G-G base-pairing in nucleobase adducts of the anticancer drug cis-[PtCl2(NH3)(2-picoline)] and its trans isomer.
cis-[PtCl2(NH3)(2-picoline)] (AMD473) is a sterically-hindered anticancer complex with a profile of chemical and biological activity that differs significantly from that of cisplatin. Adducts of AMD473 with neutral 9-ethylguanine (9-EtGH) and anionic (N1-deprotonated) 9-ethylguanine (9-EtG) as perchlorate and nitrate salts, and also a nitrate salt of the trans isomer (AMD443), were prepared and their structures determined by X-ray crystallography: cis-[Pt(NH3)(2-pic)(9-EtGH)2](ClO4)2 (1).2H(2)OMe(2)CO, cis-[Pt(NH3)(2-pic)(9-EtGH)2](NO3)2 (2).2H2O, cis-[Pt(NH3)(2-pic)(9-EtGH)(9-EtG)]NO3 (3),3.5 H2O, trans-[Pt(NH3)(2-pic)(9-EtGH)(9-EtG)]NO3 (4).8H2O. In all cases, platinum coordination is through N7 of neutral (1, 2) and anionic (3, 4) guanine. In each complex, the guanine bases are arranged in the head-to-tail conformation. In complex 1, there is an infinite array of six-molecule cycles, based on both hydrogen bonding and pi-pi stacking of the 2-picoline and guanine rings. Platinum(II) coordinated at N7 acidifies the N1 proton of neutral 9-ethylguanine (pKa = 9.57) to give pKa1 = 8.40 and pKa2 = 8.75 for complex 2, and pKa1 = 7.77 and pKa2 = 9.00 for complex 4. In complexes 3 and 4, three intermolecular hydrogen bonds are formed between neutral and deprotonated guanine ligands involving O6, N1 and N2 sites. Unusually, both of the platinated guanine bases of complexes 3 and 4 participate in this triple G triple bond G hydrogen bonding. This is the first report of X-ray crystal structures of nucleobase adducts of the promising anticancer drug AMD473.
McGowan
Geraldine
G
School of Chemistry, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JJ, UK.
Parsons
Simon
S
Sadler
Peter J
PJ
D000970:Antineoplastic Agents / Q000737:chemistry*; D020029:Base Pairing; D018360:Crystallography, X-Ray; D018736:DNA Adducts / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D017671:Platinum Compounds / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization
D000970:Antineoplastic Agents; D018736:DNA Adducts; D017671:Platinum Compounds; D006147:Guanine