理学院学术报告—化学百家讲堂第16期

报告题目：Reversible Covalent Reactions of Nucleic Acids

报 告 人：Prof. Steven Rokita，Johns Hopkins University

报告时间：2023年11月13日  10：00

报告地点：2教2B408

主办：理学院

报告人简介：Steven E. Rokita 教授于1979年在麻省理工学院（Massachusetts Institute of Technology）取得博士学位，后任马里兰大学(University of Maryland, College Park)教授。2012年起，任约翰•霍普金斯大学（Johns Hopkins University）教授。

Rokita教授长期从事：1.自然界中的还原脱卤， 2. DNA光化学和电子转移， 3. DNA醌甲基中间体的可逆的烷基化等方面的研究。在核酸生物有机化学方面取得了一系列重要成果，在Nature Commun., J. Am. Chem. Soc., Angew. Chem. Int. Ed. 等重要期刊发表论文100余篇，Wiley Series on Reactive Intermediates in Chemistry and Biology丛书编辑，撰写专著多部，多项专利已得到应用。

报告内容：The vast majority of drugs and reagents designed to interact covalently with nucleic acids react irreversibly and stoichiometrically.  Once the resulting lesions are repaired, their biological impact is minimal.  In contrast, a reversible reagent has the potential to support a continuum of reoccurring reactions despite lesion repair.  The potential utility for such a strategy will be tested after optimizing quinone methide alkylation and regeneration.  This electrophilic intermediate is sufficiently promiscuous to act under control of its attached ligand and may be designed for either alkylation or cross-linking of a chosen nucleic acid target.  Subtle changes in the linker used for conjugation also have a significant impact on reaction efficiency.  Results to date suggest that specificity can be built into the linker as well as the site-directing ligand.

The photochemical [2+2] cyclization of adjacent pyrimidines is also reversible, but this has rarely been appreciated in biology.  Nevertheless, a competition between formation and reversion of the resulting cyclobutane pyrimidine dimer (CPD) defines its highly variable accumulation.  The kinetics of CPD formation was previously considered as the sole variable, but now the dynamics of formation and reversion is shown to contribute to CPD accumulation by demonstrating a rapid response of CPD profiles to a change in DNA conformation.  Thus, the in vivo levels of CPD generated in a number of laboratories is influenced by conformation as well as sequence.  Ultimately, regions of high CPD accumulation may be used to probe changes in DNA structure in response to natural cellular processes.