Studies on the Reaction Products of Antitumor Platinum Complex with d(ApG), d(GpA), and d(pGpA). 2′-Deoxy Sugar Is Favourable for G-N7, A-N1 Chelation

The reaction products of dichloro[(1R,2R)-1,2-cyclohexanediamine]platinum(II), Pt(R,R-dach)Cl2, with dinucleotides, d(ApG), d(GpA), and d(pGpA) have been separated by HPLC, and each product fractionated has been characterized by UV and CD spectral analyses. The reaction of Pt(R,R-dach)Cl2 with d(ApG) yields Pt(R,R-daich)(d(ApG)-N1(1),N7(2)) (1, 16%), Pt(R,R-dach)(d(ApG)-N7(1),N7(2)) (2, 80%) and uncharacterized minor product (4%). The reaction with d(GpA) yielded two Pt(R,R-dach)(d(GpA)-N7(1),N1(2)), (3, 22% and 5, 61%), and Pt(R,R-dach)(d(GpA)-N7(1),N7(2)), (4, 17%), but surprisingly 5 isomerizes very slowly to 3 and 4 under the subsequent incubation (half life of 5; about 6 days at 37 °C). The reverse reaction (3 and 4→5) was not observed. The reaction with d(pGpA) also yielded two Pt(R,R-dach)(d(pGpA)-N7(1),N1(2)), (3′, 8% and 5′, 80%) and Pt(R,R-dach)(d(pGpA)-N7(1),N7(2)), (4′, 12%). The adduct, 5′, also isomerizes to 3′ and 4′. The platinum adducts, 3′, 4′, and 5′, are compatible with 3,4, and 5, respectively, after removal of the 5′-phosphate group upon treatment with alkaline phosphatase. A competition reaction between d(ApG) and d(GpA) for Pt(R,R-dach)Cl2 indicates that d(ApG) was about 2 times more reactive than d(GpA). The reactivity decreases along the series; d(pGpA)>d(ApG)>d(GpA).