Mannich bases of phenolic azobenzenes possessing cytotoxic activity

Abstract

Summary A number of arylazophenols 1 were converted into the corresponding mono Mannich bases 2 from which two quaternary salts 3a,b and an ester 3c were prepared. A series of bis Mannich bases 4 were also synthesized. The angles (θ) made between one of the aryl rings and the adjacent azo linkage were determined by electronic absorption spectroscopy. X-ray crystallographic data were obtained for some of the Mannich bases. The compounds were evaluated against murine P388 D1 and L1210 cells and two human T-lymphocyte (Molt 4, CEM) lines, and most of the derivatives were also screened against a panel of human tumour cell lines. A number of correlations were noted between cytotoxicity and various physicochemical constants as well as some structural features determined by X-ray crystallography. Several of the Mannich bases were shown to have mutagenic properties using the A RK mutatest; the compounds in series 2 and 4 have the ability to penetrate the central nervous system, as revealed by their anticonvulsant properties. While series 2–4 have the potential to deaminate forming ortho quinone methides which would be capable of alkylating cellular thiols, the results of stability studies suggest that the bioactivities noted were due to the molecules per se.