Conformation and recognition of DNA damaged by antitumor cis-dichlorido platinum(II) complex of CDK inhibitor bohemine

• DNA damage by cis-[Pt(boh)2Cl2] (C1) (boh = CDK inhibitor, bohemine) is described.
• DNA binding of C1 and formation of cross-links are slower compared to cisplatin.
• Bifunctional adducts bend DNA less than cisplatin.
• DNA adducts of C1 efficiently block DNA polymerization and transcription.
• Reaction of C1 with glutathione is slower than that of cisplatin.

A substitution of the ammine ligands of cisplatin, cis-[Pt(NH3)2Cl2], for cyclin dependent kinase (CDK) inhibitor bohemine (boh), [2-(3-hydroxypropylamino)-6-benzylamino-9-isopropylpurine], results in a compound, cis-[Pt(boh)2Cl2] (C1), with the unique anticancer profile which may be associated with some features of the damaged DNA and/or its cellular processing (Travnicek Z et al. (2003) J Inorg Biochem94, 307–316; Liskova B (2012) Chem Res Toxicol25, 500–509). A combination of biochemical and molecular biology techniques was used to establish mechanistic differences between cisplatin and C1 with respect to the DNA damage they produce and their interactions with critical DNA-binding proteins, DNA-processing enzymes and glutathione. The results show that replacement of the NH3 groups in cisplatin by bohemine modulates some aspects of the mechanism of action of C1. More specifically, the results of the present work are consistent with the thesis that, in comparison with cisplatin, effects of other factors, such as: (i) slower rate of initial binding of C1 to DNA; (ii) the lower efficiency of C1 to form bifunctional adducts; (iii) the reduced bend of longitudinal DNA axis induced by the major 1,2-GG intrastrand cross-link of C1; (iv) the reduced affinity of HMG domain proteins to the major adduct of C1; (v) the enhanced efficiency of the DNA adducts of C1 to block DNA polymerization and to inhibit transcription activity of human RNA pol II and RNA transcription; (vi) slower rate of the reaction of C1 with glutathione, may partially contribute to the unique activity of C1.

Figure optionsDownload as PowerPoint slide