Natural and synthetic homoisoflavonoids as inhibitors of ocular angiogenesis.

Pathogenic neovascularization underlies a number of degenerative ocular diseases, which together are the most common causes of blindness in children and adults. Novel therapies are sorely needed to treat these diseases as even the newer, highly expensive, anti-vascular endothelial growth factor (VEGF) drugs, such as ranibizumab, can have acute, systemic side effects. Natural product chemistry involves the extraction of potentially pharmacologically active phytochemicals from plants. Homoisoflavonoids are a class of active compounds isolated from the Scilloideae sub-family of the Asparagaceae family. Homoisoflavonoids are frequently extracted from the Scilloideae sub-family and are considered promising pharmacological candidates due to their anti-bacterial, anti-mutagenic, anti-oxidant and anti-inflammatory effects. Cremastranone is a homoisoflavonoid extracted from an orchid used in traditional medicine, Cremastra appendiculata, and has an anti-proliferative effect on blood vessels. This compound has been shown to be effective in treating pathogenic neovascularisation in premature mice. A synthetic method, which can be used to produce a wide variety of homoisoflavonoid compounds, is reported here with the goal to synthesise the most promising homoisoflavonoid candidates extracted in this work for in vivo studies. The sub-family Scilloideae contains the tribes Ornithogaleae, Hyacintheae, Urgineeae and Oziroëeae. Seven plant species from the Hyacintheae, Urgineeae and Oziroëeae tribes were investigated in this work. This is the first report of the phytochemical investigation of Rhodocodon cryptopodus, R. rotundus, Massonia (Whiteheadia) bifolia and Oziroë arida. Rhodocodon cryptopodus (Baker) and Rhodocodon rotundus (H. Perrier) bulbs were investigated, producing six known compounds identified as triterpenoids, cinnamic acid derivatives and a homoisoflavonoid and four novel compounds. From R. cryptopodus one novel coumarin was extracted and from R. rotundus, two novel bufadienolides and one novel 3S-homoisoflavonoid were extracted Plants within the Eucomis (L'Her) genus are known to contain many homoisoflavonoids. E. autumnalis (Mill. Chitt.), E. bicolor (Baker) and E. comosa (Hort ex. Wehrh) were investigated. These species have been investigated previously. They were reinvestigated using bulbs from a commercial bulb supplier as large quantities were available and large amounts of extracted compounds were required for screening purposes. Phytochemical investigations yielded a spirocyclic nortriterpenoid, phenolic compounds, a chromanone, a purine nucleoside and homoisoflavonoids. One novel homoisoflavonoid was extracted from E. autumnalis and two novel homoisoflavonoids were extracted from E. comosa. The phytochemistry of Massonia (Whiteheadia) bifolia ((Jacq.) J.C. Manning & Goldblatt) was investigated. Analysis of the bulbs of M. bifolia yielded four known compounds including a spirocyclic nortriterpenoid and three homoisoflavonoids. Novel compounds included a xanthone and two homoisoflavonoid compounds. A phytochemical analysis of Oziroë arida (Raf.) bulbs yielded six known compounds, identified as two phytosterols, a cinnamic acid derivative, a purine nucleoside and two homoisoflavonoids. Extracted and synthetic homoisoflavonoids were tested for their anti-proliferative activities in cell-based assays. Active compounds were also tested for their anti-angiogenic activities in vitro. Results indicated that several homoisoflavonoids are very active at stopping the proliferation, migration and tube formation of cultured endothelial cells. Selected promising compounds will be taken on for in vivo studies in the future