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Design, synthesis, and biological evaluation of indenoisoquinoline topoisomerase I inhibitors featuring polyamine side chains on the lactam nitrogen.
J Med Chem. 2003 Dec 18; 46(26):5712-24.JM

Abstract

The indenoisoquinolines are a class of noncamptothecin topoisomerase I inhibitors that display significant cytotoxicity in human cancer cell cultures. They offer a number of potential advantages over the camptothecins, including greater chemical stability, formation of more persistent cleavage complexes, and induction of a unique pattern of DNA cleavage sites. Molecular modeling has suggested that substituents on the indenoisoquinoline lactam nitrogen would protrude out of the DNA duplex in the ternary cleavage complex through the major groove. This indicates that relatively large substituents in that location would be tolerated without compromising biological activity. As a strategy for increasing the potencies and potential therapeutic usefulness of the indenoisoquinolines, a series of compounds was synthesized containing polyamine side chains on the lactam nitrogen. The rationale for the synthesis of these compounds was that the positively charged ammonium cations would increase DNA affinity through electrostatic binding to the negatively charged DNA backbone, and the polyamines might also facilitate cellular uptake by utilization of polyamine transporters. The key step in the synthesis involved the condensation of Schiff bases, containing protected amine side chains, with substituted homophthalic anhydrides, to afford cis-3-aryl-4-carboxy-1-isoquinolones. These isoquinolones were then converted to indenoisoquinolines with thionyl chloride. Although monoamines were much more potent than the lead compound, no significant increase in potency was observed through incorporation of additional amino groups in the side chain. However, one of the monoamine analogues, which features a bis(2-hydroxyethyl)amino group in the side chain, proved to be one of the most cytotoxic indenoisoquinoline synthesized to date, with a GI50 mean-graph midpoint (MGM) of 0.07 microM in the NIH human cancer cell culture screen, and topoisomerase I inhibitory activity comparable to that of camptothecin.

Authors+Show Affiliations

Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14667224

Citation

Nagarajan, Muthukaman, et al. "Design, Synthesis, and Biological Evaluation of Indenoisoquinoline Topoisomerase I Inhibitors Featuring Polyamine Side Chains On the Lactam Nitrogen." Journal of Medicinal Chemistry, vol. 46, no. 26, 2003, pp. 5712-24.
Nagarajan M, Xiao X, Antony S, et al. Design, synthesis, and biological evaluation of indenoisoquinoline topoisomerase I inhibitors featuring polyamine side chains on the lactam nitrogen. J Med Chem. 2003;46(26):5712-24.
Nagarajan, M., Xiao, X., Antony, S., Kohlhagen, G., Pommier, Y., & Cushman, M. (2003). Design, synthesis, and biological evaluation of indenoisoquinoline topoisomerase I inhibitors featuring polyamine side chains on the lactam nitrogen. Journal of Medicinal Chemistry, 46(26), 5712-24.
Nagarajan M, et al. Design, Synthesis, and Biological Evaluation of Indenoisoquinoline Topoisomerase I Inhibitors Featuring Polyamine Side Chains On the Lactam Nitrogen. J Med Chem. 2003 Dec 18;46(26):5712-24. PubMed PMID: 14667224.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis, and biological evaluation of indenoisoquinoline topoisomerase I inhibitors featuring polyamine side chains on the lactam nitrogen. AU - Nagarajan,Muthukaman, AU - Xiao,Xiangshu, AU - Antony,Smitha, AU - Kohlhagen,Glenda, AU - Pommier,Yves, AU - Cushman,Mark, PY - 2003/12/12/pubmed PY - 2004/1/21/medline PY - 2003/12/12/entrez SP - 5712 EP - 24 JF - Journal of medicinal chemistry JO - J Med Chem VL - 46 IS - 26 N2 - The indenoisoquinolines are a class of noncamptothecin topoisomerase I inhibitors that display significant cytotoxicity in human cancer cell cultures. They offer a number of potential advantages over the camptothecins, including greater chemical stability, formation of more persistent cleavage complexes, and induction of a unique pattern of DNA cleavage sites. Molecular modeling has suggested that substituents on the indenoisoquinoline lactam nitrogen would protrude out of the DNA duplex in the ternary cleavage complex through the major groove. This indicates that relatively large substituents in that location would be tolerated without compromising biological activity. As a strategy for increasing the potencies and potential therapeutic usefulness of the indenoisoquinolines, a series of compounds was synthesized containing polyamine side chains on the lactam nitrogen. The rationale for the synthesis of these compounds was that the positively charged ammonium cations would increase DNA affinity through electrostatic binding to the negatively charged DNA backbone, and the polyamines might also facilitate cellular uptake by utilization of polyamine transporters. The key step in the synthesis involved the condensation of Schiff bases, containing protected amine side chains, with substituted homophthalic anhydrides, to afford cis-3-aryl-4-carboxy-1-isoquinolones. These isoquinolones were then converted to indenoisoquinolines with thionyl chloride. Although monoamines were much more potent than the lead compound, no significant increase in potency was observed through incorporation of additional amino groups in the side chain. However, one of the monoamine analogues, which features a bis(2-hydroxyethyl)amino group in the side chain, proved to be one of the most cytotoxic indenoisoquinoline synthesized to date, with a GI50 mean-graph midpoint (MGM) of 0.07 microM in the NIH human cancer cell culture screen, and topoisomerase I inhibitory activity comparable to that of camptothecin. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/14667224/Design_synthesis_and_biological_evaluation_of_indenoisoquinoline_topoisomerase_I_inhibitors_featuring_polyamine_side_chains_on_the_lactam_nitrogen_ L2 - https://doi.org/10.1021/jm030313f DB - PRIME DP - Unbound Medicine ER -