Wang Hao, Kozekov Ivan D, Harris Thomas M, Rizzo Carmelo J
Department of Chemistry and Center in Molecular Toxicology, Vanderbilt University, Nashville, Tennessee 37235-1822, USA.
J Am Chem Soc. 2003 May 14;125(19):5687-700. doi: 10.1021/ja0288800.
trans-4-Hydroxynonenal (HNE) is a major peroxidation product of omega-6 polyunsaturated fatty acids. The reaction of HNE with DNA gives four diastereomeric 1,N(2)-gamma-hydroxypropano adducts of deoxyguanosine; background levels of these adducts have been detected in animal tissue. Stereospecific syntheses of these four adducts at the nucleoside level have been accomplished. In addition, a versatile strategy for their site-specific incorporation into oligonucleotides has been developed. These adducts are destabilizing as measured by melting temperature when compared to an unadducted strand. The thermal destablization of the adducted 12-mers ranged from 5 to 16 degrees C and is dependent on the absolute stereochemistry of the adduct. The HNE adducts were also examined for their ability to form interstrand DNA-DNA cross-links when incorporated into a CpG sequence. We find that only one of the HNE stereoisomers formed interstrand DNA-DNA cross-links.
反式-4-羟基壬烯醛（HNE）是ω-6多不饱和脂肪酸的主要过氧化产物。HNE与DNA反应会生成四种脱氧鸟苷的非对映体1,N(2)-γ-羟基丙烷加合物；在动物组织中已检测到这些加合物的背景水平。已在核苷水平完成了这四种加合物的立体定向合成。此外，还开发了一种将它们位点特异性掺入寡核苷酸的通用策略。与未加合的链相比，通过解链温度测量发现这些加合物会使双链不稳定。加合的12聚体的热稳定性降低范围为5至16摄氏度，并且取决于加合物的绝对立体化学结构。还研究了HNE加合物掺入CpG序列时形成链间DNA-DNA交联的能力。我们发现只有一种HNE立体异构体形成了链间DNA-DNA交联。
