Hiles, Jacob (2019) The synthesis, cytotoxicity, COX inhibitory activity, and anti-angiogenic activity of homoisoflavonoid analogues. (MSc(R) thesis), Kingston University, .
Abstract
Natural products have been used for the treatment of various maladies for thousands of years. Naturally occurring analogues of homoisoflavonoids have shown a range of interesting activities, including anti-inflammatory and anti-cancer activities. Homoisoflavonoids have been primarily isolated from the Hyacinthaceae (Asparagaceae). NSAIDs are a class of drugs widely used. However, due to the numerous side effects due to the poor selectivity (inhibition of both COX-I and COX-II) of the NSAIDs on the cyclooxygenase enzyme (COX), a need for selective COX-II inhibitors has arisen. A series of the sulphur analogues of homoisoflavonoids, 3-benzylidene thiochroman-4-ones, were synthesised and screened for: cytotoxicity via the neutral red assay, selective cytotoxicity towards HREC cells as a measure of potential antiangiogenic activity via the alamarBlue assay, and selective COX activity via the COX screening kit (CAYMAN CHEMICAL). These compounds were evaluated against the cancerous cell line, HeLa (human cervical carcinoma), and non-cancerous cell lines; HREC (human retinal endothelial cells), and ARPE-19 (human retinal pigment epithelial cells). The compound found to be the most cytotoxic against HeLa cells produced an IC50 of 6.08 μM. The compound found to be the most active with respect to antiproliferation against HREC cells exhibited a GI50 of 3.07 μM. All compounds demonstrated selectivity with all GI50 values against ARPE-19 >100 µM. The compound found to be the most active against COX-II produced 22.7 % inhibition at 4.35 nM.
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