Design,synthesis and evaluation of novel indirubin-based N-hydroxybenzamides,N-hydroxypropenamides and N-hydroxyheptanamides as histone deacetylase inhibitors and antitumor agents |
| |
| Affiliation: | 1. Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, Viet Nam;2. College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyung-1, Heungdeok, Cheongju, Chungbuk 28160, Republic of Korea;3. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk, Republic of Korea;4. Faculty of Pharmacy, PHENIKAA University, Hanoi 12116, Viet Nam;5. PHENIKAA Institute for Advanced Study (PIAS), PHENIKAA University, Hanoi 12116, Viet Nam;1. Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States;2. Department of Biochemistry and Molecular Biology and Center for Tropical and Emerging Global Diseases (CTEGD), University of Georgia, 120 Green Street, Athens, GA 30602, United States;1. Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA;2. Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA;1. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, 250012 Ji’nan, Shandong, PR China;2. School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, 250012 Ji’nan, Shandong, PR China;1. School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400 USA;2. School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332-0400 USA;3. Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0400 USA;4. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332-0400 USA |
| |
| Abstract: | Several novel indirubin-based N-hydroxybenzamides, N-hydropropenamides and N-hydroxyheptanamides (4a-h, 7a-h, 10a-h) were designed using a fragment-based approach with structural features extracted from several previously reported HDAC inhibitors, such as SAHA (vorinostat), MGCD0103 (mocetinostat), nexturastat A and PXD-101 (belinostat). The biological results reveal that our compounds showed excellent cytotoxicity toward three common human cancer cell lines (SW620, PC-3 and NCI-H23) with IC50 values ranging from 0.09 to 0.007 µM. The cytotoxicity of the compounds was equipotent or even up to 10-times more potent than adriamycin and up to 205-times more potent than SAHA. Among the series of N-hydroxypropenamides, compounds 10a-d were the most potent HDAC inhibitors as well as cytotoxicity toward the cell lines tested. In addition, the strong inhibitory activites toward HDAC of our compounds were observed with IC50 values of below-micromolar range. Especially, compound 4a inhibited HDAC6 with an IC50 value of 29-fold lower than that against HDAC2 isoform. Representative compounds 4a and 7a were found to significantly arrest SW620 cells at G0/G1 phase. Compounds 7a and 10a were found to strongly induce apoptosis in SW620 cells. Docking studies revealed some important features affecting the selectivity against HDAC6 isoform. The results clearly demonstrate the potential of the indirubin-hydroxamic acid hybrids and these compounds should be very promising for further development. |
| |
| Keywords: | Histone deacetylase (HDAC) inhibitors Hydroxamic acids Docking simulation ADMET profiling |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
