Single-Stranded Oligonucleotide Adducts Formed by Pt Complexes Favoring Left-Handed Base Canting: Steric Effect of Flanking Residues and Relevance to DNA Adducts Formed by Pt Anticancer Drugs

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• 作者：Jamil S. Saad ; Patricia A. Marzilli ; Francesco P. Intini ; Giovanni Natile ; Luigi G. Marzilli
• 刊名：Inorganic Chemistry
• 出版年：2011
• 出版时间：September 5, 2011
• 年：2011
• 卷：50
• 期：17
• 页码：8608-8620
• 全文大小：1086K
• 年卷期：v.50,no.17(September 5, 2011)
• ISSN：1520-510X

文摘

Platinum anticancer drug binding to DNA creates large distortions in the cross-link (G*G*) and the adjacent XG* base pair (bp) steps (G* = N7-platinated G). These distortions, which are responsible for anticancer activity, depend on features of the duplex (e.g., base pairing) and of the cross-link moiety (e.g., the position and canting of the G* bases). The duplex structure stabilizes the head-to-head (HH) over the head-to-tail (HT) orientation and right-handed (R) over left-handed (L) canting of the G* bases. To provide fundamental chemical information relevant to the assessment of such duplex effects, we examine (S,R,R,S)-BipPt(oligo) adducts (Bip = 2,2鈥?bipiperidine with S,R,R,S chiral centers at the N, C, C, and N chelate ring atoms, respectively; oligo = d(G*pG*) with 3鈥? and/or 5鈥?substituents). The moderately bulky (S,R,R,S)-Bip ligand favors L canting and slows rotation about the Pt鈥揋* bonds, and the (S,R,R,S)-BipPt(oligo) models provide more useful data than do dynamic models derived from active Pt drugs. All 5鈥?substituents in (S,R,R,S)-BipPt(oligo) adducts favor the normal HH conformer (97%) by destabilizing the HT conformer through clashes with the 3鈥?G* residue rather than through favorable H-bonding interactions with the carrier ligand in the HH conformer. For all (S,R,R,S)-BipPt(oligo) adducts, the S pucker of the 5鈥?X residue is retained. For these adducts, a 5鈥?substituent had only modest effects on the degree of L canting for the (S,R,R,S)-BipPt(oligo) HH conformer. This small flanking 5鈥?substituent effect on an L-canted HH conformer contrasts with the significant decrease in the degree of R canting previously observed for flanking 5鈥?substituents in the R-canted (R,S,S,R)-BipPt(oligo) analogues. The present data support our earlier hypothesis that the distortion distinctive to the XG* bp step (S to N pucker change and movement of the X residue) is required for normal stacking and X路X鈥?WC H bonding and to prevent XG* residue clashes.