Discovery, bioactivity and docking simulation of Vorinostat analogues containing 1,2,4-oxadiazole moiety as potent histone deacetylase inhibitors and antitumor agents

Jin Cai; Hongtao Wei; Kwon Ho Hong; Xiaoqing Wu; Xi Zong; Meng Cao; Peng Wang; Lushen Li; Chunlong Sun; Bo Chen; Gaoxing Zhou; Junqing Chen; Min Ji

doi:10.1016/j.bmc.2015.04.028

Discovery, bioactivity and docking simulation of Vorinostat analogues containing 1,2,4-oxadiazole moiety as potent histone deacetylase inhibitors and antitumor agents

Jin Cai, Hongtao Wei, Kwon Ho Hong, Xiaoqing Wu, Xi Zong, Meng Cao, Peng Wang, Lushen Li, Chunlong Sun, Bo Chen, Gaoxing Zhou, Junqing Chen, Min Ji

Medicinal Chemistry

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Abstract

Abstract In our study, three series of hydroxamate, 2-aminobenzamide, and trifluoromethyl ketone analogues have been designed and synthesized. The synthesized compounds were investigated for their in vitro antiproliferative activities using the MTT-based assay against three human cancer cell lines including A549, NCI-H661, and U937. Most analogues exhibited higher antiproliferative activities against human acute myeloid leukemia cell U937 than the other two human lung cancer cell lines. Furthermore, the compounds were examined against HDAC1, 2, and 8 isoforms. Docking study of compounds 6h, 9b, and 10a suggested that they might bind tightly to the binding pocket of HDAC2 and/or HDAC8. The results suggest that these compounds might have potential as lead compounds for the development of anti-tumor drugs with HDACs inhibitory activities.

Original language	English (US)
Article number	12240
Pages (from-to)	3457-3471
Number of pages	15
Journal	Bioorganic and Medicinal Chemistry
Volume	23
Issue number	13
DOIs	https://doi.org/10.1016/j.bmc.2015.04.028
State	Published - 2015

Bibliographical note

Funding Information:
This work is supported by The Fundamental Research Funds for the Central Universities ( 2242014R30019 ), Technology Supporting Program of Jiangsu Province ( BE2012657 ), and National Basin Research Program of China (No. 2011CB933503 ). We thank the Minnesota Supercomputing Institute for their support for our molecular modeling study.

Publisher Copyright:
© 2015 Elsevier Ltd.

Keywords

2-Aminobenzamide
Antiproliferative activity
Docking simulation
Histone deacetylases (HDAC)
Hydroxamate
Trifluoromethyl ketone

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Cai, J., Wei, H., Hong, K. H., Wu, X., Zong, X., Cao, M., Wang, P., Li, L., Sun, C., Chen, B., Zhou, G., Chen, J., & Ji, M. (2015). Discovery, bioactivity and docking simulation of Vorinostat analogues containing 1,2,4-oxadiazole moiety as potent histone deacetylase inhibitors and antitumor agents. Bioorganic and Medicinal Chemistry, 23(13), 3457-3471. Article 12240. https://doi.org/10.1016/j.bmc.2015.04.028

Cai, J, Wei, H, Hong, KH, Wu, X, Zong, X, Cao, M, Wang, P, Li, L, Sun, C, Chen, B, Zhou, G, Chen, J & Ji, M 2015, 'Discovery, bioactivity and docking simulation of Vorinostat analogues containing 1,2,4-oxadiazole moiety as potent histone deacetylase inhibitors and antitumor agents', Bioorganic and Medicinal Chemistry, vol. 23, no. 13, 12240, pp. 3457-3471. https://doi.org/10.1016/j.bmc.2015.04.028

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abstract = "Abstract In our study, three series of hydroxamate, 2-aminobenzamide, and trifluoromethyl ketone analogues have been designed and synthesized. The synthesized compounds were investigated for their in vitro antiproliferative activities using the MTT-based assay against three human cancer cell lines including A549, NCI-H661, and U937. Most analogues exhibited higher antiproliferative activities against human acute myeloid leukemia cell U937 than the other two human lung cancer cell lines. Furthermore, the compounds were examined against HDAC1, 2, and 8 isoforms. Docking study of compounds 6h, 9b, and 10a suggested that they might bind tightly to the binding pocket of HDAC2 and/or HDAC8. The results suggest that these compounds might have potential as lead compounds for the development of anti-tumor drugs with HDACs inhibitory activities.",

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AB - Abstract In our study, three series of hydroxamate, 2-aminobenzamide, and trifluoromethyl ketone analogues have been designed and synthesized. The synthesized compounds were investigated for their in vitro antiproliferative activities using the MTT-based assay against three human cancer cell lines including A549, NCI-H661, and U937. Most analogues exhibited higher antiproliferative activities against human acute myeloid leukemia cell U937 than the other two human lung cancer cell lines. Furthermore, the compounds were examined against HDAC1, 2, and 8 isoforms. Docking study of compounds 6h, 9b, and 10a suggested that they might bind tightly to the binding pocket of HDAC2 and/or HDAC8. The results suggest that these compounds might have potential as lead compounds for the development of anti-tumor drugs with HDACs inhibitory activities.

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Discovery, bioactivity and docking simulation of Vorinostat analogues containing 1,2,4-oxadiazole moiety as potent histone deacetylase inhibitors and antitumor agents

Abstract

Bibliographical note

Keywords

UN SDGs

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