Design of cancer-specific antitumor agents based on aziridinylcyclopent[b]indoloquinones

Chengguo Xing, Ping Wu, Edward B. Skibo, Robert T Dorr

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The merits of N-unsubstituted indoles and cyclopent[b]indoles as DNA- directed reductive alkylating agents are described. These systems represent a departure from N-substituted and pyrrolo[1,2-a]-fused systems such as the mitomycins and mitosenes. The cyclopent[b]indole-based aziridinylquinone system, when bearing an acetate leaving group with or without an N-acetyl group, was cytotoxic and displayed significant in vivo activity against syngeneic tumor implants. These analogues were superior to the others studied in terms of both high specificity for the activating enzyme DT-diaphorase and high percent DNA alkylation. Alkylation by a quinone methide intermediate as well as by the aziridinyl group could lead to cross-linking. The possible metabolites of the most active indole species were prepared and found to retain cytotoxicity, suggesting that in vivo activity could be sustained. The indole systems in the present study display selectivity for melanoma and, depending on the substituents present, selectivity for non-small-cell lung, colon, renal, and prostate cancers. The cancer specificities observed are believed to pertain to differential substrate specificities for DT- diaphorase.

Original languageEnglish (US)
Pages (from-to)457-466
Number of pages10
JournalJournal of Medicinal Chemistry
Volume43
Issue number3
DOIs
StatePublished - Feb 10 2000

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Indolequinones
Antineoplastic Agents
NAD(P)H Dehydrogenase (Quinone)
Indoles
Alkylation
Mitomycins
Bearings (structural)
Neoplasms
Kidney Neoplasms
Alkylating Agents
DNA
Cytotoxicity
Metabolites
Substrate Specificity
Non-Small Cell Lung Carcinoma
Colonic Neoplasms
Tumors
Melanoma
Prostatic Neoplasms
Acetates

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Design of cancer-specific antitumor agents based on aziridinylcyclopent[b]indoloquinones. / Xing, Chengguo; Wu, Ping; Skibo, Edward B.; Dorr, Robert T.

In: Journal of Medicinal Chemistry, Vol. 43, No. 3, 10.02.2000, p. 457-466.

Research output: Contribution to journalArticle

Xing, Chengguo ; Wu, Ping ; Skibo, Edward B. ; Dorr, Robert T. / Design of cancer-specific antitumor agents based on aziridinylcyclopent[b]indoloquinones. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 3. pp. 457-466.
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