Abstract 3903: Synthesis of substituted N-{4-[(2-hydroxyethyl)sulfanyl]-3,6-dihydropyridin-1(2h)-yl} benzamide/benzenesulfonamide as antiinflamatory and anticancer agents

Abstract

Abstract Breast cancer is the most common type of cancer among women in the industrialized world, accounting for nearly one of every three cancers diagnosed. There is a strong association between chronic inflammatory conditions in a particular organ and cancer specific to that organ. The longer the inflammation persists, the higher the risk of associated carcinogenesis. There is abundant epidemiological and experimental evidence that NSAID's might inhibit tumor development in a number of organs. COX-2 expression may be a fundamental step in breast cancer pathogenesis acting through prostaglandin-dependent mechanisms. Tetrahydropyridine (THP) analogs are compounds of diverse biological activities like analgesics, anti-inflammatory and chemotherapeutic agents. Our earlier research results indicated that some of the THP derivatives showed COX-2 inhibition and anti-inflammatory activities on rat paw edema assay studies. There has been remarkable effort in developing new classes of compounds to minimize the side effects of the NSAIDs and increase the selectivity of COX-2 inhibitors. We now report the synthesis of substituted N-{4-[(2-hydroxyethyl)sulfanyl]-3,6-dihydropyridin-1(2H)-yl} benzamide/benzenesulfonamide as anti-inflammatory and anticancer agents to continue the development of new classes of anti-inflammatory and anticancer agents. The starting material ethyl (pyridin-4-ylsulfanyl)acetate was obtained by the reaction of (4-pyridylthio)acetic acid dissolved in ethanol and several drops of 98% H2SO4 and the mixture was heated to reflux for 12 h. 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). Ethyl (pyridin-4-ylsulfanyl)acetate was reacted with MSH in dichloromethane to produce 1-amino-4-(2-ethoxy-2-oxoethylthio)pyridinium mesitylenesulfonate. Reaction of the amino salt with substituted benzoyl chloride/benzenesulfonyl chloride in anhydrous tetrahydrofuran gave stable benzoyl/benzene sulfonyl imino ylides. This was followed by reduction with sodium borohydride in absolute ethanol, which furnished the target THP compounds. 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. Two compounds showed potent anticancer activities using these cell lines. 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 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3903. doi:1538-7445.AM2012-3903