Design and synthesis of dual-action inhibitors targeting histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme a reductase for cancer treatment
Journal
Journal of Medicinal Chemistry
Journal Volume
56
Journal Issue
9
Pages
3645-3655
Date Issued
2013
Author(s)
Abstract
A series of dual-action compounds were designed to target histone deacetylase (HDAC) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) by having a hydroxamate group essential for chelation with the zinc ion in the active site of HDAC and the key structural elements of statin for binding with both proteins. In our study, the statin hydroxamic acids prepared by a fused strategy are most promising in cancer treatments. These compounds showed potent inhibitory activities against HDACs and HMGR with IC50 values in the nanomolar range. These compounds also effectively reduced the HMGR activity as well as promoted the acetylations of histone and tubulin in cancer cells, but were not toxic to normal cells. ? 2013 American Chemical Society.
SDGs
Other Subjects
7(2(4 fluorophenyl) 5 isopropyl 3 phenyl 4 phenylcarbamoylpyrrol 1 yl] 3,5 dihydroxy n hydroxyheptanamide; 7(4(4 fluorophenyl) 2 (n methyl (methylsulfonyl) amino) 6 isopropylpyrimidin 5 yl) 3,5 dihydroxy n hydroxyhept 6 enoic amide; 8[((4(1(7 (hydroxyamino) 7 oxoheptyl) 1h 1,2,3 triazol 4 ylbenzylcarbamoyloxy) 2,6 dimethyl 1,2,6,7,8,8a hexahydronaphthyl)ethyl] 4 [(tertbutyldimethylsilyl)oxy] 3,4,5,6 tetrahydro 2h pyran 2 one; 8[(4(1(7 (hydroxyamino) 7oxoheptyl) 1h 1,2,3 triazol 4 yl)phenylcarbamoyl)oxy] 2,6 dimethyl 1,2,6,7,8,8a hexahydronaphthylethyl 4 (tertbutyldimethylsilyloxy) 3,4,5,6 tetrahydro 2h pyran 2 one; 8[(7 (hydroxyamino) 7 oxoheptyl] carbamoyloxy 2,6 dimethyl 1,2,6,7,8,8a hexahydronaphthylethyl 4 [(tert butyldimethylsilyl) oxy] 3,4,5,6 tetrahydro 2h pyran 2 one; atorvastatin; hexahydro 2,6 dimethyl 8[(2 dimethylbutyryloxy) naphthalenyl] 3,5 dihydroxy n hydroxyheptanamide; hexahydro 2,6 dimethyl 8[(2 methylbutyryloxy) naphthalenyl] 3,5 dihydroxy n hydroxyheptanamide; histone deacetylase; histone deacetylase inhibitor; hydroxamic acid derivative; hydroxymethylglutaryl coenzyme A reductase; hydroxymethylglutaryl coenzyme A reductase inhibitor; mevinolin; rosuvastatin; simvastatin; unclassified drug; vorinostat; animal cell; article; binding affinity; cancer cell; cancer inhibition; cancer therapy; controlled study; cytotoxicity; drug design; drug structure; drug synthesis; drug targeting; enzyme activity; enzyme inhibition; human; human cell; IC 50; molecular model; mouse; nonhuman; Western blotting; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; Drug Design; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Models, Molecular; Protein Conformation
Type
journal article