Discovery and structure-activity relationships of (2-(arylthio)benzylideneamino)guanidines as a novel series of potent apoptosis inducers.
1-(2-(2,5-Dimethoxyphenylthio)benzylidene)semicarbazide (2a) was discovered as a potent apoptosis inducer through our cell based HTS assay. SAR study led to the discovery of a more aqueous soluble analog (2-(2,5-dimethoxyphenylthio)-6-methoxybenzylideneamino)guanidine (5e) with EC(50) value of 60 nM in the caspase activation assay and GI(50) value of 62 nM in the growth inhibition assay in T47D cells. Compound 5e was found to be an inhibitor of tubulin polymerization and efficacious in a MX-1 breast tumor model.
Zhang
Han-Zhong
HZ
EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
Crogan-Grundy
Candace
C
May
Chris
C
Drewe
John
J
Tseng
Ben
B
Cai
Sui Xiong
SX
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis; D001597:Benzylidene Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D012663:Semicarbazides / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
C541073:(2-(2,5-dimethoxyphenylthio)-6-methoxybenzylideneamino)guanidine; C541072:1-(2-(2,5-dimethoxyphenylthio)benzylidene)semicarbazide; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D006146:Guanidines; D012663:Semicarbazides; D050257:Tubulin Modulators