Amino acid-linked platinum(II) compounds: non-canonical nucleoside preferences and influence on glycosidic bond stabilities

被引：6

作者：

Kimutai, Bett ^{[1
]}

He, C. C. ^{[1
]}

Roberts, Andrew ^{[1
]}

Jones, Marcel L. ^{[1
]}

Bao, Xun ^{[1
]}

Jiang, Jun ^{[1
]}

Yang, Zhihua ^{[1
]}

Rodgers, M. T. ^{[1
]}

Chow, Christine S. ^{[1
]}

机构：

[1] Wayne State Univ, Dept Chem, Detroit, MI 48202 USA

来源：

JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY | 2019年 / 24卷 / 07期

基金：

美国国家科学基金会;

关键词：

Cisplatin; Amino acid-linked platinum(II) compounds; Kinetics; Adenosine adduct; Glycosidic bonds; ANTICANCER DRUG CISPLATIN; GAS-PHASE CONFORMATIONS; CROSS-LINKING; IN-VITRO; SODIUM CATIONIZATION; MASS-SPECTROMETRY; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; DNA-BINDING; RNA;

D O I：

10.1007/s00775-019-01693-y

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Nucleobases serve as ideal targets where drugs bind and exert their anticancer activities. Cisplatin (cisPt) preferentially coordinates to 2 '-deoxyguanosine (dGuo) residues within DNA. The dGuo adducts that are formed alter the DNA structure, contributing to inhibition of function and ultimately cancer cell death. Despite its success as an anticancer drug, cisPt has a number of drawbacks that reduce its efficacy, including repair of adducts and drug resistance. Some approaches to overcome this problem involve development of compounds that coordinate to other purine nucleobases, including those found in RNA. In this work, amino acid-linked platinum(II) (AAPt) compounds of alanine and ornithine (AlaPt and OrnPt, respectively) were studied. Their reactivity preferences for DNA and RNA purine nucleosides (i.e., 2 '-deoxyadenosine (dAdo), adenosine (Ado), dGuo, and guanosine (Guo)) were determined. The chosen compounds form predominantly monofunctional adducts by reacting at the N1, N3, or N7 positions of purine nucleobases. In addition, features of AAPt compounds that impact the glycosidic bond stability of Ado residues were explored. The glycosidic bond cleavage is activated differentially for AlaPt-Ado and OrnPt-Ado isomers. Formation of unique adducts at non-canonical residues and subsequent destabilization of the glycosidic bonds are important features that could circumvent platinum-based drug resistance. [GRAPHICS]

引用

页码：985 / 997

页数：13

共 73 条

[71] Effects of sodium cationization versus protonation on the conformations and N-glycosidic bond stabilities of sodium cationized Urd and dUrd: solution conformation of [Urd+Na]+ is preserved upon ESI [J].