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Synthesis and cytotoxic activity of polyamine analogues of camptothecin.
J Med Chem. 2006 Aug 24; 49(17):5177-86.JM

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+Show Affiliations

Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, Via Celoria 2, 20133 Milano, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16913706

Citation

Dallavalle, Sabrina, et al. "Synthesis and Cytotoxic Activity of Polyamine Analogues of Camptothecin." Journal of Medicinal Chemistry, vol. 49, no. 17, 2006, pp. 5177-86.
Dallavalle S, Giannini G, Alloatti D, et al. Synthesis and cytotoxic activity of polyamine analogues of camptothecin. J Med Chem. 2006;49(17):5177-86.
Dallavalle, S., Giannini, G., Alloatti, D., Casati, A., Marastoni, E., Musso, L., Merlini, L., Morini, G., Penco, S., Pisano, C., Tinelli, S., De Cesare, M., Beretta, G. L., & Zunino, F. (2006). Synthesis and cytotoxic activity of polyamine analogues of camptothecin. Journal of Medicinal Chemistry, 49(17), 5177-86.
Dallavalle S, et al. Synthesis and Cytotoxic Activity of Polyamine Analogues of Camptothecin. J Med Chem. 2006 Aug 24;49(17):5177-86. PubMed PMID: 16913706.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis and cytotoxic activity of polyamine analogues of camptothecin. AU - Dallavalle,Sabrina, AU - Giannini,Giuseppe, AU - Alloatti,Domenico, AU - Casati,Andrea, AU - Marastoni,Elena, AU - Musso,Loana, AU - Merlini,Lucio, AU - Morini,Gabriella, AU - Penco,Sergio, AU - Pisano,Claudio, AU - Tinelli,Stella, AU - De Cesare,Michelandrea, AU - Beretta,Giovanni Luca, AU - Zunino,Franco, PY - 2006/8/18/pubmed PY - 2006/10/4/medline PY - 2006/8/18/entrez SP - 5177 EP - 86 JF - Journal of medicinal chemistry JO - J Med Chem VL - 49 IS - 17 N2 - 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. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/16913706/Synthesis_and_cytotoxic_activity_of_polyamine_analogues_of_camptothecin_ L2 - https://doi.org/10.1021/jm060285b DB - PRIME DP - Unbound Medicine ER -