Inversion of the cis geometry requirement for cytotoxicity in structurally novel platinum(II) complexes containing...

Water soluble platinum(II) complexes have been synthesized that contain the N,O-chelate pyridin-2-yl acetate (PyAc) as a novel structural motif in platinum antitumor complexes. The trans-platinum complex trans-[PtCl(PyAc-N,O)(NH3)] (2) (N-donors are trans) and its isomer cis-[PtCl(PyAc-N,O)(NH3)] (4) (N trans to Cl) were prepared from trans-[PtCl2((NH3)(PyAcH)].H2O (1.H2O) and cis-[PtCl2(NH3)(PyAcMe) (3), respectively, employing the bidentate ligand as its methylester (PyAcMe). 2 and 4 are readily formed from the respective dichloro species, even at low pH and in the presence of extra chloride, indicating a high thermodynamic stability of the PyAc chelate ring. 1.H2O and 2-4 were characterized by 1H NMR and IR spectroscopy and elemental analyses. The solid-state structure of 2 was determined: triclinic, P1 (no. 2), with a = 8.170(2) A, b = 9.274(3) A, c = 7.374(2) A, alpha = 108.68(2) degrees, beta = 113.27(2) degrees, gamma = 74.40(2) degrees, V = 479.7(6) A3, Z = 2. The six-membered metallacyclus in 2 adopts a "boat" form, allowing a strainless coordination of platinum. The most promising cytotoxic properties in the above series of compounds have been established for 2 (and 1, which rapidly transforms into 2 at 37 degrees C and neutral pH). Preliminary ID50 values were 0.88 and 1.26 microM, respectively, in cisplatin-sensitive L1210 leukemia. Both compounds proved to be cross-resistant to the clinical drug. Reactions of 2 and 4 with 5'-guanosine monophosphate (5'-GMP) under physiological conditions gave the monofunctional adducts trans- and cis-[Pt(5'-GMP-N7)(PyAc-N,O)(NH3)] (I and II). Chelate-bound carboxylate was not replaced by guanine-N7 when an excess of nucleotide was applied (NMR). In an analogous reaction, 2 reacts with the oligonucleotide d(TCGT) [5'-T(1)-C(2)-G(3)-T(4)-3'] to give the adduct d(TCGT)-N7(3)-Pt(PyAc-O,N)(NH3) (III), which was characterized by a combination of total correlation spectroscopy, double-quantum-filtered correlation spectroscopy, nuclear Overhauser effect spectrometry, and rotating-frame Overhauser enhancement spectroscopy experiments. Binding of the [Pt(PyAc-N,O)(NH3)]+ fragment to N7 of G(3) causes an increase of N-type character of the T(4) and G(3) deoxyribose residues relative to the unplatinated sequence, while those of T(1) and C(2) remain S-type. An internucleotide nuclear Overhauser effect between H6(4) and H2'(3) indicates stacking between guanine and the 3'-thymine base. The most striking feature proved to be the pronounced upfield shift and broadening of the 1H NMR signals assigned to the base protons H5 and H6 in III. Magnetization transfer between H5(2) and H3 of pyridine suggests that this effect is caused by base-base interactions involving the planar ligand on platinum, which must be situated on the 5' face of guanine. Possible implications for the DNA binding and cytotoxic effect of the compounds are discussed.