Synthesis, in vitro structure-activity relationship, and in vivo studies of 2-arylthiazolidine-4-carboxylic acid amides as anticancer agents.
A series of (2RS,4R)-2-arylthiazolidine-4-carboxylic acid amide (ATCAA) was synthesized. Antiproliferative activity against melanoma and prostate cancer cells compared with control cells (fibroblast and RH7777, respectively) was evaluated. Compound 3id showed the best selectivity and growth-inhibition activity against three melanoma cell lines (B16-F1, A375, and WM-164). Compounds 15b and 3ac had good selectivity and potency against four prostate cancer cell lines (DU 145, PC-3, LNCaP, and PPC-1). The structure-activity relationship (SAR) of the side chain, the thiazolidine ring, and phenyl substituents is discussed. Cell cycle analysis showed that the percentage of cancer cells undergoing apoptosis (sub-G1 phase) increased after treatment with 1b and 3ad, which also strongly inhibited melanoma colony formation. In vivo studies on nude mice bearing A375 melanoma tumors showed that compound 1b inhibited tumor growth in a dose-dependent manner. At a dose of 10mg/kg, 1b significantly inhibited melanoma tumor growth and showed higher efficacy than did dacarbazine at 60mg/kg.
Lu
Yan
Y
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
Wang
Zhao
Z
Li
Chien-Ming
CM
Chen
Jianjun
J
Dalton
James T
JT
Li
Wei
W
Miller
Duane D
DD
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000577:Amides; D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D053778:Thiazolidines