Discovery of N-hydroxy-4-(3-phenylpropanamido)benzamide derivative 5j, a novel histone deacetylase inhibitor, as a potential therapeutic agent for human breast cancer.
A novel series of N-hydroxy-4-(3-phenylpropanamido)benzamide (HPPB) derivatives comprising N-hydroxybenzamide group as zinc-chelating moiety were designed, synthesized and evaluated as histone deacetylases inhibitors. The thiophene substituted derivative 5j exhibited the best HDAC inhibition activity among these compounds. The present study was designed to evaluate the efficacy of 5j as a candidate compound for cancer therapy. Our results indicated that 5j exhibited better HDAC1, 8 and hela nuclear extract inhibition activities than SAHA, and good antiproliferative activities against a broad spectrum of human cancer cell lines especially for breast cancer. 5j induced cell cycle arrest at G(2)/M phase, and eventual apoptosis possibly by modulating p21, caspase-3 and Bcl-x(L) on MDA-MB-231 cells. In addition, 5j down regulated the active form of MMP2, and inhibited the invasion of MDA-MB-231 cell lines. Moreover, 5j significantly delayed the growth of MDA-MB-231 xenografts in mice after 3 weeks of peritoneal injection. In summary, our results suggest that 5j might have therapeutic potential for the treatment of human breast cancer.
Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
Jinhong
J
Feng
Hao
H
Fang
Xuejian
X
Wang
Yuping
Y
Jia
Lei
L
Zhang
Jie
J
Jiao
Jian
J
Zhang
Lichuan
L
Gu
Wenfang
W
Xu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism
D001549:Benzamides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; C560972:N-hydroxy-4-(3-(3-methoxy-4-(thiophen-2-ylmethyl)phenyl)propanamido)benzamide; D013876:Thiophenes; D051020:bcl-X Protein; D053148:Caspase 3