Investigating Structural Requirements for the Antiproliferative Activity of Biphenyl Nicotinamides. (3rd August 2017)

• Record Type: Journal Article
• Authors: Majellaro, Maria; Stefanachi, Angela; Tardia, Piero; Vicenti, Chiara; Boccarelli, Angelina; Pannunzio, Alessandra; Campanella, Federica; Coluccia, Mauro; Denora, Nunzio; Leonetti, Francesco; de Candia, Modesto; Altomare, Cosimo Damiano; Cellamare, Saverio
• Is Part Of: ChemMedChem. Volume 12:Number 16(2017)
• Page Start: 1380
• Page End: 1389
• Publication Date: 2017-08-03
• Subjects: antiproliferative activity -- cell-cycle analysis -- MCF-7 -- MDA-MB-231 -- nicotinoyl anilides; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201700365
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Compound36 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, compound36 also induced G1 ‐phase arrest at low doses (20–40 nm ), but did not inhibit in vitro tubulin polymerization. Abstract : Stopping the cell cycle : The screening of a small library of trimethoxybenzoic and nicotinic acid anilides, previously studied as P‐gp modulators, allowed us to identify some N ‐biphenyl nicotinoyl anilides that show very interesting antiproliferative activities. The next hit refinement by a bioisosteric approach led us to observe potent antiproliferative activity of the cyano derivative36 against MCF‐7 and MDA‐MB‐231 cell lines.