title: Aziridinyl quinone antitumor agents based on indoles and cyclopent[b]indoles: structure-activity relationships for cytotoxicity and antitumor activity.
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 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 3alpha-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.
authors.affiliation: Arizona Cancer Center, University of Arizona, Tucson, AZ 85721, USA. ESkibo@ASU.edu
authors.forename: E B
authors.initials: EB
authors.lastname: Skibo
authors.forename: C
authors.initials: C
authors.lastname: Xing
authors.forename: R T
authors.initials: RT
authors.lastname: Dorr
mesh_terms: D000478:Alkylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001388:Aziridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002417:Cattle; D004247:DNA / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D007211:Indoles; D004247:DNA; D016660:NAD(P)H Dehydrogenase (Quinone)