Theoretical study on the stability of N-glycosyl bonds: Why does N7-platination not promote depurination?

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The depurination reaction of guanosine, protonated or modified with cisplatin at the N7 position, has been studied by density functional theory (DFT), coupled with a continuum treatment of solvation. Protonation accelerates the depurination reaction whereas N7-platination, the initial product of cisplatin binding to DNA, does not. The computed reaction energy profiles demonstrate that N7-platination has only a minor effect on the energetics of the transition state, whereas protonation lowers it by similar to10 kcal mol(-1). The orbitals involved in N7-Pt/H bonding are examined, and electronic differences between the two substituted guanines are identified. Natural bond orbital analysis, fragment orbital analysis, and extended transition-state theory reveal how the electronically different substituents at the N7 position control the stability of the N9-C1' bond. The detailed description of the electronic structure of the N7-substituted guanosines and the computational protocol developed to obtain a realistic model for these systems not only explain a longstanding enigma but also provide guidelines for further studies toward understanding the interactions of cisplatin with DNA.
Publisher
AMER CHEMICAL SOC
Issue Date
2002-04
Language
English
Article Type
Article
Keywords

EFFECTIVE CORE POTENTIALS; TRANSITION-STATE METHOD; REGULAR 2-COMPONENT HAMILTONIANS; CONTINUUM DIELECTRIC THEORY; ANTICANCER DRUG CISPLATIN; DENSITY-FUNCTIONAL THEORY; INTRASTRAND CROSS-LINK; BASE-EXCISION REPAIR; MOLECULAR CALCULATIONS; AB-INITIO

Citation

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, v.124, no.16, pp.4495 - 4503

ISSN
0002-7863
DOI
10.1021/ja017588+
URI
http://hdl.handle.net/10203/203373
Appears in Collection
CH-Journal Papers(저널논문)
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