Modulation of the chemical and biological properties of trans platinum complexes: monofunctional platinum complexes containing one nucleobase as potential antiviral chemotypes.
Replacement of one of the chloride leaving groups in trans-[PtCl2(NH3)(L)] by the nucleobase 9-ethylguanine gives the nucleobase cations [SP-4-2]-[PtCl(9-ethylguanine)(NH3)(L)]+ (L = NH3, 1; L = quinoline, 3), which are models for the monofunctional adduct on DNA. Displacement of Cl- in 1 and 3 by either 5'-guanosine monophosphate (5'-GMP) or N-acetyl-L-methionine (N-AcMet) showed clear kinetic preference for the sulfur (estimated half-lives of 1.5 and 4 h with N-AcMet against 7 and 17 h for 5'-GMP for 1 and 3, respectively). To further examine the kinetic preference, 1-methylcytosine (1-MeCyt) analogs were prepared, [SP-4-2]-[PtCl(1-Me-Cyt)(NH3)(L)]+ (L=NH3, 2; L=quinoline, 4). The -MeCyt compounds, 2 and 4, resulted in slower rates of substitution by both 5'-GMP and N-AcMet in comparison to 1 and 3 (estimated half-lives for N-AcMet of 5 and 13.5 h and for 5'-GMP of 6 and 14 h for 2 and 4, respectively). Interestingly in this case, however, no selectivity for the sulfur site was observed, a possible explanation being that molecular recognition across the square plane enhances the rate of reaction with 5'-GMP. The affinity of 3 towards S-donor ligands was exploited to remove zinc from the zinc-finger site of the C-terminal finger of the HIV-nucleocapsid protein, NCp7. The ability to eject zinc further suggested the biological antiviral application of [SP-4-2]-[PtCl(nucleobase)(NH3)(L)]+. A preliminary survey against HIV and herpes viruses indeed showed encouraging results with some antiviral specificity, dependent on the exact nature of the compound. The initial results suggest consideration of [SP-4-2]-[PtCl(nucleobase)(NH3)(L)]+ as a novel antiviral chemotype.
Sartori
D A
DA
Department of Chemistry, Virginia Commonwealth University, Richmond 23284-2006, USA. nfarrell@saturn.vcu.edu
Miller
B
B
Biebach
U
U
Farrell
N
N
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology; D003596:Cytosine / Q000031:analogs & derivatives; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives; D006860:Hydrogen Bonding; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D017671:Platinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013696:Temperature; D013816:Thermodynamics; D016335:Zinc Fingers
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D018736:DNA Adducts; D017671:Platinum Compounds; D013438:Sulfhydryl Compounds; C034697:transplatin; D006147:Guanine; D003596:Cytosine; D002945:Cisplatin