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• 作者：Hui-Chung Tai ; Ralf Brodbeck ; Jana Kasparkova ; Nicola J. Farrer ; Viktor Brabec ; Peter J. Sadler ; Robert J. Deeth
• 刊名：Inorganic Chemistry
• 出版年：2012
• 出版时间：June 18, 2012
• 年：2012
• 卷：51
• 期：12
• 页码：6830-6841
• 全文大小：590K
• 年卷期：v.51,no.12(June 18, 2012)
• ISSN：1520-510X

文摘

Molecular modeling and extensive experimental studies are used to study DNA distortions induced by binding platinum(II)-containing fragments derived from cisplatin and a new class of photoactive platinum anticancer drugs. The major photoproduct of the novel platinum(IV) prodrug trans,trans,trans-[Pt(N₃)₂(OH)₂(py)₂] (1) contains the trans-{Pt(py)₂}²⁺ moiety. Using a tailored DNA sequence, experimental studies establish the possibility of interstrand binding of trans-{Pt(py)₂}²⁺ (P) to guanine N7 positions on each DNA strand. Ligand field molecular mechanics (LFMM) parameters for Pt鈥揼uanine interactions are then derived and validated against a range of experimental structures from the Cambridge Structural Database, published quantum mechanics (QM)/molecular mechanics (MM) structures of model Pt鈥揇NA systems and additional density-functional theory (DFT) studies. Ligand field molecular dynamics (LFMD) simulation protocols are developed and validated using experimentally characterized bifunctional DNA adducts involving both an intra- and an interstrand cross-link of cisplatin. We then turn to the interaction of P with the DNA duplex dodecamer, d(5鈥?C₁C₂T₃C₄T₅C₆G₇T₈C₉T₁₀C₁₁C₁₂-3鈥?路d(5鈥?G₁₃G₁₄A₁₅G₁₆A₁₇C₁₈G₁₉A₂₀G₂₁A₂₂G₂₃G₂₄-3鈥? which is known to form a monofunctional adduct with cis-{Pt(NH₃)₂(py)}. P coordinated to G₇ and G₁₉ is simulated giving a predicted bend toward the minor groove. This is widened at one end of the platinated site and deepened at the opposite end, while the P鈥揇NA complex exhibits a global bend of 67掳 and an unwinding of 20掳. Such cross-links offer possibilities for specific protein鈥揇NA interactions and suggest possible mechanisms to explain the high potency of this photoactivated complex.