Inversion of the Cis Geometry Requirement for Cytotoxicity in Structurally Novel Platinum(II) Complexes Containing the Bidentate N,O-Donor Pyridin-2-yl-acetate.

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 from trans-[PtCl2((NH3)(PyAcH)]·H2O (1·H2O) and cis-[PtCl2(NH3)(PyAcMe) (3), respectively, the bidentate ligand as its methylester (PyAcMe). 2 and 4 are readily formed from the respective species, even at low pH and in the presence of extra chloride, indicating a high thermodynamic stability the PyAc chelate ring. 1·H2O and 2−4 were characterized by 1H NMR and IR spectroscopy and elemental. The solid-state structure of 2 was determined: triclinic, P1̄ (no. 2), with a = 8.170(2) Å, b = 9.274(3)Å, c = 7.374(2) Å, α = 108.68(2)°, β = 113.27(2)°, γ = 74.40(2)°, V = 479.7(6) Å3, Z = 2. The six-membered in 2 adopts a “boat” form, allowing a strainless coordination of platinum. The most promising properties in the above series of compounds have been established for 2 (and 1, which rapidly transforms 2 at 37 °C and neutral pH). Preliminary ID50 values were 0.88 and 1.26 μM, respectively, in cisplatin-sensitive L1210 leukemia. Both compounds proved to be cross-resistant to the clinical drug. Reactions of 2 and4 with 5‘-guanosine monophosphate (5‘-GMP) under physiological conditions gave the monofunctional adducts- and cis-[Pt(5‘-GMP-N7)(PyAc-N,O)(NH3)] (I and II). Chelate-bound carboxylate was not replaced by-N7 when an excess of nucleotide was applied (NMR). In an analogous reaction, 2 reacts with the 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), was characterized by a combination of total correlation spectroscopy, double-quantum-filtered correlation, nuclear Overhauser effect spectrometry, and rotating-frame Overhauser enhancement spectroscopy. Binding of the [Pt(PyAc-N,O)(NH3)]+ fragment to N7 of G(3) causes an increase of N-type character the T(4) and G(3) deoxyribose residues relative to the unplatinated sequence, while those of T(1) and C(2) S-type. An internucleotide nuclear Overhauser effect between H6(4) and H2‘(3) indicates stacking between and the 3‘-thymine base. The most striking feature proved to be the pronounced upfield shift and broadening the 1H NMR signals assigned to the base protons H5 and H6 in III. Magnetization transfer between H5(2) and3 of pyridine suggests that this effect is caused by base−base interactions involving the planar ligand on platinum, must be situated on the 5‘ face of guanine. Possible implications for the DNA binding and cytotoxic effect the compounds are discussed.