Chimeric Platinum-Polyamines and DNA Binding. Kinetics of DNA Interstrand Cross-Link Formation by Dinuclear Platinum Complexes with Polyamine Linkers
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- 作者：Rasha A. Ruhayel ; Janina S. Langner ; Matilda-Jane Oke ; Susan J. Berners-Price ; Ibrahim Zgani ; Nicholas P. Farrell
- 刊名：The Journal of the American Chemical Society
- 出版年：2012
- 出版时间：April 25, 2012
- 年：2012
- 卷：134
- 期：16
- 页码：7135-7146
- 全文大小：548K
- 年卷期：v.134,no.16(April 25, 2012)
- ISSN：1520-5126
文摘
The first observation of a polyamine鈥揇NA interaction using 2D [1H, 15N] HSQC NMR spectroscopy allows study of the role of the linker in polynuclear platinum-DNA interactions and a novel 鈥渁nchoring鈥?of the polyamine by Pt鈥揇NA bond formation allows examination of the details of conformational B 鈫?Z transitions induced by the polyamine. The kinetics and mechanism of the stepwise formation of 5鈥?5鈥?1,4-GG interstrand cross-links (IXLs) by fully 15N-labeled [{trans-PtCl(15NH3)2}2{渭-(15NH2(CH2)615NH2(CH2)615NH2)}]3+ (1,1/t,t-6,6, 1) and [{trans-PtCl(15NH3)2}2{渭-(15NH2(CH2)615NH2(CH2)215NH2(CH2)615NH2)}]4+ (1,1/t,t鈥?,2,6, 1鈥? with the self-complementary oligonucleotide 5鈥?{d(ATATGTACATAT)2} (duplex I) are compared to the analogous reaction with 1,0,1/t,t,t (BBR3464) under identical conditions (pH 5.4, 298 K). Initial electrostatic interactions with the DNA are delocalized and followed by aquation to form the monoaqua monochloro species. The rate constant for monofunctional adduct formation, kMF, for 1 (0.87 M鈥? s鈥?) is 3.5 fold higher than for 1,0,1/t,t,t (0.25 M鈥? s鈥?; the value could not be calculated for 1鈥?due to peak overlap). The evidence suggests that several conformers of the bifunctional adduct form, whereas for 1,0,1/t,t,t only two discrete conformers were observed. The combined effect of the conformers observed for 1 and 1鈥?may play a crucial role in the increased potency of these novel complexes compared to 1,0,1/t,t,t. Treated as a single final product, the rate of formation of the 5鈥?5鈥?1,4-GG IXL, kCH, for 1 (kCH = 4.37 脳 10鈥? s鈥?) is similar to that of 1,0,1/t,t,t, whereas the value for 1鈥?is marginally higher (kCH = 5.4 脳 10鈥? s鈥?).