PMID: 11606119Oct 19, 2001Paper

Aziridinyl quinone antitumor agents based on indoles and cyclopent[b]indoles: structure-activity relationships for cytotoxicity and antitumor activity

Journal of Medicinal Chemistry
E B SkiboR T Dorr

Abstract

A large number of aziridinyl quinones represented by series 1-9 were studied with respect to their DT-diaphorase substrate activity, DNA reductive alkylation, cytostatic/cytotoxic activity, and in vivo activity. As a result, generalizations have been made with respect with respect to the following: DT-diaphorase substrate design, DT-diaphorase-cytotoxicity quantitative structure-activity relationship (QSAR), and DNA reductive alkylating agent design. A saturating relationship exists between the substrate specificity for human recombinant DT-diaphorase and the cytotoxicity in the human H460 non-small-cell lung cancer cell line. The interpretation of this relationship is that reductive activation is no longer rate-limiting for substrates with high DT-diaphorase substrate specificities. High DT-diaphorase substrate specificity is not desirable in the indole and cylopent[b]indole systems because of the result is the loss of cancer selectivity along with increased toxicity. We conclude that aziridinyl quinones of this type should possess a substrate specificity (V(max)/K(M)) < 10 x 10(-4) s(-1) for DT-diaphorase in order not to be too toxic or nonselective. While some DNA alkylation was required for cytostatic and cytotoxic activity...Continue Reading

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Citations

Aug 28, 2003·Bioorganic & Medicinal Chemistry Letters·Robert HargreavesEdward B Skibo
Sep 13, 2013·Anti-cancer Drugs·Wen-Tai LiChiung-Tong Chen
Aug 30, 2011·The Annals of Thoracic Surgery·Yunge ZhaoChristine L Lau
Oct 13, 2015·European Journal of Medicinal Chemistry·Chih-Wei FuWen-Shan Li
Jul 11, 2012·Journal of Peptide Science : an Official Publication of the European Peptide Society·R Suhas, D Channe Gowda
Jan 3, 2013·Journal of Mass Spectrometry : JMS·Ricardo VessecchiNorberto P Lopes
Dec 16, 2004·Bioorganic & Medicinal Chemistry·Daniel V Labarbera, Edward B Skibo
Apr 19, 2016·European Journal of Medicinal Chemistry·K Jones M SwapnajaKiran Kumar Sriram
Jun 7, 2018·Anais Da Academia Brasileira De Ciências·Débora O FuturoVitor Francisco Ferreira
Oct 30, 2007·ChemMedChem·Felix KratzAndré Warnecke
Sep 15, 2010·Organic & Biomolecular Chemistry·Vitor Francisco FerreiraFernando de Carvalho da Silva
Jul 1, 2018·Pharmaceutical Research·Alexander L PerrymanJoel S Freundlich
Mar 28, 2008·Journal of Medicinal Chemistry·Robert H J HargreavesEdward B Skibo
Jul 3, 2010·Journal of Combinatorial Chemistry·Tao ChenShun-Jun Ji

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