Design, synthesis and pharmacological evaluation of new acyl sulfonamides as potent and selective Bcl-2 inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 26; no. 2; pp. 443 - 454
• Main Authors: Liu, Xiaohua, Zhang, Yu, Huang, Wenjing, Tan, Wenfu, Zhang, Ao
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.01.2018; Elsevier
• Subjects: Apoptosis; Bcl-2; Bcl-xL; Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Design; Humans; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Navitoclax; Pharmacology & Pharmacy; Physical Sciences; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Science & Technology; Structure-Activity Relationship; Sulfonamide; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Bcl-2; Bcl-xL; Sulfonamide; Navitoclax; Apoptosis; DISCOVERIES; DOCKING; ANTAGONISTS; PROTEINS; FAMILY
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.12.001

[Display omitted] The antiapoptotic protein Bcl-2, overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, we report a different structural modification approach on ABT-263 by merging the piperazinyl-phenyl fragment into a bicyclic framework leading to a series of novel analogues, among which tetrahydroisoquinoline 13 was nearly equally potent against Bcl-2 as ABT-263. Further SAR in the P4-interaction pocket affored the difluoroazetidine substituted analogue 55, which retained good Bcl-2 activity with improved Bcl-2/Bcl-xL selectivity.