. 285-291

Little previous phytochemical investigation has been conducted on South African Sterculiaceae species used in traditional medicine. In this study, five species, varying in growth type (small herbs, shrubs and large trees) and traditional usage were investigated. The species screened were Cola greenwayi Brenan, Cola natalensis Oliv., Dombeya burgessiae Gerr. ex Harv., Dombeya cymosa Harv. and Hermannia depressa N.E.Br. Extracts were screened for alkaloids, cardiac glycosides, cyanogenic glycosides, saponins and tannins. The probable presence of bufadienolides in the leaf material of Dombeya burgessiae and Dombeya cymosa was determined. Alkaloids, cyanogenic glycosides and saponins were absent in all the plant material investigated. Tannins were detected in the leaf extract of Cola greenwayi and in the leaves, stems and roots of Hermannia depressa. Extracts were screened for anti-inflammatory and antibacterial activity using the cyclooxygenase-1 (COX-1) inhibition assay and the microdilution antibacterial assay. The ethanol and dichloromethane extracts of Cola greenwayi, Dombeya burgessiae and Dombeya cymosa, and the dichloromethane extracts of Hermannia depressa showed the highest levels of COX-1 inhibition. It is possible that the high levels observed may be due to the presence of tannins in some of the extracts. Generally, all the aqueous extracts exhibited low activity. Similarly, no antibacterial activity was observed with the aqueous extracts, although some mild activity was exhibited with some of the ethanol and ethyl acetate extracts. Following the general phytochemical and pharmacological screening, extracts showing antibacterial activity were further purified using bioassay-guided fractionation. Dombeya rotundifolia (Hochst.) Planch., which was screened in a previous study, was also included in the isolation of active compounds. A bioautographic assay, using Staphylococcus aureus, was used to detect the presence of the antibacterial compounds. These were isolated and identified as fatty acids.

K du Toit, EE Elgorashi, SF Malan, SE Drewes, J van Staden, NR Crouch, DA Mulholland (2005)Anti-inflammatory activity and QSAR studies of compounds isolated from Hyacinthaceae species and Tachiadenus longiflorus Griseb. (Gentianaceae)., In: Bioorg Med Chem13(7)pp. 2561-2568

Twenty-two homoisoflavanones and structurally related compounds isolated from plants were screened for anti-inflammatory activity. Seventeen compounds were isolated from southern African Hyacinthaceae species, one from the Madagascan gentian Tachiadenus longiflorus Griseb. and four were of synthetic origin. Inhibition of prostaglandin synthesis in cell microsomal fractions was first evaluated, followed by screening for specific inhibition of isolated cyclooxygenase enzymes (COX-1 and COX-2). Six homoisoflavanone and structurally related compounds showed significantly high levels of anti-inflammatory activity in the microsomal fraction assay. Only one compound exhibited a high level of anti-inflammatory activity in the COX-1 enzyme assay and no significant activity was detected in the COX-2 enzyme assay. Biological screening was followed by a computer-based quantitative structure-activity relationship (QSAR) study. The physicochemical descriptors: strain energy, heat of formation, volume, surface area, aqueous phase energy, dipole moment, enthalpy, entropy, molar refractivity, parachor, density, refractive index, surface tension, polarizability, logP, Van der Waals interaction energy, Coulombic interaction energy and nonbonded interaction energy were used to characterize the structures of the homoisoflavanones and structurally related compounds. This study produced three equations with significant prediction values for the anti-inflammatory activity of the compounds investigated. The derived models also provided valuable parameter guidelines for those properties influencing the anti-inflammatory activity of the studied compounds.

F Fusi, A Ferrara, C Koorbanally, NR Crouch, DA Mulholland, G Sgaragli (2008)Vascular myorelaxing activity of isolates from South African Hyacinthaceae partly mediated by activation of soluble guanylyl cyclase in rat aortic ring preparations, In: JOURNAL OF PHARMACY AND PHARMACOLOGY60(4)pp. 489-497 PHARMACEUTICAL PRESS-ROYAL PHARMACEUTICAL SOC GREAT BRITIAN