No abstract

A model compound of the second most abundant DNA adduct of the antitumor agent cisplatin has been synthesized and structurally and spectroscopically characterized and its conformational behavior examined: cis-[(NH(3))(2)Pt(9-MeA-N7)(9-EtGH-N7)](NO(3))(2).2H(2)O (9-MeA = 9-methyladenine; 9-EtGH = 9-ethylguanine) crystallizes in the monoclinic system, space group P2(1)/n (No. 14) with a = 7.931(2), b = 11.035(3), c = 26.757(6) Å, beta = 94.94(2) degrees, and Z = 4. The two purine bases adopt a head-to-head orientation, with NH(2) of 9-MeA and CO of 9-EtGH being at the same side of the Pt coordination plane. A theoretical conformational analysis of the complex cis-[(NH(3))(2)Pt(Ade)(Gua)](2+) (Ade = adenine; Gua = guanine) based on molecular mechanics calculations of the nonbonded energy has revealed four minimum-energy zones similar to those derived previously for cis-[(NH(3))(2)Pt(Gua)(2)](2+) (Kozelka; et al. Eur. J. Biochem. 1992, 205, 895). This conformational analysis has allowed, together with the calculation of chemical shifts due to ring effects, the attribution of the two conformers observed for cis-[(NH(3))(2)Pt{d(ApG)}](+) by Dijt et al. (Eur. J. Biochem. 1989, 179, 344) to the two head-to-head conformational zones. The orientation of the two nucleobases in the crystal structure of cis-[(NH(3))(2)Pt(9-MeA)(9-EtGH)](2+) corresponds, according to our analysis, roughly to that preferentially assumed by the minor rotamer of cis-[(NH(3))(2)Pt{d(ApG)}](+).

The counterions X in cis-[Pt(NH3)2(9-MeA-N7)(9-EtGH-N7)]X2 (1) determine, in the solid state, which of the possible orientations the two purine nucleobases display. With X = PF6 -, the right-handed helicoidal head−head conformation R2 encountered in double-stranded oligonucleotide adducts of cis-Pt(NH3)2 2+ is realized, together with its enantiomeric counterpart L2. 1 therefore provides a model of the d(ApG) intrastrand adduct of cisplatin with double-stranded DNA. H-bond formation between the platinated guanine in 1 and 1-methylcytosine in DMSO-d 6 is not strictly analogous to that between the Watson−Crick pair of free 9-EtGH and 1-MeC.

No abstract