Synthesis of 1-(2,4-difluorphenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives and investigation of their anticancer activity

Abstract

One of the main causes of cancer is the multiplication of damaged cells and the formation of tumors [1]. New synthetic molecules are being synthesized and studied which could be characterized by antitumor activity and low toxicity. The list of drugs approved by U.S. FDA shows that fluorinated compounds are included in the composition of many medicinal molecules [2]. For this reason, molecules with a fluorine atom in the aromatic ring becoming an interesting object for research. By reaction of 2,4-difluoroaniline (1) with itaconic acid, the starting compound 1-(2,4-difluorophenyl)-5- oxopyrrolidine-3-carboxylic acid (2) was prepared. Methyl 1-(2,4-difluorophenyl)pyrrolidin-2-one carboxylate (5) was obtained from the esterification reaction using catalytic amount of sulfuric acid. In order to synthesize a compound with functional group of hydrazide, methyl ester 5 was transformed into the hydrazide 6 by reaction with hydrazine monohydrate in refluxing isopropanol. The desired products 7a-b and 9a-h were obtained by stirring hydrazide 6 with corresponding aromatic aldehydes in isopropanol. Alkylation of compound 9 using iodoethane was carried out by dissolving the starting material in DMF, in strongly alkaline medium. (Fig. 1). The activity of the synthesized compounds was studied against three types of cancer cells – breast cancer (MDA-MB-23), prostate cancer (PPC-1) and melanoma (A375). The cytotoxicity of pyrrolidinecarboxylic acid derivatives was investigated using MTT method. It was found that compounds 7b, 9a, 9c, 9e, 9f, 10 had the best anticancer activity against MDA-MB-231, PPC-1 and A375 cell lines (Fig. 2).