Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, Kaunas LT-50254, Lithuania.
Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius LT-10257, Lithuania.
Bioorg Chem. 2020 Apr;97:103658. doi: 10.1016/j.bioorg.2020.103658. Epub 2020 Feb 13.
A novel set of pyrrolidinone-based chlorinated benzenesulfonamide derivatives were synthesized and investigated for their binding affinity and selectivity against recombinant human carbonic anhydrases I-XIV using fluorescent thermal shift, p-nitrophenyl acetate hydrolysis and stopped-flow enzymatic inhibition assays. The hydrazones 10-22 prepared from 1-(2-chloro-4-sulfamoylphenyl)-5-oxopyrrolidine-3-carboxylic acid exhibited low nanomolar affinity against cancer-related CA IX (K in the range of 5.0-37 nM). Compounds with triazole or oxadiazole groups attached directly to pyrrolidinone moiety bound all CAs weaker than compounds with more flexible tail groups. Chloro group at the meta position of benzenesulfonamide derivatives increased affinity to all CAs as compared with binding data for nonchlorinated compounds. The compounds have a potential for further development of CA inhibitors with higher selectivity for a particular CA isozyme.
合成了一组新型基于吡咯烷酮的氯化苯磺酰胺衍生物，并使用荧光热位移、对硝基苯乙酸酯水解和停流酶抑制测定法研究了它们与重组人碳酸酐酶 I-XIV 的结合亲和力和选择性。由 1-(2-氯-4-磺酰胺基苯基)-5-氧代吡咯烷-3-羧酸制备的腙 10-22 对与癌症相关的 CAIX 表现出低纳摩尔亲和力（K 值在 5.0-37 nM 范围内）。直接连接在吡咯烷酮部分上的三唑或噁二唑基团的化合物与具有更灵活的尾部基团的化合物相比，与所有 CA 的结合较弱。与非氯化化合物的结合数据相比，苯磺酰胺衍生物中氯位于间位增加了与所有 CA 的亲和力。这些化合物有可能进一步开发对特定 CA 同工酶具有更高选择性的 CA 抑制剂。
