title: A novel series of l-2-benzyloxycarbonylamino-8-(2-pyridyl)-disulfidyloctanoic acid derivatives as histone deacetylase inhibitors: design, synthesis and molecular modeling study.
abstract: Histone deacetylases inhibitors (HDACIs) have become an attractive class of anticancer agents. In order to find some novel potent HDACIs, we designed and synthesized a series of l-2-benzyloxycarbonylamino-8-(2-pyridyl)-disulfidyloctanoic acid derivatives. All compounds exhibited potent HDAC-inhibitory activity, and two of them had similar potency to TSA. The introduction of 2-amino-4-phenylthiazole or 9-methyleneoxy-fluorenyl group at the surface recognize domain of these HDACIs could greatly increase their HDAC-inhibitory activity. Molecular modeling studies indicated that coordination of the zinc ion by these inhibitors, and formation of hydrogen bond and hydrophobic interaction between inhibitors and HDACs were essential for the HDAC-inhibitory activities of these inhibitors. Asp181, Asp269, Leu276 and Tyr308 in the active site of HDAC2 gave favorable contributions for binding with all compounds.
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, No.2 Linggong Road, Dalian 116024, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Huang
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.forename: Yingdong
authors.initials: Y
authors.lastname: Wei
authors.forename: Zhilong
authors.initials: Z
authors.lastname: Xiu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002210:Caprylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D002210:Caprylates; D056572:Histone Deacetylase Inhibitors; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2