Novel 2-oxoindoline-based hydroxamic acids: synthesis, cytotoxicity, and inhibition of histone deacetylation

作者：Tran Thi Lan Huong; Do Thi Mai Dung; Phan Thi Phuong Dung^*; Phung Thanh Huong; Tran Khac Vu; Hahn Hyunggu; Han Byung Woo; Kim Jisung; Pyo Minji; Han Sang Bae; Nguyen Hai Nam

来源：Tetrahedron Letters, 2015, 56(46): 6425-6429.

DOI：10.1016/j.tetlet.2015.09.147

• Histone deacetylase (HDAC) inhibitors
• Hydroxamic acids
• Isatin
• Heterocycle

In a continuation of a research program to discover novel small molecules targeting histone deacetylases, a series of 2'-oxospiro[1,3]dioxolane/dithiolane-2,3'-indoline-based hydroxamic acids have been designed and synthesized. These 2-oxoindoline-based hydroxamic acids displayed potent cytotoxicity against three human cancer cell lines, including SW620 (colon cancer), PC-3 (prostate cancer) and AsPC-1 (pancreatic cancer), with IC50 values as low as 0.05-0.07 mu M, 74-fold lower than that of SAHA (1.64-3.70 mu M). Additionally, compounds in this series exhibited good inhibition against histone-H3 and histone-H4 deacetylation, as evaluated by Western blot assay. These compounds also strongly inhibited HDAC2 with IC50 values as low as 0.03 mu M. Docking studies performed using Autodock Vina showed all compounds bound to HDAC2 with relatively higher affinities (from -7.7 to -8.0 kcal/mol) compared to SAHA (-7.4 kcal/mol).

• 出版日期2015-11-18