Synthesis, antiproliferative, and antiplatelet activities of oxime- and methyloxime-containing flavone and isoflavone derivatives

Certain oxime- and methyloxime-containing flavone and isoflavone derivatives were synthesized and evaluated for their antiproliferative activity against three solid cancer cells, human cervical epithelioid carcinoma (HeLa), hepatocellular carcinoma (SKHep1), and oral squamous cell carcinoma (SAS), which are commonly seen in Asian countries, including Taiwan. Selective compounds were also evaluated in the full panel of 60 human tumor cell lines and their mean GI₅₀ values were obtained. The preliminary assays indicated flavone-6-yl derivatives are the most cytotoxic while isoflavone-7-yl derivatives are the best antiplatelet agents. Among them, (E)-6-(2- methoxyiminopropoxy)-2-phenyl-4H-1-benzopyran-4-one (14), (Z)-6-(2-hydroxyimino- 2-phenylethoxy)-2-phenyl-4H-1-benzopyran-4-one (18a), and (Z)-6-[2-hydroxyimino- 2-(4-methoxyphenyl)ethoxy]-2-phenyl-4H-1-benzopyran-4-one (18c) are three of the best antiproliferative agents with GI₅₀ values of 0.8, 0.7, and 0.8 μM, respectively, against the growth of SKHep1; 0.9, 0.8, and 1.0 μM, respectively, against the growth of HeLa cells. Compound 18c is not only the most cytotoxic with a mean GI₅₀ value of 0.08 μM against the full panel of 60 human tumor cell lines but also the only flavone derivative that exhibited a GI₅₀ value of less than 1 μM against the growth of SAS. Flow cytometric analyses revealed that growth inhibition by 18c was due to accumulation in G2/M phase arrest and followed by apoptosis.