Antiangiogenic Activity and Cytotoxicity of Triterpenoids and Homoisoflavonoids from Massonia pustulata and Massonia bifolia

Sianne L. Schwikkard; Hannah Whitmore; Timothy W. Corson; Kamakshi Sishtla; Moses K. Langat; Mark Carew; Dulcie A. Mulholland

doi:10.1055/a-0577-5322

Planta Medica, Table of Contents

Planta Med 2018; 84(09/10): 638-644
DOI: 10.1055/a-0577-5322

Biological and Pharmacological Activity

Original Papers

Georg Thieme Verlag KG Stuttgart · New York

Antiangiogenic Activity and Cytotoxicity of Triterpenoids and Homoisoflavonoids from Massonia pustulata and Massonia bifolia

Sianne L. Schwikkard

¹School of Life Sciences, Pharmacy and Chemistry, Kingston University, Kingston-upon-Thames, United Kingdom

²Natural Products Research Group, Department of Chemistry, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, United Kingdom

,

Hannah Whitmore

²Natural Products Research Group, Department of Chemistry, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, United Kingdom

,

Timothy W. Corson

³Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, U. S. A.

,

Kamakshi Sishtla

³Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, U. S. A.

,

Moses K. Langat

²Natural Products Research Group, Department of Chemistry, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, United Kingdom

⁴School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa

,

Mark Carew

¹School of Life Sciences, Pharmacy and Chemistry, Kingston University, Kingston-upon-Thames, United Kingdom

,

Dulcie A. Mulholland

³Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, U. S. A.

⁴School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa

› Author Affiliations

Abstract

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.

Key words

Massonia species - Hyacinthaceae - homoisoflavonoids - spirocyclic nortriterpenoids - cytotoxicity - angiogenesis

