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Design, synthesis, and biological evaluation of cytotoxic 11-alkenylindenoisoquinoline topoisomerase I inhibitors and indenoisoquinoline-camptothecin hybrids.
J Med Chem. 2003 Jul 17; 46(15):3275-82.JM

Abstract

The indenoisoquinolines are a novel class of topoisomerase I (top1) inhibitors that are cytotoxic in cancer cell cultures and are therefore under development as potential anticancer agents. As inhibitors of the DNA religation reaction occurring after DNA cleavage by the enzyme, they are classified as top1 poisons, similar to the camptothecins. Two strategies were employed in order to further develop the structure-activity relationships of the indenoisoquinolines and enhance their therapeutic potential. The first strategy involved the synthesis of indenoisoquinoline-camptothecin hybrid molecules to take advantage of a proposed structural analogy between the indenoisoquinolines and camptothecin. The desired hybrids were synthesized by reaction of halogenated phthalides with a dihydropyrroloquinoline. The second strategy involved the attachment of various alkenyl substituents to the C-11 position of the indenoisoquinolines, which were assumed to project into the DNA minor groove. The required C-11-substituted indenoisoquinolines were synthesized by McMurry reactions of 11-ketoindenoisoquinolines with aldehydes, and the geometries of the resulting alkenes were established by nuclear Overhauser effect difference NMR spectroscopy. All of the new indenoisoquinolines were examined for cytotoxicity in human cancer cell cultures as well as for activity vs top1. Although the indenoisoquinoline-camptothecin hybrid molecules proved to be less cytotoxic and displayed less activity against top1, an analogue incorporating a 3'-aminoalkenyl substituent at the C-11 position of the indenoisoquinoline system was significantly more potent than the prototype indenoisoquinoline in both assays. These results indicate that C-11 aminoalkyl substituents that are assumed to project into the minor groove enhance the cytotoxicity and top1 inhibitory activity of the parent indenoisoquinoline system.

Authors+Show Affiliations

Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.No 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, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12852757

Citation

Fox, Brian M., et al. "Design, Synthesis, and Biological Evaluation of Cytotoxic 11-alkenylindenoisoquinoline Topoisomerase I Inhibitors and Indenoisoquinoline-camptothecin Hybrids." Journal of Medicinal Chemistry, vol. 46, no. 15, 2003, pp. 3275-82.
Fox BM, Xiao X, Antony S, et al. Design, synthesis, and biological evaluation of cytotoxic 11-alkenylindenoisoquinoline topoisomerase I inhibitors and indenoisoquinoline-camptothecin hybrids. J Med Chem. 2003;46(15):3275-82.
Fox, B. M., Xiao, X., Antony, S., Kohlhagen, G., Pommier, Y., Staker, B. L., Stewart, L., & Cushman, M. (2003). Design, synthesis, and biological evaluation of cytotoxic 11-alkenylindenoisoquinoline topoisomerase I inhibitors and indenoisoquinoline-camptothecin hybrids. Journal of Medicinal Chemistry, 46(15), 3275-82.
Fox BM, et al. Design, Synthesis, and Biological Evaluation of Cytotoxic 11-alkenylindenoisoquinoline Topoisomerase I Inhibitors and Indenoisoquinoline-camptothecin Hybrids. J Med Chem. 2003 Jul 17;46(15):3275-82. PubMed PMID: 12852757.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, synthesis, and biological evaluation of cytotoxic 11-alkenylindenoisoquinoline topoisomerase I inhibitors and indenoisoquinoline-camptothecin hybrids. AU - Fox,Brian M, AU - Xiao,Xiangshu, AU - Antony,Smitha, AU - Kohlhagen,Glenda, AU - Pommier,Yves, AU - Staker,Bart L, AU - Stewart,Lance, AU - Cushman,Mark, PY - 2003/7/11/pubmed PY - 2003/8/19/medline PY - 2003/7/11/entrez SP - 3275 EP - 82 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 46 IS - 15 N2 - The indenoisoquinolines are a novel class of topoisomerase I (top1) inhibitors that are cytotoxic in cancer cell cultures and are therefore under development as potential anticancer agents. As inhibitors of the DNA religation reaction occurring after DNA cleavage by the enzyme, they are classified as top1 poisons, similar to the camptothecins. Two strategies were employed in order to further develop the structure-activity relationships of the indenoisoquinolines and enhance their therapeutic potential. The first strategy involved the synthesis of indenoisoquinoline-camptothecin hybrid molecules to take advantage of a proposed structural analogy between the indenoisoquinolines and camptothecin. The desired hybrids were synthesized by reaction of halogenated phthalides with a dihydropyrroloquinoline. The second strategy involved the attachment of various alkenyl substituents to the C-11 position of the indenoisoquinolines, which were assumed to project into the DNA minor groove. The required C-11-substituted indenoisoquinolines were synthesized by McMurry reactions of 11-ketoindenoisoquinolines with aldehydes, and the geometries of the resulting alkenes were established by nuclear Overhauser effect difference NMR spectroscopy. All of the new indenoisoquinolines were examined for cytotoxicity in human cancer cell cultures as well as for activity vs top1. Although the indenoisoquinoline-camptothecin hybrid molecules proved to be less cytotoxic and displayed less activity against top1, an analogue incorporating a 3'-aminoalkenyl substituent at the C-11 position of the indenoisoquinoline system was significantly more potent than the prototype indenoisoquinoline in both assays. These results indicate that C-11 aminoalkyl substituents that are assumed to project into the minor groove enhance the cytotoxicity and top1 inhibitory activity of the parent indenoisoquinoline system. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/12852757/Design_synthesis_and_biological_evaluation_of_cytotoxic_11_alkenylindenoisoquinoline_topoisomerase_I_inhibitors_and_indenoisoquinoline_camptothecin_hybrids_ L2 - https://dx.doi.org/10.1021/jm0300476 DB - PRIME DP - Unbound Medicine ER -