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Browsing by Author "Mulholland, Dulcie A."
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Item Antiangiogenic Activity and Cytotoxicity of Triterpenoids and Homoisoflavonoids from Massonia pustulata and Massonia bifolia(Thieme, 2018-07) Schwikkard, Sianne L.; Whitmore, Hannah; Corson, Timothy W.; Sishtla, Kamakshi; Langat, Moses K.; Carew, Mark; Mulholland, Dulcie A.; Ophthalmology, School of MedicineThe 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.Item Bufadienolides and anti-angiogenic homoisoflavonoids from Rhodocodon cryptopodus, Rhodocodon rotundus and Rhodocodon cyathiformis(Elsevier, 2020) Whitmore, Hannah; Sishtla, Kamakshi; Knirsch, Walter; Andriantiana, Jacky L.; Schwikkard, Sianne; Mas-Claret, Eduard; Nassief, Sarah M.; Isyaka, Sani M.; Corson, Timothy W.; Mulholland, Dulcie A.; Ophthalmology, School of MedicineBackground 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.