Steric control of stereoselective interactions between the platinum(II) complex [PtCl2(1,4-diazacycloheptane)] and DNA: comparison with cis-[PtCl2(NH3)(2)] and [PtCl2(ethane-1,2-diamine)] using DNA binding and molecular modeling studies

The rate and extent of binding of [PtCl2(hpip)] (hpip =homopiperazine=1,4-d iazacycloheptane) and CiS-[PtCl2(NH3)(2)] to calf thymus DNA was measured u sing atomic absorption spectroscopy and it was found that [PtCl2(hpip)] bou nd both more rapidly and to a greater extent than did cis-[PtCl2(NH3)(2)]. The binding of [PtCl2(hpip)] and [PtCl2(en)] (en=ethane-1,2-diamine) to sal mon sperm DNA and to synthetic, self-complementary 10-base-pair and 52-base -pair oligonucleotides was studied using enzymatic digestion and HPLC analy sis of the products. [PtCl2(hpip)] forms approximately two-fold fewer GpG a nd ApG intrastrand adducts and concomitantly more monofunctional adducts th an does [PtCl2(en)]. In the case of [PtCl2(hpip)], two GpG adducts, corresp onding to the different orientations of the hpip ligand with respect to the DNA, were observed in a 1:3.3 ratio. The minor product corresponds to the orientation in which the bulkier propylene chain of the hpip ligand is adja cent to, and makes close contacts with, the floor of the major groove. When the reaction was repeated with a synthetic oligonucleotide decamer duplex, the ratio of the two forms was approximately 1:1.9 and with the 52-mer dup lex it was 1:2.4, revealing an apparent systematic dependence of stereosele ctivity on nucleotide size. Computer modeling of the two adducts formed by [PtCl2(hpip)] and those formed by [PtCl2(en)] and cis-[PtCl2(NH3)(2)] revea led that non-bonded interactions between the hpip ligand and the DNA were p robably responsible for both the decreased proportion of GpG adducts formed by [PtCl2(hpip)] and the stereoselectivity exhibited in the formation of t hese adducts. This is the first case in which the stereoselectivity can be ascribed to steric factors alone.