A spectroscopic investigation into the binding of novel platinum(IV) and platium(II) anticancer drugs with DNA

Abstract

Platinum(II) complexes have had enormous success in cancer chemotherapy and novel PtIV complexes show potential for reduced toxic side effects and different mechanisms of action. While the action of PtII anticancer drugs with DNA has been well characterized with X-ray and many spectroscopic modalities, the mechanisms of binding PtIV complexes to DNA require further fundamental studies. In the present work using ATR-FTIR spectroscopy, we have extensively analyzed conformational changes in both single-stranded (ss) and double-stranded (ds) calf-thymus DNA, after binding to the PtIV anticancer complex, [Pt{((p-HC6F4)NCH2)2}(py)2(OH)2] (py=pyridine) (Pt103(OH)2), and its PtII analogue, [Pt{((p-HC6F4)NCH2)2}(py)2] (Pt103) in buffered aqueous acetone (55% water), under which conditions no hydrolysis of drugs occurs. To aid in band assignments of the Pt derivatives, DFT calculations using the M062X/cc-pVDZ level of theory were performed. The ssDNA is distorted and its conformation changes more towards the A-like DNA of dsDNA upon binding to both Pt103 and Pt103(OH)2. This conclusion is derived from the changes in the PO2− symmetric stretching vibrations (1086 to 1093cm−1) and CO (1055 to 1062cm−1) and CC (968 to 965cm−1) stretching vibrations of the phosphodiester backbone. Unlike ssDNA, only Pt103 binding to dsDNA induces distortions along with a conformational change in dsDNA from a more B-DNA like form to the more compact and distorted A-DNA form. The results show that there is no apparent reduction of Pt103(OH)2. Moreover, we demonstrate that Pt103(OH)2 can directly bind to ssDNA without any prior reduction. This study provides new insights into how these novel PtII and PtIV complexes interact with DNA. These results may have implications relevant to the development of new anti-cancer agents.