Antitumor agents 270. Novel substituted 6-phenyl-4H-furo[3,2-c]pyran-4-one derivatives as potent and highly selective anti-breast cancer agents

Abstract

6-Phenyl-4H-furo[3,2-c]pyran-4-one derivatives based on neo-tashinlactone (1) were synthesized and evaluated as novel anti-breast cancer agents. Compounds 10-13, 23, 25, and 27 showed potent inhibition against the SK-BR-3 breast cancer cell line. Importantly, 25 and 27 showed the highest cancer cell line selectivity, being approximately 100-250-fold more potent against SK-BR-3 (ED(50) 0.28 and 0.44microM, respectively) compared with other cancer cell lines tested. In addition, 25 displayed low cytotoxicity against normal breast cell lines 184A1 and MCF10A. Compounds 25 and 27 merit further investigation in our continuing program to generate and develop selective anti-breast cancer agents.

Figure 1

Structures of neo-tanshinlactone (1), a first generation neo-tanshinlactone analog 2, a second generation optimized analog 3, and a newly designed scaffold 4

Figure 2

Selective in vitro anticancer activity of 25 against SK-BR-3 breast cancer versus normal breast tissue-derived cell lines (MCF10A and 184A1). Legend: Cell line description, source and activity determination using the MTT-dye assay are described in the experimental section. Graphical data are the mean and standard deviation of values obtained from replicates in a single experiment.

Scheme 1