Synthesis and Antitumour Activity of Hybrid Compounds Based on 4-Aminophenylarsonic Acid and Spatially Hindered Phenols.

Abstract

One of the main modern approaches to the creation of effective drugs is the design of new biologically active substances containing two or more pharmacophore groups in their structure. In recent years, there have been many publications on the synthesis and study of biological activity, including antitumour activity, of new organo-arsenic compounds. It is known that spatially hindered phenols can also have antitumor activity, so the synthesis and study of hybrid compounds based on organo-arsenic compounds and spatially hindered phenols is a relevant area of research. In this work, the modification of 4-aminophenylarsonic acid with 3,5-di-tert-butyl-4-hydroxybenzylacetate was carried out. In contrast to a similar transformation of 2-aminophenylarsonic acid, in this case it was possible to obtain both mono- and di-benzyl derivatives of the acid. Using the Zandmeyer method, the oxime isatin containing an arsonic acid fragment in the fifth position of the heterocycle was synthesised. Azo derivatives containing fragments of para-aminophenylarsonic acid and sterically hindered phenols were obtained. 4-((3,5-Di-tert-butyl-2-hydroxyphenyl)diazenyl)phenylarsonic acid was isolated in pure form. At the same time, it was found that the reaction of the diazonium azo salt of 4-aminophenylarsonic acid with 2-hydroxymethyl-4-tert-butylphenol proceeds in two directions. In addition to the classical diazotisation reaction at the 6-position of 2-hydroxymethyl-4-tert-butylphenol, a diazotisation accompanied by a dehydroxymethylation process occurs. The obtained compounds showed cytotoxic activity against human tumor cell lines M-HeLa (cervical epithelioid carcinoma) and HuTu 80 (duodenal adenocarcinoma cells). The most promising is the sodium salt of 4-((3,5-di-tert-butyl-2-hydroxyphenyl)diazenyl)phenylarsonic acid, which is superior to Tamoxifen and 5-fluorouracil in terms of selectivity index towards M-HeLa and HuTu 80 cells.