REACTION-PRODUCTS OF [PT(ETHYLENEDIAMINE)(DIMETHYL SULFOXIDE)CL]CL AND [PT(ETHYLENEDIAMINE)CL2] WITH D(GPG) AND 5'GMP - UNAMBIGUOUS EVIDENCE FOR STABLE 1-1 INTERMEDIATE N7 ADDUCTS WITH COORDINATED DIMETHYL-SULFOXIDE

The reactions of [Pt(en)(Me2SO)Cl]Cl, [Pt(en)(Me2SO)(D2O)](NO3)2, [Pt(en)(Cl2], and [Pt(en)(D2O)2](NO3)2 with d(GpG) and with 5'GMP have been investigated by H-1 magnetic resonance spectroscopy (en = ethylenediamine; Me2SO = dimethyl sulfoxide). [Pt(en)(Me2SO)X] (X = D2O, Cl-) and 5'GMP form an intermediate product [Pt(en)(Me2SO)(5'GMP-N7)] (1), which consists of two rotamers 1a and 1b, the interconversion of which is slow on the NMR time scale at 294 K. The ratio 1a:1b shifts from 2.0 at pH 5 to 1.2 at pH 11, as a result of the dehydronation at the guanine N1 atom. 1 may react further with a second equivalent of 5'GMP, forming [Pt(en)(5'GMP-N7)2] (2) and free Me2SO. When reacted with d(GpG), [Pt(en)(Me2SO)X] (X = D2O, Cl-) forms two intermediate products [Pt(en)(Me2SO){d(GpG)-N7(1)}] (5) and [Pt(en)(Me2SO){d(GpG)-N7(2)}] (6) with a ratio of 70:30. Both 5 and 6 react further, each forming the chelate [Pt(en){d(GpG)-N7(1),N7(2)}] (7) and free Me2SO. Both 5 and 6 consist of two rotamers (5a,b;6a,b), the interconversion of which occurs at an intermediate rate on the NMR time scale at 294 K. Also, [Pt(en)X2] (X = D2O, Cl-) reacts with 5'GMP and d(GpG), forming respectively 2 and 7. For the corresponding 1:1 intermediates [Pt(en)(D2O)(5'GMP-N7)] (3), [Pt(en)Cl(5'GMP-N7)] (4), [Pt(en)Cl{d(GpG-N7(1)}] (8), and [Pt(en)Cl{d(GpG)-N7(2)}] (9), no rotamers were found at room temperature, which is rationalized by the smaller size of Cl- and D2O compared to Me2SO. The overall reactions of [Pt(en)Cl2] with the guanine fragments are about a factor of 4-5 faster, compared to those of [Pt(en)(Me2SO)Cl]Cl. These results indicate that for [Pt(en)(Me2SO)Cl]Cl similar DNA adducts are formed as compared to the case of the well-known antitumor-active agents, like [cis-Pt(NH3)2Cl2], and therefore the mechanism of action of both types of compounds might well be related to each other.