Structure-based design of rhodanine-based acylsulfonamide derivatives as antagonists of the anti-apoptotic Bcl-2 protein.
A series of novel rhodanine-based acylsulfonamide derivatives were designed, synthesized, and evaluated as small-molecule inhibitors of anti-apoptotic Bcl-2 protein. These compounds exhibit potent antiproliferative activity in three human tumor cell lines (Hep G2, PC-3 and B16-F10). Among them, the most potent compounds 10 and 11 bind to Bcl-2 with a K(i) of 20 and 25 nM, respectively. Docking studies demonstrated that these two compounds orient similarly at the binding site of Bcl-2, and the calculated binding affinities (Glide XP score) of compound 10 is more negative than that of compound 11. The binding interactions of compounds with high binding affinity to Bcl-2 protein were analyzed.
College of Pharmaceutical Science, Soochow University, PR China.
Huan-qiu
HQ
Li
Jing
J
Yang
Shuhua
S
Ma
Chunhua
C
Qiao
D000970:Antineoplastic Agents / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012236:Rhodanine / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D012236:Rhodanine