Investigating Structural Requirements for the Antiproliferative Activity of Biphenyl Nicotinamides

A number of trimethoxybenzoic acid anilides, previously studied as permeability glycoprotein (P-gp) modulators, were screened with the aim of identifying new anticancer agents. One of these compounds, which showed antiproliferative activity against resistant MCF-7 cell line, was selected as the hit structure. Replacement of the trimethoxybenzoyl moiety with a nicotinoyl group, in order to overcome solubility issues, led to a new series of N-biphenyl nicotinoyl anilides, among which a nitro derivative, N-(3′,5′-difluoro-3-nitro-[1,1′-biphenyl]-4-yl)nicotinamide (3), displayed antiproliferative activity against MCF-7 and MDA-MB-231 cells in the nanomolar range. The search for a bioisostere of the nitro group led to nitrile analogue N-(3-cyano-4′-fluoro-[1,1′-biphenyl]-4-yl)nicotinamide (36), which shows a strong increase in activity against MCF-7 and MDA-MB-231 cells. Compound 36 induced a dose-dependent accumulation of G2- and M-phase MCF-7 cell populations, and a decrease in S-phase cells. Relative to vinblastine, a well-known potent antimitotic agent, compound 36 also induced G1-phase arrest at low doses (20–40 nm), but did not inhibit in vitro tubulin polymerization.