title: Synthesis and cytotoxic activity of polyamine analogues of camptothecin.
abstract: A number of derivatives of camptothecin with a polyamine chain linked to position 7 of camptothecin via an amino, imino, or oxyiminomethyl group were synthesized and tested for their biological activity. All compounds showed marked growth inhibitory activity against the H460 human lung carcinoma cell line. In particular, the iminomethyl derivatives where the amino groups of the chain were protected with Boc groups exhibited a high potency, with IC50 values of approximately 10(-8) M. The pattern of DNA cleavage in vitro and the persistence of the cleavable ternary complex drug-DNA-topoisomerase I observed with polyamine conjugates containing free amino groups support a contribution of specific drug interaction with DNA as a determinant of activity. Modeling of compound 7c in the complex with topoisomerase 1 and DNA is consistent with this hypothesis. The lack of a specific correlation between stabilization of the cleavable complex and growth inhibition likely reflects multiple factors including the cellular pharmacokinetic behavior related to the variable lipophilicity of the conjugate, and the nature and linkage of the polyamine moiety.
authors.affiliation: Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dallavalle
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.forename: Domenico
authors.initials: D
authors.lastname: Alloatti
authors.forename: Andrea
authors.initials: A
authors.lastname: Casati
authors.forename: Elena
authors.initials: E
authors.lastname: Marastoni
authors.forename: Loana
authors.initials: L
authors.lastname: Musso
authors.forename: Lucio
authors.initials: L
authors.lastname: Merlini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Morini
authors.forename: Sergio
authors.initials: S
authors.lastname: Penco
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Stella
authors.initials: S
authors.lastname: Tinelli
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Beretta
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D015394:Molecular Structure; D011073:Polyamines / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D011073:Polyamines; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin