Mannich bases and other related compounds designed principally as candidate cytotoxic and anticancer agents
Vashishtha, Sarvesh Chandra
This study describes principally the synthesis of a number of Mannich bases of 1-aryl-1-ethanones, 4-aryl-3-buten-2-ones and their quaternary ammonium salts. These compounds were evaluated against P388 and L1210 leukemic cells, human T lymphocytes and a variety of human tumor cell lines. There were four reasons for undertaking the synthesis of these compounds. First, to examine the theory of sequential cytotoxicity which states that the successive release of two or more cytotoxic agents will cause greater damage to malignant rather than normal cells. The cytotoxicity data using human tumor cell lines were in accord with the hypothesis in general while use of murine leukemic cells supported this theory in one third to half of the cases. Another series of compounds namely azomethines (series 13, 14) of certain cytotoxic Mannich bases, i.e., 1-(4-aryl)-3- dimethylamino-2-dimethylaminomethyl-1-propanone dihydrochlorides, discovered earlier in this laboratory and O or O,O$\sp\prime$-bis Mannich bases of 4-hydroxy benzoyl hydrazine (compounds XX and XXII respectively), were designed on the basis of the known difference in pH values between cancer and normal cells, in order to evaluate the theory of sequential cytotoxicity. But difficulties in their synthesis aborted their evaluation. The second reason was to search for new prototypic cytotoxic and anticancer molecules. The bioevaluation revealed a number of potent cytotoxic agents. In addition, N,N-bis(5-(4-methylphenyl)-3-oxo-4-pentenyl) ethylamine hydrochloride (XIIId) reduced the size of human colon xenografts in athymic mice. Third, quantitative structure-activity relationships (QSAR) were established between various physicochemical constants of the aryl substituents and cytotoxicity. Preliminary in vitro cytotoxicity results for one of the several compounds designed on the basis of QSAR results indicate that compound XIIIi has higher IC50 values and greater selectivity towards colorectal cancer as compared to the lead molecule (XIIId). Thus, this particular class of compounds (series 7) has the capability to be developed as antineoplastic agents. In vivo testing of XIIIi in athymic mice is in progress. In addition, the stabilities of representative compounds in solution using TLC and 1H NMR indicated that the mono Mannich bases underwent deamination extensively, the bis Mannich bases were much more stable while the quaternary ammonium salts decomposed completely to unidentified compounds. An attempt was made to explain these results by comparing the theoretical pKa values of the leaving groups. However the results of the stability studies indicated that much more experimentation is required in order to understand the decomposition pathways of a number of these compounds and the reasons for their fragilities. Fourth, to screen the proposed compounds against pathogenic fungi from which N,N-bis(5-aryl-3-oxo-4-pentenyl)-N-ethylamine hydrochlorides (series 7) were revealed as a novel class of potential antifungal agents. These compounds (XIIIa-e) in general, had minimum inhibitory concentrations (MIC) figures of 0.2-100 ìM against a variety of fungi and the antifungal activity seemed to be favored by hydrophobic, electron-attracting substituents in the aryl ring. Finally, the mode of cell death induced by a representative Mannich base XIIId, in the human Jurkat T leukemia cell line was determined. Morphological evidences indicated that XIIId induced death in the cells by apoptosis.