Photoinduced DNA Cleavage Reactions by Designed Analogues of Co(III)-Bleomycin: The Metalated Core Is the Primary Determinant of Sequence Specificity

Edgardo T. Farinas, Jennifer D. Tan, Pradip K. Mascharak

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25 Scopus citations

Abstract

A 2,4′-bithiazole group has been covalently attached to the Co(III) complex of a designed ligand PMAH that mimics the metal-binding locus of the antitumor drug bleomycin (BLM). The deprotonated PMA- ligand binds Co(III) via five nitrogens located in primary and secondary amines, a pyrimidine and an imidazole ring, and a peptide moiety. The 2,4′-bitbiazole group is tethered to the [Co(PMA)]2+ unit via an imidazole that is connected to the bithiazole moiety with a (CH2)3 spacer. The structure of this hybrid analogue, namely, [Co(PMA)(Bit)]Cl2 (7, Bit = 2′-methyl-2,4′-bithiazole-4-carboxamido-N'-(3-propyl)imidazole) has been established by spectroscopic techniques. 7 promotes photocleavage of DNA at micromolar concentrations. Unlike simpler analogues like [Co(PMA)(H2O)]2+ and [Co(PMA)Cl)]+ which induce random DNA cleavage upon UV illumination, 7 exhibits sequence specificity in the DNA photocleavage reaction. Intriguing is to note that 7 exhibits the same 5′GG-N3′ sequence preference as another hybrid analogue [Co(PMA)(Int-A)]Cl2 (6, Int-A = acridine-9-carboxamido-N'-(3-propyI)imidazoIe) that contains an acridine moiety as the DNA-binding group. The observed sequence specificity of 6 and 7 therefore does not reflect the sequence preferences of the DNA-binding groups (acridine and bithiazole). The results indicate that the metalated core of the hybrid analogues, i.e., the [Co(PMA)]2+ unit is the key factor, in determining their sequence specificity.

Original languageEnglish (US)
Pages (from-to)2637-2643
Number of pages7
JournalInorganic Chemistry
Volume35
Issue number9
DOIs
StatePublished - 1996
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physical and Theoretical Chemistry
  • Inorganic Chemistry

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