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Design, synthesis, and biological evaluation of cytotoxic 11-aminoalkenylindenoisoquinoline and 11-diaminoalkenylindenoisoquinoline topoisomerase I inhibitors.
Bioorg Med Chem. 2004 Oct 01; 12(19):5147-60.BM

Abstract

The cytotoxic indenoisoquinolines are a novel class of noncamptothecin topoisomerase I inhibitors having certain features that compare favorably with the camptothecins. A new strategy was adopted to attach aminoalkenyl substituents at C-11 of the indenoisoquinoline ring system, which, according to molecular modeling, would orient the side chains toward the DNA minor groove. All of the newly synthesized compounds were more cytotoxic than the parent indenoisoquinoline NSC 314622. Despite an imperfect correlation between cytotoxicities and topoisomerase I inhibition results, the hypothetical structural model of the cleavage complex presented here provides a conceptual framework to explain the structure-activity relationships.

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Authors+Show Affiliations

Xiao X
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA.
Antony S
No affiliation info available
Kohlhagen G
No affiliation info available
Pommier Y
No affiliation info available
Cushman M
No affiliation info available

MeSH

Cell Line, TumorCell ProliferationDNADrug DesignEnzyme InhibitorsHumansIsoquinolinesModels, MolecularStructure-Activity RelationshipTopoisomerase I Inhibitors

Pub Type(s)

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

Language

eng

PubMed ID

15351398

Citation

Xiao, Xiangshu, et al. "Design, Synthesis, and Biological Evaluation of Cytotoxic 11-aminoalkenylindenoisoquinoline and 11-diaminoalkenylindenoisoquinoline Topoisomerase I Inhibitors." Bioorganic & Medicinal Chemistry, vol. 12, no. 19, 2004, pp. 5147-60.
Xiao X, Antony S, Kohlhagen G, et al. Design, synthesis, and biological evaluation of cytotoxic 11-aminoalkenylindenoisoquinoline and 11-diaminoalkenylindenoisoquinoline topoisomerase I inhibitors. Bioorg Med Chem. 2004;12(19):5147-60.
Xiao, X., Antony, S., Kohlhagen, G., Pommier, Y., & Cushman, M. (2004). Design, synthesis, and biological evaluation of cytotoxic 11-aminoalkenylindenoisoquinoline and 11-diaminoalkenylindenoisoquinoline topoisomerase I inhibitors. Bioorganic & Medicinal Chemistry, 12(19), 5147-60.
Xiao X, et al. Design, Synthesis, and Biological Evaluation of Cytotoxic 11-aminoalkenylindenoisoquinoline and 11-diaminoalkenylindenoisoquinoline Topoisomerase I Inhibitors. Bioorg Med Chem. 2004 Oct 1;12(19):5147-60. PubMed PMID: 15351398.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis, and biological evaluation of cytotoxic 11-aminoalkenylindenoisoquinoline and 11-diaminoalkenylindenoisoquinoline topoisomerase I inhibitors. AU - Xiao,Xiangshu, AU - Antony,Smitha, AU - Kohlhagen,Glenda, AU - Pommier,Yves, AU - Cushman,Mark, PY - 2004/06/15/received PY - 2004/07/13/revised PY - 2004/07/13/accepted PY - 2004/9/8/pubmed PY - 2005/4/19/medline PY - 2004/9/8/entrez SP - 5147 EP - 60 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 12 IS - 19 N2 - The cytotoxic indenoisoquinolines are a novel class of noncamptothecin topoisomerase I inhibitors having certain features that compare favorably with the camptothecins. A new strategy was adopted to attach aminoalkenyl substituents at C-11 of the indenoisoquinoline ring system, which, according to molecular modeling, would orient the side chains toward the DNA minor groove. All of the newly synthesized compounds were more cytotoxic than the parent indenoisoquinoline NSC 314622. Despite an imperfect correlation between cytotoxicities and topoisomerase I inhibition results, the hypothetical structural model of the cleavage complex presented here provides a conceptual framework to explain the structure-activity relationships. SN - 0968-0896 UR - https://www.unboundmedicine.com/medline/citation/15351398/Design_synthesis_and_biological_evaluation_of_cytotoxic_11_aminoalkenylindenoisoquinoline_and_11_diaminoalkenylindenoisoquinoline_topoisomerase_I_inhibitors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(04)00533-4 DB - PRIME DP - Unbound Medicine ER -