Alkylation of DNA by C-10 of 2,7-diaminomitosene

Bhashyam S. Iyengar, Robert T. Dorr, Robert T Dorr, William A. Remers

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Mitomycin C and certain analogues alkylate DNA with their C-1 position and cross-link it by a second alkylation involving C-10. We now show that monoalkylation by C-10 (carbamate group) can occur for mitosene analogues that have no reactive C-1 functionality. Sodium dithionite reduction of 2,7-diaminomitosene or 2,7-diamino-1-hydroxymitosene in the presence of calf thymus DNA resulted in alkylation of the DNA to the extent of one molecule per 14 and 11 bases, respectively, although no covalent binding was observed on catalytic reduction. Reduction of each of these mitosenes by sodium dithionite in the presence of 2′-deoxyguanosine gave monoalkylation on the 2-amino group of this nucleotide. The 2,7-diaminomitosenes inhibited L-1210 leukemia cell colony formation in vitro at concentrations 3-4-fold greater (less potent) than mitomycin C. DNA single-strand breaks were also produced by each mitosene, but these lesions did not correlate with cytotoxicity and were less prominent than breaks produced by another monofunctional alkylating agent, methyl methanesulfonate. Mitosene-induced DNA strand breaks are probably due to excission-repair endonuclease activity and not from oxygen free radicals produced by redox cycling of the quinone moiety. There was no evidence of DNA-DNA cross-links by either 2,7-diaminomitosene.

Original languageEnglish (US)
Pages (from-to)253-257
Number of pages5
JournalJournal of Medicinal Chemistry
Volume33
Issue number1
StatePublished - 1990
Externally publishedYes

Fingerprint

Alkylation
Dithionite
DNA
Mitomycin
Methyl Methanesulfonate
Leukemia L1210
Single-Stranded DNA Breaks
Deoxyguanosine
DNA Breaks
Carbamates
Endonucleases
Alkylating Agents
Oxidation-Reduction
Free Radicals
Reactive Oxygen Species
Nucleotides
Cytotoxicity
2,7-diaminomitosene
Repair
Oxygen

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Iyengar, B. S., Dorr, R. T., Dorr, R. T., & Remers, W. A. (1990). Alkylation of DNA by C-10 of 2,7-diaminomitosene. Journal of Medicinal Chemistry, 33(1), 253-257.

Alkylation of DNA by C-10 of 2,7-diaminomitosene. / Iyengar, Bhashyam S.; Dorr, Robert T.; Dorr, Robert T; Remers, William A.

In: Journal of Medicinal Chemistry, Vol. 33, No. 1, 1990, p. 253-257.

Research output: Contribution to journalArticle

Iyengar, BS, Dorr, RT, Dorr, RT & Remers, WA 1990, 'Alkylation of DNA by C-10 of 2,7-diaminomitosene', Journal of Medicinal Chemistry, vol. 33, no. 1, pp. 253-257.
Iyengar, Bhashyam S. ; Dorr, Robert T. ; Dorr, Robert T ; Remers, William A. / Alkylation of DNA by C-10 of 2,7-diaminomitosene. In: Journal of Medicinal Chemistry. 1990 ; Vol. 33, No. 1. pp. 253-257.
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