Full Text

References

References
1 Martinez-Azorin M, Pinter M, Crespo MB, Slade J, Deutsch G, Wetschnig W. Clarification of Massonia echinata and some other frequently misunderstood Massonia species (Asparagaceae, Scilloideae), with the description of M. pseudoechinata and M. roggeveldensis . Phytotaxa 2015; 239: 101-129
2 Martínez-Azorín M, Pinter M, Crespo M, Pfosser M, Wetschnig W. Massonia mimetica (Hyacinthaceae, Hyacinthoideae), a new remarkable species from South Africa. STAPFIA 2013; 99: 187-197
3 Jacquin NJ. Plantarum rariorum horti caesarei Schoenbrunnensis descriptiones et icones. Schönbrunn: Austria; 1804
4 DeBeer J, Van Wyk BE. An ethnobotanical survey of the Agter-Hantam region, Northern Cape Province of South Africa. S Afr J Bot 2011; 77: 741-754
5 Manning JP, Goldblatt P, Saunders R. 721. Massonia bifolia . Curtisʼs Botanical Magazine 2011; 28: 324-332
6 Manning JC, Goldblatt P, Fay M. Revised generic synopsis of Hyacinthaceae in sub-Saharan Africa, based on molecular evidence, including new combinations and the new tribe Pseudoprospereae. Edinb J Bot 2003; 60: 533-568
7 Mulholland DA, Schwikkard SL, Crouch NR. The chemistry and biological activity of the Hyacinthaceae. Nat Prod Reports 2013; 30: 1165-1210
8 Gaidamashvili A, van Staden J. Prostaglandin inhibitory activity by lectin-like proteins from South African medicinal plants. S Afr J Bot 2006; 72: 661-663
9 du Toit K, Kweyama A, Bodenstein J. Anti-inflammatory and antimicrobial profiles of Scilla nervosa (Burch.) Jessop (Hyacinthaceae). S A J Sci 2011; 107: 96-100
10 Waller CP, Thumser AE, Langat MK, Crouch NR, Mulholland DA. COX-2 inhibitory activity of homoisoflavanones and xanthones from the bulbs of the Southern African Ledebouria socialis and Ledebouria ovatifolia (Hyacinthaceae: Hyacinthoideae). Phytochemistry 2013; 95: 284-290
11 Abegaz BM. Novel phenylanthraquinones, isofuranonaphthoquinones, homoisoflavonoids, and biflavonoids from African plants in the genera Bulbine, Scilla, Ledebouria, and Rhus . Phytochem Rev 2002; 1: 299-310
12 Silayo A, Ngadjui BT, Abegaz BM. Homoisoflavonoids and stilbenes from the bulbs of Scilla nervosa subsp rigidifolia . Phytochemistry 1999; 52: 947-955
13 Mimaki Y, Nishino H, Ori K, Kuroda M, Matsui T, Sashida Y. Lanosterol oligosaccharides from plants of the subfamily Scilloideae and their antitumor-promoter activity. Chem Pharm Bull 1994; 42: 327-333
14 Ori K, Koroda M, Mimaki Y, Sakagami H, Sashida Y. Lanosterol and tetranorlanosterol glycosides from the bulbs of Muscari paradoxum . Phytochemistry 2003; 64: 1351-1359
15 Ori K, Kuroda M, Mimaki Y, Sakagami H, Sashida Y. Norlanostane and lanostane glycosides from the bulbs of Chionodoxa luciliae and their cytotoxic activity. Chem Pharm Bull 2003; 51: 92-95
16 Kuroda M, Mimaki Y, Ori K, Koshino H, Nukada T, Sakagami H, Sashida Y. Lucilianosides A and B, two novel tetranor-lanostane hexaglycosides from the bulbs of Chionodoxa luciliae . Tetrahedron 2002; 58: 6735-6740
17 Shim JS, Kim JH, Lee J, Kim SN, Kwon HJ. Anti-angiogenic activity of a homoisoflavanone from Cremastra appendiculata . Planta Med 2004; 70: 171-173
18 Basavarajappa HD, Lee B, Fei X, Lim D, Callaghan B, Mund JA, Case J, Rajashekhar G, Seo SY, Corson TW. Synthesis and mechanistic studies of a novel homoisoflavanone inhibitor of endothelial cell growth. PLoS One 2014; 9: e95694
19 Basavarajappa HD, Lee B, Lee H, Sulaiman RS, An H, Magana C, Shadmand M, Vayl A, Rajashekhar G, Kim EY, Suh YG, Lee K, Seo SY, Corson TW. Synthesis and biological evaluation of novel homoisoflavonoids for retinal neovascularization. J Med Chem 2015; 58: 5015-5027
20 Sulaiman RS, Basavarajappa HD, Corson TW. Natural product inhibitors of ocular angiogenesis. Exp Eye Res 2014; 129: 161-171
21 Langlois A, Mulholland DA, Duncan GD, Crouch NR, Edwards TJ. A novel 3-benzylchromone from the South African Lachenalia rubida (Hyacinthaceae). Biochem Syst Ecol 2005; 33: 961-966
22 Mutanyatta J, Matapa BG, Shushu DD, Abegaza BM. Homoisoflavonoids and xanthones from the tubers of wild and in vitro regenerated Ledebouria graminifolia and cytotoxic activities of some of the homoisoflavonoids. Phytochemistry 2003; 62: 797-804
23 Ziegler R, Tamm C. Isolation and structureof eucosterol and 16β-hydroxyeucosterol, two novel spirocyclic nortriterpenes, and of a new 24-nor-5α-chola-8, 16-dien-oic acid, from bulbs of several Eucomis species. Helv Chim Acta 1976; 59: 1997-2011
24 Sihra JK, Thumser AE, Langat MK, Crouch NR, Mulholland DA. Constituents of bulbs of three species of the Hyacinthaceae (Hyacinthoideae): Eucomis vandermerwei, E. zambesiaca and Resnova humifusa . Nat Prod Comm 2015; 10: 1207-1209
25 Ren F, Wang L, Wang F, Li B. Chemical constituents from Scilla scilloides . Chinese Trad Herbal Drugs 2014; 14: 1984-1988
26 Adinolfi M, Barone G, Belardini M, Lanzetta R, Laonigro G, Parrilli M. Three 3-benzyl-4-chromanones from Muscari comosum . Phytochemistry 1984; 23: 2091-2093
27 Nishida Y, Eto M, Miyashita H, Ikeda T, Yamaguchi K, Yoshimitsu H, Nohara T, Ono M. A new homostilbene and two new homoisoflavonoids from the bulbs of Scilla scilloides . Chem Pharm Bull 2008; 56: 1022-1025
28 Koorbanally C, Sewjee S, Mulholland D, Crouch N, Dold A. Homoisoflavanones from Pseudoprospero firmifolium of the monotypic tribe Pseudoprospereae (Hyacinthaceae: Hyacinthoideae). Phytochemistry 2007; 68: 2753-2756
29 Ren FC, Wang LX, Yu Q, Jiang XJ, Wang F. Lanostane-type triterpenoids from Scilla scilloides and structure revision of drimiopsin D. Nat Prod Bioprospect 2015; 5: 263-270
30 Moodley N, Crouch N, Mulholland D, Slade D, Ferreira D. 3-Benzyl-4-chromanones (homoisoflavanones) from bulbs of the ethnomedicinal geophyte Ledebouria revoluta (Hyacinthaceae). S Afr J Bot 2006; 72: 517-520
31 Koorbanally C, Crouch N, Langlois A, DuToit K, Mulholland D, Drewes S. Homoisoflavanones and spirocyclic nortriterpenoids from three Eucomis species: E. comosa, E. schijffii and E. pallidiflora subsp. pole-evansii (Hyacinthaceae). S Afr J Bot 2006; 72: 428-433
32 Repetto G, del Peso A, Zurita JL. Neutral red uptake assay for the estimation of cell viability/cytotoxicity. Nat Protoc 2008; 3: 1125-1131
33 Zhang JH, Chung TDY, Oldenburg KR. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen 1999; 4: 67-73
34 Basavarajappa HD, Sulaiman RS, Qi X, Shetty T, Sheik Pran Babu S, Sishtla KL, Lee B, Quigley J, Alkhairy S, Briggs CM, Gupta K, Tang B, Shadmand M, Grant MB, Boulton ME, Seo SY, Corson TW. Ferrochelatase is a therapeutic target for ocular neovascularization. EMBO Mol Med 2017; 9: 786-801
35 Carpentier G. Angiogenesis Analyzer for ImageJ. Available at: http://imagej.nih.gov/ij/macros/toolsets/Angiogenesis Analyzer.txt Accessed November 30, 2017

Supplementary Material

Supporting Information