Synthesis and biological evaluation of triazol-4-ylphenyl-bearing histone deacetylase inhibitors as anticancer agents.
Our triazole-based histone deacetylase inhibitor (HDACI), octanedioic acid hydroxyamide[3-(1-phenyl-1H-[1,2,3]triazol-4-yl)phenyl]amide (4a), suppresses pancreatic cancer cell growth in vitro with the lowest IC(50) value of 20 nM against MiaPaca-2 cell. In this study, we continued our efforts to develop triazol-4-ylphenyl bearing hydroxamate analogues by embellishing the terminal phenyl ring of 4a with different substituents. The isoform inhibitory profile of these hydroxamate analogues was similar to those of 4a. All of these triazol-4-ylphenyl bearing hydroxamates are pan-HDACIs like SAHA. Moreover, compounds 4h and 11a were found to be very effective inhibitors of cancer cell growth in the HupT3 (IC(50) = 50 nM) and MiaPaca-2 (IC(50) = 40 nM) cancer cell lines, respectively. Compound 4a was found to reactivate the expression of CDK inhibitor proteins and to suppress pancreatic cancer cell growth in vivo. Taken together, these data further support the value of the triazol-4-ylphenyl bearing hydroxamates in identifying potential pancreatic cancer therapies.
He
Rong
R
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
Chen
Yufeng
Y
Chen
Yihua
Y
Ougolkov
Andrei V
AV
Zhang
Jin-San
JS
Savoy
Doris N
DN
Billadeau
Daniel D
DD
Kozikowski
Alan P
AP
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014230:Triazoles; C531072:octanedioic acid hydroxyamide (3-(1-phenyl-1H-(1,2,3)triazol-4-yl)phenyl)amide; D018844:Cyclin-Dependent Kinases; D006655:Histone Deacetylases