Mannich bases of chalcones and cyclohexanones as candidate cytotoxic agents

Abstract

This investigation was carried out with a view to overcome some of the disadvantages that are associated with the use of presently available cancer chemotherapeutic agents. It involved the synthesis of various derivatives of 4-hydroxychalcones and different esters of 2-(4-hydroxyphenylmethylene)cyclohexanones and their conversion into the corresponding Mannich bases. The reason for their proposed synthesis and cytotoxic evaluation were as follows. A number of α,β unsaturated ketones have demonstrated preferential reactivity towards thiols in contrast to amino and hydroxy groups and hence these compounds may be free from the problems of mutagenicity and carcinogenicity which are associated with a number of alkylating agents used in cancer chemotherapy. Also results from this laboratory have revealed that conversion of various acyclic conjugated styryl ketons into the corresponding Mannich bases was often accompanied by increased bioactivity both 'in vitro' and 'in vivo'. Most of these compounds were assayed for cytotoxic activity against P388 and L1210 leukemia cells and a panel of human tumor cell lines. In addition, several other chemical, physicochemical and biochemical studies were undertaken. This study has shown that Mannich bases of both chalcones and the esters of 2-(4-hydroxyphenylmethylene)cyclohexanones are novel cytotoxic agents. In general, Mannich bases displayed more cytotoxic activity than the precursor ketones with the exception of most chalcones whose cytotoxic activity towards P388 cells was greater than the corresponding Mannich bases. A number of these compounds displayed selective toxicity to certain malignant tissues. Many lead molecules have been revealed with high potency towards P388 cells, L1210 cells and human tumors. Three compounds among the Mannich bases of esters of 2-(4-hydroxyphenylmethylene)cyclohexanone displayed very good selectivity towards a panel of leukemia cell lines in the human tumor cell line screen. QSAR studies revealed good correlations between the cytotoxic activity of the Mannich bases of chalcones and various physicochemical parameters including the π, σ and MR constants of the aryl rings and redox potentials along with other structural features unveiled by X-ray crystallography and molecular modelling. Representative compounds among the Mannich bases of chalcones did not show mutagenicity in an intrachromosomal recombination assay in yeast and reacted with glutathione in the presence of π isozyme of glutathione S-transferase.