Histone deacetylase (HDAC) is a promising target for cancer treatment. HDAC inhibitors consist of three pharmacophoric features: an aromatic cap group, zinc binding group (ZBG), and a linker chain connecting cap group to ZBG. Herein, we report on (i) substituted isatin moiety as the cap group that recognizes the surface of active enzyme pocket and (ii) thiosemicarbazide moiety incorporated as linker group responsible for connecting the cap group to ZBG (hydroxamic acid). The synthesized compounds were evaluated for their antiproliferative activity and HDAC enzyme inhibition. The binding mode analysis of proposed compounds was evaluated by docking studies. Several analogs were found to inhibit HDAC and cellular proliferation of Hela cervical cancer cells, with GI50 values in the micromolar range. One compound (Vd) was found to have greater in vitro antiproliferative activity in comparison to other compounds.
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References
J. E. Bolden, M. J. Peart, and R. W. Johnstone, Nat. Rev. Drug Disc., 5(9), 769 – 784 (2006).
H. Rajak, A. Singh, P. K. Dewangan, et al., Curr. Med. Chem., 20(14), 1887 – 1903 (2013).
H. Rajak, A. Singh, K. Raghuwanshi, et al., Curr. Med. Chem., 21(23), 2642 – 2664 (2014).
B. E. Gryder, Q. H. Sodji, and A. K. Oyelere, Future Med. Chem., 4(4), 505 – 524 (2012).
http://www.fda.gov/NewsEvents/Newsroom/Press-Announcements/ucm435296.htm; February 23, 2015.
http://www.prnewswire.com/news-releases/chipscreen-biosciences-announces-cfda-approval-of-chidamide-epidaza-forptcls-in-china-300017763.html; January 09, 2015.
L. Matesic, J. M. Locke, J. B. Bremner, et al., Bioorg. Med. Chem., 16(6), 3118 – 3124 (2008).
K. L. Vine, J. M. Locke, M. Ranson, et al., J. Med. Chem., 50(21), 5109 – 5117 (2007).
K. L. Vine, J. M. Locke, M. Ranson, et al., Bioorg. Med. Chem., 15(2), 931 – 938 (2007).
H. Prenen, J. Cools, N. Mentens, et al., Clin. Cancer Res., 12(8), 2622 – 2627 (2006).
G. Henry and A. H. Blatt, in: Organic Synthesis Collective, 2nd Edition, John Wiley and Sons, New York (1964), Vol. 6, pp. 327 – 334.
S. S. Karki, S. Thota, S. Y. Darj, et al., Bioorg. Med. Chem., 15(21), 6632 – 6641 (2007).
A. Mai, S. Massa, R. Ragno, et al., J. Med. Chem., 45(9), 1778 – 1784 (2002).
V. Vichai, and K. Kirtikara, Nature Protocols, 1(3), 1112 – 1116 (2006).
Acknowledgements
Two of the authors, Avineesh Singh and Deepak K Jain are thankful to the Council of Scientific and Industrial Research (CSIR), New Delhi, India for providing financial support in the form of Senior Research Fellowship. One of the authors, Harish Rajak, is grateful to the Science & Engineering Research Board – Department of Science & Technology (SERB-DST), New Delhi, India and the All India Council for Technical Education (AICTE), New Delhi for providing financial support in the form of a Research Project [Grant number: SERB/LS-385/2013] and “Career Award for Young Teachers”, respectively.
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Singh, A., Raghuwanshi, K., Patel, V.K. et al. Assessment of 5-substituted Isatin as Surface Recognition Group: Design, Synthesis, and Antiproliferative Evaluation of Hydroxamates as Novel Histone Deacetylase Inhibitors. Pharm Chem J 51, 366–374 (2017). https://doi.org/10.1007/s11094-017-1616-1
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DOI: https://doi.org/10.1007/s11094-017-1616-1