Synthesis and cytotoxic activity of substituted 7-aryliminomethyl derivatives of camptothecin.

A series of imines derived from camptothecin-7-aldehyde (CPT-CHO) and aromatic amines were synthesised and tested for their cytotoxicity against tumour cell line H460, that expresses a high level of topoisomerase I. In general ortho-substituted compounds showed higher cytotoxic potency than the corresponding para-substituted imines. This effect was dependent on the nature of the substituent. Structure-activity relationships were studied by calculation of docking energy with a model of the ternary complex camptothecin-DNA-topoisomerase I. The ability of selected compounds to stimulate the topoisomerase I-mediated DNA cleavage and the persistence of the cleavable complex were consistent with the cytotoxic activity.