HYBRID MOLECULES CONTAINING PROPARGYLIC SULFONES AND DNA MINOR GROOVE-BINDING LEXITROPSINS - SYNTHESIS, SEQUENCE SPECIFICITY OF REACTION WITH DNA AND BIOLOGICAL EVALUATION

A series of hybrids, 4-13, incorporating propargylic sulfones and minor groove-binding oligopeptide carriers, was synthesized. The anticipated preferential binding at adenine sites within the minor groove was confirmed by sequencing determination of these agents on high-resolution gels, indicating preferential alkylation at guanine, and significantly, high selectivity for 5'-GACG and 5'-GGTC. The ability of these hybrids to cleave DNA, as determined by agarose-gel assay, is consistent with the ethidium bromide fluorescence assay. The cytotoxicities of these compounds were also determined against human KB cells in vitro. Higher cytotoxic activities were observed for the compounds containing fewer N-methylpyrrole units, an imidazole group and a 2,3-disubstituted naphthyl moiety.