Abstract 1369: Synthesis of substituted N-[(3-(1H-pyrrol-1yl)methyl]-5,6-dihydropyridin-1(2H)-yl) benzamide/benzene sulfonamide as anticancer agents

Abstract

Abstract Cancer has proven to be one of the most intractable human diseases, and as yet no anticancer agents that are highly effective and safe are available. Therefore, synthesis of novel, potent, selective and less toxic anticancer agents remains the most pressing goal of many investigators. Tetrahydropyridine (THP) ring moieties have attracted synthetic interests for being essential structures in many agrochemicals as well as medicinal agents. The anti-inflammatory and anticancer activities of compounds consisting of reduced pyridine ring systems were investigated in our laboratory. The pharmacological activities of the (THP) derivatives depended on the nature of the substituents on the THP ring moiety. In the current investigation, we synthesized many analogs maintaining the N-(3-[(1-H-pyrrol-1-yl)methyl]-5,6-dihydropyridin-1(2H)-yl) benzamide/benzene sulfonamides, at which the phenyl ring was substituted with groups having different electronic, steric and lipophilic properties. Mesitylene sulfonyl chloride was added with stirring to a solution of ethylacetohydroxymate and triethylamine in dimethylformamide at 0o C. Hydrolysis of this compound with the mixture of p-dioxane-70% perchloric acid and allowing them to react for 45 min gave a white solid of O-mesitylene sulfonyl hydroxylamine (MSH). MSH was used to prepare the N-amino salt since it served as an aminating agent. 3-[(1H-pyrrol-1-yl)methyl]pyridine was reacted with MSH in dichloromethane to produce 3-[(1H-pyrrol-1-yl)methyl]-1-aminopyridinium mesitylenesulfonate, the N-amino salt. Reaction of the amino salt with substituted benzoyl chloride/benzenesulfonyl chloride in anhydrous tetrahydrofuran containing triethylamine gave stable benzoyl/benzene sulfonyl imino ylides. This was followed by reduction with sodium borohydride in absolute ethanol, which furnished the target compounds substituted N-(3-[(1H-pyrrol-1-yl)methyl]-5,6-dihydropyridin-1(2H)-yl) benzamide/benzene sulfonamides. These compounds were evaluated for their cytotoxic effects on MCF-7 estrogen receptor positive breast cancer cells, MDA-MB-231 estrogen receptor negative breast cancer cell line, and Ishikawa cells, using the CellTiter-Glo (CTG) luminescent cell viability assay. N-(3-[(1H-pyrrol-1-yl)methyl]-5,6-dihydropyridin-1(2H)-yl)-4-methoxybenzene- sulfonamide showed the most potent cytotoxicity with an IC50 values of 47, 28, and 44 µM on MCF-7, Ishikawa and MDA-MB-231 cell lines, respectively. This research was supported by NIH/ RCMI Grant # G12 RR 03020 and Pharmaceutical Research Center NIH/NCRR Grant 1 C06 RR12512-01. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1369. doi:10.1158/1538-7445.AM2011-1369