Inversion of the cis geometry requirement for cytotoxicity in structurallynovel 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 pla tinum 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 re spective dichloro species, even at low pH and in the presence of extra chlo ride, indicating a high thermodynamic stability of the PyAc chelate ring. 1 . H2O and 2-4 were characterized by H-1 NMR and IR spectroscopy and elemen tal analyses. The solid-state structure of 2 was determined: triclinic, P ( 1) over bar (no. 2), with a = 8.170(2) Angstrom, b = 9.274(3) Angstrom, c = 7.374(2) Angstrom, alpha = 108.58(2)degrees, beta = 113.27(2)degrees gamma = 74.40(2)degrees, V = 479.7(6) Angstrom(3) Z = 2. The six-membered I meta llacyclus in 2 adopts a "boat" form, allowing a strainless coordination of platinum. The most promising cytotoxic properties in the above series of co mpounds have been established for 2 land 1, which rapidly transforms into 2 at 37 degrees C and neutral pH). Preliminary ID50 values were 0.88 and 1.2 6 mu M, respectively, in cisplatin-sensitive L1210 leukemia. Both compounds proved to be cross-resistant to the clinical drug. Reactions of 2 and 4 wi th 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 a dduct cl(TCGT)-N7(3)-Pt(PyAc-O,N)(NH3) (III), which was characterized by a combination of total correlation spectroscopy, double-quantum-filtered corr elation spectroscopy, nuclear Overhauser effect spectrometry, and rotating- frame Overhauser enhancement spectroscopy experiments. Binding of the [Pt(P yAc-N,O)(NH3)](+) fragment to N7 of G(3) causes an increase of N-type chara cter 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 n uclear Overhauser effect between H6(4) and H2'(3) indicates stacking betwee n guanine and the 3'-thymine base. The most striking feature proved to be t he pronounced upfield shift and broadening of the H-1 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 interac tions involving the planar ligand on platinum, which must be situated on th e 5' face of guanine. Possible implications for the DNA binding and cytotox ic effect of the compounds are discussed.