Structural studies on bioactive compounds.: 40.: Synthesis and biological properties of fluoro-, methoxyl-, and amino-substituted 3-phenyl-4H-1-benzopyran-4-ones and a comparison of their antitumor activities with the activities of related 2-phenylbenzothiazoles

A new series of fluoro-, methoxyl-, and amino-substituted isoflavones have been synthesized as potential antitumor agents based on structural similarities to known flavones and isoflavones ( quercetin and genistein respectively) and antitumor 2-phenylbenzothiazoles. Target compounds were synthesized using palladium-catalyzed coupling methodologies to construct the central aryl carbon-carbon single bond. The new isoflavone derivatives were tested for in vitro activity in human breast ( MDA-MB-468 and MCF-7) and colon ( HT29 and HCT-116) cancer cell lines. Low micromolar GI(50) values were obtained in a number of cases, with the MDA-MB-468 cell line being the most sensitive overall. Notably, significant potentiation of growth inhibitory activity ( GI(50) < 1 AM for 12d, 12f, 12h, 12k, 12l, 12o but not the methylene-bridged derivative 12i) was observed when MDA-MB-468 cells were co-incubated with TBDD, a powerful inducer of cytochrome P450 ( CYP)-1A1 activity, suggesting that isoflavone derivatives can act as substrates for CYP1A1 bioactivation.