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5-Aryl-1,3,4-Thiadiazole-Based Hydroxamic Acids as Histone Deacetylase Inhibitors and Antitumor Agents: Synthesis, Bioevaluation and Docking Study

[ Vol. 11 , Issue. 3 ]

Author(s):

Tran Thi Lan Huong, Do Thi Mai Dung, Dao Thi Kim Oanh, Tran Thi Bich Lan, Phan Thi Phuong Dung, Vu Duc Loi, Kyung Rok Kim, Byung Woo Han, Jieun Yun, Jong Soon Kang, Youngsoo Kim, Sang-Bae Han and Nguyen-Hai Nam   Pages 296 - 304 ( 9 )

Abstract:


The search for newer histone deacetylase (HDAC) inhibitors has attracted a great deal of interest of medicinal chemists worldwide, especially after the first HDAC inhibitor (Zolinza®, widely known as SAHA or Suberoylanilide hydroxamic acid) was approved by the FDA for the treatment of Tcell lymphoma in 2006. As a continuity of our ongoing research in this area, we designed and synthesized a series of 5-aryl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA and evaluated their biological activities. Most of the compounds in this series, e.g. compounds with 5-aryl moiety being 2- furfuryl (5a), 5-bromofuran-2-yl (5b), 5-methylfuran-2-yl (5c), thiophen-2-yl (5d), 5-methylthiophen-2-yl (5f) and pyridyl (5g-i), were found to have potent anticancer cytotoxicity with IC50 values of generally 5- to 10-fold lower than that of SAHA in 4 human cancer cell lines assayed. Those compounds with potent cytotoxicity were also found to have strong HDAC inhibition effects. Docking studies revealed that compounds 5a and 5d displayed high affinities towards HDAC2 and 8.

Keywords:

Histone deacetylase (HDAC) inhibitors, 5-aryl-1, 3, 4-thiadiazole, cytotoxicity, heterocycle.

Affiliation:

Department of Pharmaceutical Chemistry, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Vietnam.

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