title: Optimization of heterocyclic substituted benzenesulfonamides as novel carbonic anhydrase IX inhibitors and their structure activity relationship.
abstract: In this study, starting from a lead compound discovered by virtual screening, a series of novel heterocyclic substituted benzenesulfonamides were designed and synthesized as new carbonic anhydrase IX (CA IX) inhibitors. Some compounds exhibited potent inhibitory effects against CA IX (in the low nanomolar range) as well as high selectivity against other carbonic anhydrase isozymes (CA I and CA II). The most potent and selective compound 27 could inhibit CA IX in the subnanomolar level with IC50 of 0.48 nM, which increased the potency by about 40-fold against CA IX compared with the lead compound 26, and presented more than 10(3) fold selectivity over CA I and CA II. The structure-activity relationship (SAR) based on the docking experiments further elucidated the effects of the compounds on the bioactivity and selectivity.
authors: State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, East China University of Science and Technology, Shanghai 200237, China.
authors: Rui
authors: R
authors: Gao
authors: Sha
authors: S
authors: Liao
authors: Chen
authors: C
authors: Zhang
authors: Weilong
authors: W
authors: Zhu
authors: Liyan
authors: L
authors: Wang
authors: Jin
authors: J
authors: Huang
authors: Zhenjiang
authors: Z
authors: Zhao
authors: Honglin
authors: H
authors: Li
authors: Xuhong
authors: X
authors: Qian
authors: Yufang
authors: Y
authors: Xu
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D000951:Antigens, Neoplasm; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D006571:Heterocyclic Compounds; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C089226:CA9 protein, human