title: Synthesis and cytotoxic activity of substituted 7-aryliminomethyl derivatives of camptothecin.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Molecolari Agroalimentari, Sezione di Chimica, Università di Milano, Via Celoria 2, 20133 Milan, Italy. sabrina.dallavalle@unimi.it
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dallavalle
authors.forename: Lucio
authors.initials: L
authors.lastname: Merlini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Morini
authors.forename: Loana
authors.initials: L
authors.lastname: Musso
authors.forename: Sergio
authors.initials: S
authors.lastname: Penco
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Beretta
authors.forename: Stella
authors.initials: S
authors.lastname: Tinelli
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002166:Camptothecin / Q000138:chemical synthesis* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007097:Imines / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008168:Lung / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007097:Imines; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin