ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Exploration of some indole-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents

Tran Thi Lan Huong, Le Van Cuong, Pham Thu Huong, Tran Phuong Thao, Le-Thi-Thu Huong, Phan Thi Phuong Dung, Dao Thi Kim Oanh, Nguyen Thi Mai Huong, Hoang-Van Quan, Tran Khac Vu, Jisung Kim, Jae-Hee Lee, Sang-Bae Han, Pham-The Hai, and Nguyen-Hai Nam

Hanoi University of Pharmacy, Hanoi, Vietnam

E-mail: shan@chungbuk.ac.kr

Abstract: In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized a series of novel hydroxamic acids incorporating indole moiety as a cap group (3a–l). Biological evaluation showed that these hydroxamic acids potently inhibited HDAC2 with IC₅₀ values in submicromolar range and up to tenfold (compound 3j) better than that of SAHA (also known as suberoylanilide hydroxamic acid). In four human cancer cell lines [SW620 (colon), PC-3 (prostate), AsPC-1 (pancreatic), NCI-H23 (lung)], the synthesized compounds that exhibited potent cytotoxicity with several compounds (3k, 3l) were found to be 12- to 77-fold more cytotoxic than SAHA. Docking experiments indicated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA. Our present results demonstrate that these novel hydroxamic acids are potential for further development as anticancer agents.

Keywords: Histone deacetylase (HDAC) inhibitors; Hydroxamic acids; Antitumor agents

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-017-0172-1

Chemical Papers 71 (9) 1759–1769 (2017)