Structure-based optimization of click-based histone deacetylase inhibitors

• Published in: European journal of medicinal chemistry Vol. 46; no. 8; pp. 3190 - 3200
• Main Authors: Hou, Jingli, Feng, Congran, Li, Zhonghua, Fang, Qinghong, Wang, Huihui, Gu, Guoxian, Shi, Yikang, Liu, Pi, Xu, Feng, Yin, Zheng, Shen, Jie, Wang, Peng
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Masson SAS 01-08-2011; Elsevier
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Binding Sites; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Click Chemistry; Crystallography, X-Ray; Drug Design; Drug Screening Assays, Antitumor; General aspects; Histone Deacetylase 1 - chemistry; Histone Deacetylase 1 - metabolism; Histone Deacetylase 2 - chemistry; Histone Deacetylase 2 - metabolism; Histone deacetylase inhibitor; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydrophobic and Hydrophilic Interactions; Hydroxamic acid; Hydroxamic Acids - chemical synthesis; Hydroxamic Acids - pharmacology; Medical sciences; Models, Molecular; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - pathology; Pharmacology. Drug treatments; Phenylalanine - chemistry; Phenylalanine - metabolism; Protein Binding; Protein Structure, Secondary; Structure-Activity Relationship; Structure-based optimization; Triazoles - chemical synthesis; Triazoles - pharmacology; SAHA; Histone deacetylase inhibitor; TSA; Structure-based optimization; Hydroxamic acid; Click chemistry; HDAC; Histone deacetylase; Enzyme; Enzyme inhibitor; Modeling; Biological activity; Optimization; Molecular model; Hydrolases; Chemical synthesis; Ethylenic compound
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.04.027

Previously, we reported a click-chemistry based approach to the synthesis of a novel class of histone deacetylase (HDAC) inhibitors
[1]. The lead compound NSC746457 was found to be as potent as SAHA (Vorinostat). Further optimization of NSC746457 by using the HDAC2-TSA crystal structure is described herein. Docking of NSC746457 into HDAC2 binding domain suggested that the hydrophobic residue Phe210 flanking the cap-group binding-motif could be exploited for structural optimization. Substitution on the methylene group of cinnamic cap region led to identification of more potent HDAC inhibitors: isopropyl derivative
5 and tert-butyl derivative
6, with an IC
50 value of 22 nM and 18 nM, respectively.
Optimization of lead compound NSC746457 led to identification of two compounds with potent activity against HDAC enzymes.
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► The lead compound NSC746457 was optimized using the HDAC2-TSA crystal structure. ► Docking the NSC746457 into the histone deacetylase 2 suggested that Phe210 could be exploited for structure optimization. ► A series of novel HDAC inhibitors was designed and synthesized and two compounds showed strong activity against HDAC enzymes.