| Abstract
| - H-bonding of G O6 to (NH)Me2DAB is not possible in the favored (HT) form of Me2DABPtG2 retro models (Me2DAB = N,N‘-dimethyl-2,3-diaminobutane; G = guanine derivative). The bulky six-membered G base rings are closer to each other and to the bulky Me2DABN-methyl groups in the major than in the minor HT form. The latter HT form is less stable, although the bulky groups do not clash and G O6 to NH H-bonds could exist.
- Typical cis-PtA2G2 models of key DNA lesions formed by cis-type Pt anticancer drugs are very dynamic and difficultto characterize (A2 = diamine or two amines; G = guanine derivative). Retro models have A2 carrier ligandsdesigned to decrease dynamic motion without eliminating any of three possible conformers with bases orientedhead-to-tail (two: ΔHT and ΛHT) or head-to-head (one: HH). All three were found in NMR studies of eightMe2DABPtG2 retro models (Me2DAB = N,N‘-dimethyl-2,3-diaminobutane with S,R,R,S and R,S,S,R configurationsat the chelate ring N, C, C, and N atoms, respectively; G = 5‘-GMP, 3‘-GMP, 5‘-IMP, and 3‘-IMP). The bases cantto the left (L) in (S,R,R,S)-Me2DABPtG2 adducts and to the right (R) in (R,S,S,R)-Me2DABPtG2 adducts. Relativeto the case in which the bases are both not canted, canting will move the six-membered rings closer in to eachother (“6-in” form) or farther out from each other (“6-out” form). Interligand interactions between ligand componentsnear to Pt (first-first sphere communication = FFC) or far from Pt (second-sphere communication = SSC) influencestability. In typical cases at pH < 8, the “6-in” form is favored, although the larger six-membered rings of the basesare close. In minor “6-out” HT forms, the proximity of the smaller five-membered rings could be sterically favorable.Also, G O6 is closer to the sterically less demanding NH part of the Me2DAB ligand, possibly allowing G O6−NHhydrogen bonding. These favorable FFC effects do not fully compensate for possibly stronger FFC dipole effectsin the “6-in” form. SSC, phosphate−N1H cis G interactions favor ΛHT forms in 5‘-GMP and 5‘-IMP complexes andΔHT forms in 3‘-GMP and 3‘-IMP complexes. When SSC and FFC favor the same HT conformer, it is present at>90% abundance. In six adducts [four (S,R,R,S)-Me2DABPtG2 and (R,S,S,R)-Me2DABPtG2 (G = 3‘-GMP and3‘-IMP)], the minor “6-out” HT form at pH ∼7 becomes the major form at pH ∼10, where G N1H is deprotonated,because the large distance between the negatively charged N1 atoms minimizes electrostatic repulsion and probablybecause the G O6−(NH)Me2DAB H-bond (FFC) is strengthened by N1H deprotonation. At pH ∼10, phosphate-negative N1 repulsion is an unfavorable SSC term. This factor disfavors the ΛHT R form of two (R,S,S,R)-Me2DABPtG2 (G = 5‘-GMP and 5‘-IMP) adducts to such an extent that the “6-in” ΔHT R form remains the dominantform even at pH ∼10.
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