Synthesis, structure, and reactivity of monofunctional platinum(II) and palladium(II) complexes containing the sterically hindered ligand 6-(methylpyridin-2-yl)acetate.
Three complexes containing the novel, sterically hindered ligand 6-(methylpyridin-2-yl)acetate (PICAC) have been synthesized and characterized: [Pt(NH3)2(PICAC-N,O)]NO3 (1), [Pt(en)(PICAC-N,O)]NO3 (2), and [Pd(en)(PICAC-N,O)]NO3 (3) (en = ethane-1,2-diamine). The crystal structures of 2 and 3 have been determined. The two complexes are isostructural and exhibit a mixed [N3O] coordination. In both cases, PICAC forms a sterically crowded six-membered chelate. Signal multiplicities in 1H NMR spectra of 1-3 indicate that the N,O chelates are conformationally rigid on the NMR timescale as a result of the steric bulk of the pyridine derivative. Complex 2 undergoes facile ring opening in 0.1M NaCl solution at neutral pH, resulting in a zwitterionic species in which carboxylate oxygen has been replaced with chloride. The complex was identified by X-ray crystallography as [PtCl(en)(PICAC-N)] x H2O (4), which contains a "dangling" carboxylate group. In 4, the pyridine moiety adopts an almost perpendicular orientation relative to the platinum coordination plane. Likewise, complex 2 reacts rapidly with 5'-guanosine monophosphate (5'-GMP) to form the monofunctional adduct [Pt(en)(PICAC)(5'-GMP)] (5) (NMR, 25 degrees C, t(1/2) approximately 24 min). 2-D nuclear Overhauser enhancement spectroscopy (NOESY) and double quantum-filtered correlated spectroscopy (dqf-COSY) experiments (500 MHz) and variable temperature NMR spectroscopy confirm that adduct 5 exists as a 1:1 mixture of rotamers in solution as a result of the mutual repulsion between the cis-oriented pyridine and guanine bases. While 2 readily reacts with DNA nitrogen, its monofunctional adducts show no significant effect on the conformation of native DNA. Circular dichroism (CD) spectra recorded of platinum-modified calf-thymus DNA suggest that the structural damage produced by complex 2 does not mimic that produced by the clinical agent. Both the unusual reactivity and the inability to induce cisplatin-like DNA conformational changes are proposed to be responsible for the marginal biological activity of the new complexes.
Ma
Yan
Y
Department of Chemistry, Wake Forest University, P.O. Box 7486, Reynolda Station, Winston-Salem, NC 27109, United States.
Day
Cynthia S
CS
Bierbach
Ulrich
U
D000085:Acetates / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D018736:DNA Adducts; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D010165:Palladium / Q000737:chemistry*; D017671:Platinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry*; D013329:Structure-Activity Relationship
C505744:6-(methylpyridin-2-yl)acetate; D000085:Acetates; D000970:Antineoplastic Agents; D018736:DNA Adducts; D008024:Ligands; D017671:Platinum Compounds; D011725:Pyridines; D010165:Palladium; D002945:Cisplatin