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

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• 作者：Edgardo T. Farinas ; Jennifer D. Tan ; and Pradip K. Mascharak
• 刊名：Inorganic Chemistry
• 出版年：1996
• 出版时间：April 24, 1996
• 年：1996
• 卷：35
• 期：9
• 页码：2637 - 2643
• 全文大小：293K
• 年卷期：v.35,no.9(April 24, 1996)
• ISSN：1520-510X

文摘

A 2,4'-bithiazole group has been covalently attached to theCo(III) complex of a designed ligand PMAH thatmimics the metal-binding locus of the antitumor drug bleomycin (BLM).The deprotonated PMA^- ligand bindsCo(III) via five nitrogens located in primary and secondaryamines, a pyrimidine and an imidazole ring, and apeptide moiety. The 2,4'-bithiazole group is tethered to the[Co(PMA)]²⁺ unit via an imidazole that isconnectedto 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 spectroscopictechniques. 7 promotes photocleavage of DNA atmicromolar concentrations. Unlike simpler analogueslike[Co(PMA)(H₂O)]²⁺ and[Co(PMA)Cl)]⁺ which induce random DNAcleavage upon UV illumination, 7 exhibitssequence specificity in the DNA photocleavage reaction. Intriguingis 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-propyl)imidazole) that contains an acridine moiety as theDNA-binding group. The observed sequence specificityof 6 and 7 therefore does not reflect thesequence preferences of the DNA-binding groups (acridine andbithiazole).The results indicate that the metalated core of the hybridanalogues, i.e., the [Co(PMA)]²⁺ unit is the keyfactorin determining their sequence specificity.