Sulphur analogues of homoisoflavonoids as potential treatments for neovascular eye diseases

Treatment of neovascular eye diseases like age-related macular degeneration require a compound that is not toxic to ocular cells, that can reduce inflammation and inhibit angiogenesis. Homoisoflavonoids, naturally occurring compounds isolated primarily from the Hyacinthaceae sub-family of plants, have shown promise as anti-inflammatories and inhibitors of angiogenesis. A series of sulphur analogues, (3-benzylidene thiochroman-4-ones), were synthesised via a three-step procedure. These compounds were evaluated for selectivity towards endothelial cells over non-endothelial cells and their ability to inhibit COX-II over COX-I.Their potential anti-angiogenic activity was assessed using the Matrigel tube formation assay. (3Z)-3-[(3-bromophenyl)methylidene]-6-methoxy-2,3-dihydro-4H-1-benzothiopyran-4-one (10) was most active with respect to anti-proliferation against human retinal endothelial cells (HREC cells) (GI₅₀ 3.07 μM). All demonstrated selectivity with all GI₅₀ values against retinal pigment epithelial cell line ARPE-19 >100 µM, with the exception of (3Z)-6-bromo-3-[(4-nitrophenyl)methylidene]-2,3-dihydro-4H-1-benzothiopyran-4-one (12), which was not toxic to either. (3Z)-3-[(3-bromophenyl)methylidene]-6-methoxy-2,3-dihydro-4H-1-benzothiopyran-4-one (10) showed significant reduction in angiogenesis properties in a Matrigel-based tube formation assay (38.79%, 5 µM, 56.41%, 10 µM). (3Z)-6-bromo-3-[(3-bromophenyl)methylidene]-2,3-dihydro-4H-1-benzothiopyran-4-one (7) was found to be the most active against COX-II with inhibition of 22.7 % (4.35 nM). The 3-benzylidene thiochroman-4-ones show promise as antiangiogenic agents, but limited selectivity to COX-II over COX-I.