Synthesis and cytotoxic activity of polyamine analogues of camptothecin

Sabrina Dallavalle, Giuseppe Giannini, Domenico Alloatti, Andrea Casati, Elena Marastoni, Loana Musso, Lucio Merlini, Gabriella Morini, Sergio Penco, Claudio Pisano, Stella Tinelli, Michelandrea De Cesare, Giovanni Luca Beretta, Franco Zunino

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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 IC 50 values of ∼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.

Original languageEnglish
Pages (from-to)5177-5186
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number17
Publication statusPublished - Aug 24 2006

ASJC Scopus subject areas

  • Organic Chemistry


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