与核酸兼容的化学反应开发进展  

Advances in the development of DNA-compatible chemistries

作　　者：刘子健 穆柏杨 段志强 王璇 陆晓杰 LIU Zijian;MU Baiyang;DUAN Zhiqiang;WANG Xuan;LU Xiaojie(State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academic of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100049,China;Shandong Second Medical University,Weifang 261053,Shandong,China)

机构地区：[1]中国科学院上海药物研究所,原创新药研究全国重点实验室,上海201203 [2]中国科学院大学,北京100049 [3]山东第二医科大学,山东潍坊261053

出　　处：《合成生物学》2024年第5期1102-1124,共23页Synthetic Biology Journal

基　　金：国家自然科学基金(22377139);国家重点研发计划(91953203)。

摘　　要：DNA编码化合物库(DNA-Encoded Library,DEL)技术作为一种新兴的小分子药物筛选手段已经成为新药研发中不可或缺的重要技术平台。与核酸兼容(on-DNA)的化学反应对于构建具有丰富化学空间和结构多样性的DEL具有重要意义。近年来,on-DNA化学反应的数量不断增加,极大地拓宽了可用于DEL构建的化学反应范畴。同时,一系列创新性的反应方法,诸如光催化、固相合成以及生物合成等,亦在on-DNA化学反应领域不断涌现,进一步推动了该领域的发展。本文系统综述了近年来金属催化的on-DNA化学反应,包括:C(sp^(2))—C(sp^(2))键生成反应、C(sp^(3))—C(sp^(3))键生成反应、C(sp^(2))—C(sp^(3))键生成反应以及C(sp^(2))—X键生成反应;采用目标导向合成策略和多样性导向合成策略合成具有单环、稠环、螺环等on-DNA优势骨架;光催化和酶催化on-DNA化学反应等的研究进展。然而,目前开发的on-DNA化学反应仍然存在诸如与核酸的兼容性、底物适用性等问题,开发更高效、更稳定且能在温和条件下进行的on-DNA化学反应,发展新型的on-DNA化学反应类型,以及结合高通量筛选和计算机辅助的on-DNA反应开发仍然具有重要意义。DNA-Encoded Library(DEL)technology,as an emerging means of small molecule drug screening,has become an important and indispensable technology platform for new drug discovery and development.The technology incorporates many advantages from combinatorial chemistry,molecular biology,and chemical bioinformatics,which greatly improve the efficiency of compound library synthesis and screening.Meanwhile,driven by the development of nucleic acid-compatible chemical reactions and high-throughput sequencing technology,DEL technology has made remarkable progress and gradually become a fast,economical,and efficient high-throughput screening platform,and has been more and more widely used in seedling compounds screening by universities,research institutes,and large pharmaceutical companies.The success of a DEL screening relies heavily on the chemical space and structural diversity of the compound libraries,both of which are directly affected by the number of chemical reactions compatible with nucleic acids.Therefore,developing the on-DNA chemical reactions to continuously enrich the chemical toolbox for DEL synthesis and thus enhance the structural diversity and drug potential of the molecules in the libraries has been the focus in this field.In recent years,the number of on-DNA chemical reactions has increased significantly,greatly broadening the scope of chemical reactions available for DEL construction.Meanwhile,a series of novel reaction methods,such as photocatalysis,electrocatalysis,and biosynthesis,have also emerged in the application of on-DNA chemical reactions and further expanded the field that on-DNA chemical reactions can reach.In this paper,we systematically review the metal-catalyzed on-DNA chemical reactions in recent years,including C(sp^(2))—C(sp^(2))bondformation reactions,C(sp^(3))—C(sp^(3))bond-formation reactions,C(sp^(2))—C(sp^(3))bond-formation reactions,and C(sp^(2))—X bond-formation reactions;the synthesis of on-DNA privileged heterocycles with single-ring,fused-ring,and spirocyclic rings by

关 键 词：DNA编码化合物库 on-DNA化学反应 合成策略 生物合成 

分 类 号：R914.2[医药卫生—药物化学] Q81[医药卫生—药学]