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Novel autoxidative cleavage reaction of 9-fluoredenes discovered during synthesis of a potential DNA-threading indenoisoquinoline.
J Org Chem. 2004 Oct 29; 69(22):7495-501.JO

Abstract

The indenoisoquinolines are a novel class of cytotoxic non-camptothecin topoisomerase I inhibitors. A potential DNA-threading agent was designed by attaching different amine side chains on the lactam nitrogen as well as on the C11 position of the indenoisoquinoline ring system. It was hypothesized that substituents on the lactam nitrogen could protrude out toward the DNA major groove while those on the C11 project out toward the DNA minor groove in the ternary "cleavage complex." Compound 4 was synthesized in order to test this DNA-threading scenario. It was found unexpectedly that an alkenyl substituent on the C11 position was autoxidatively cleaved under basic conditions to afford a ketone. A possible mechanism for this unusual oxidative cleavage was proposed on the basis of the studies of a 9-fluoredene model compound. The proposed mechanism was further supported by computational studies. Although the designed compound 4 showed potent cytotoxicities in various cancer cell lines, it was less potent than its nonthreading counterparts and was not a topoisomerase I inhibitor.

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 available

Pub Type(s)

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

Language

eng

PubMed ID

15497974

Citation

Xiao, Xiangshu, et al. "Novel Autoxidative Cleavage Reaction of 9-fluoredenes Discovered During Synthesis of a Potential DNA-threading Indenoisoquinoline." The Journal of Organic Chemistry, vol. 69, no. 22, 2004, pp. 7495-501.
Xiao X, Antony S, Kohlhagen G, et al. Novel autoxidative cleavage reaction of 9-fluoredenes discovered during synthesis of a potential DNA-threading indenoisoquinoline. J Org Chem. 2004;69(22):7495-501.
Xiao, X., Antony, S., Kohlhagen, G., Pommier, Y., & Cushman, M. (2004). Novel autoxidative cleavage reaction of 9-fluoredenes discovered during synthesis of a potential DNA-threading indenoisoquinoline. The Journal of Organic Chemistry, 69(22), 7495-501.
Xiao X, et al. Novel Autoxidative Cleavage Reaction of 9-fluoredenes Discovered During Synthesis of a Potential DNA-threading Indenoisoquinoline. J Org Chem. 2004 Oct 29;69(22):7495-501. PubMed PMID: 15497974.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel autoxidative cleavage reaction of 9-fluoredenes discovered during synthesis of a potential DNA-threading indenoisoquinoline. AU - Xiao,Xiangshu, AU - Antony,Smitha, AU - Kohlhagen,Glenda, AU - Pommier,Yves, AU - Cushman,Mark, PY - 2004/10/23/pubmed PY - 2004/12/16/medline PY - 2004/10/23/entrez SP - 7495 EP - 501 JF - The Journal of organic chemistry JO - J Org Chem VL - 69 IS - 22 N2 - The indenoisoquinolines are a novel class of cytotoxic non-camptothecin topoisomerase I inhibitors. A potential DNA-threading agent was designed by attaching different amine side chains on the lactam nitrogen as well as on the C11 position of the indenoisoquinoline ring system. It was hypothesized that substituents on the lactam nitrogen could protrude out toward the DNA major groove while those on the C11 project out toward the DNA minor groove in the ternary "cleavage complex." Compound 4 was synthesized in order to test this DNA-threading scenario. It was found unexpectedly that an alkenyl substituent on the C11 position was autoxidatively cleaved under basic conditions to afford a ketone. A possible mechanism for this unusual oxidative cleavage was proposed on the basis of the studies of a 9-fluoredene model compound. The proposed mechanism was further supported by computational studies. Although the designed compound 4 showed potent cytotoxicities in various cancer cell lines, it was less potent than its nonthreading counterparts and was not a topoisomerase I inhibitor. SN - 0022-3263 UR - https://www.unboundmedicine.com/medline/citation/15497974/Novel_autoxidative_cleavage_reaction_of_9_fluoredenes_discovered_during_synthesis_of_a_potential_DNA_threading_indenoisoquinoline_ L2 - https://doi.org/10.1021/jo048808f DB - PRIME DP - Unbound Medicine ER -