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

E. B. Skibo, C. Xing, R. T. Dorr

Research output: Contribution to journalArticle

86 Scopus citations

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 (Vmax/KM) < 10 × 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 by series 1-9, too much alkylation results in loss of cancer selectivity as well as increased in vivo toxicity. Indeed, the most lethal compounds are the indole systems with a leaving group in the 3α-position (like the antitumor agent EO9). We conclude that relatively poor DNA alkylating agents (according to our assay) show the lowest toxicity with the highest antitumor activity.

Original languageEnglish (US)
Pages (from-to)3545-3562
Number of pages18
JournalJournal of Medicinal Chemistry
Volume44
Issue number22
DOIs
StatePublished - Oct 25 2001

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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