Deoxyribonucleic Acid Cleavage Specificity of a Series of Acridine— and Acodazole-Iron Porphyrins as Functional Bleomycin Modelse

J. William Lown, Sham M. Sondhi, Chi Wi Ong, Andrew Skorobogaty, Hiroko Kishikawa, James C. Dabrowiak

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

A series of metalloporphyrins linked through basic chains to certain DNA interactive groups has been synthesized. Several of these agents reproduce the characteristic properties of the antitumor glycopeptide bleomycin, including the oxygen-mediated scission of DNA in the presence of thiols, antitiobic activity under aerobic conditions, and activity against human and animal tumor models. Initial screening by scission of PM2-CCC-DNA identified six of the compounds, including those bearing acridine and acodazole intercalating groups, as the most active. The specificity of the oxygen-mediated scission of a 139 base pair HindIII/NciI restriction fragment of pBR322 by these six selected agents was then determined and compared with the action of pancreatic DNase by densitometric scans. All six of these compounds produce uniform base and sequence neutral cleavage of the restriction fragment at each base site. The six active compounds bear either of two types of intercalators, 6-chloro-2-methoxyacridine or acodazole, and with linkages to the ferric binding domain of-NH(CH2)2-, -NH(CH2)3-, -NH(CH2)4- or -NH(CH2)3NH(CH2)3- and either porphyrin or deuteroporphyrin moieties. Comparison of the Kassoc values for binding to calf thymus DNA suggests that the enhanced binding observed with the linker -NH(CH2)3NH(CH2)3-contributes to the efficiency of sequence neutral DNA scission and may be a factor in the relative anticancer activities of these agents. The iron porphyrins give no evidence of the production of base propenals in DNA degradation, and the autoradiograms clearly indicate that a phosphate group is attached to the 5' end of the oligomer. The scission is partially suppressible by catalase and superoxide dismutase. These properties are in contrast to the behavior of bleomycin and suggest a mechanism of action that differs in details from that of the glycopeptide. The smooth and efficient sequence neutral scission of DNA by the metalloporphyrins suggests their application to footprinting procedures.

Original languageEnglish (US)
Pages (from-to)5111-5117
Number of pages7
JournalBiochemistry
Volume25
Issue number18
DOIs
StatePublished - Sep 1986

ASJC Scopus subject areas

  • Biochemistry

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    Lown, J. W., Sondhi, S. M., Ong, C. W., Skorobogaty, A., Kishikawa, H., & Dabrowiak, J. C. (1986). Deoxyribonucleic Acid Cleavage Specificity of a Series of Acridine— and Acodazole-Iron Porphyrins as Functional Bleomycin Modelse. Biochemistry, 25(18), 5111-5117. https://doi.org/10.1021/bi00366a020