Investigating Structural Requirements for the Antiproliferative Activity of Biphenyl Nicotinamides

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Abstract
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.
Funding Information
  • Universita degli Studi di Bari Aldo Moro

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