Design, synthesis and biological evaluation of novel HDAC inhibitors: sulphur-containing zinc binding groups

doi:10.5246/jcps.2019.06.040

Abstract

Abstract:

Zinc binding group (ZBG) is the crucial moiety in the chemical structure of any HDAC inhibitor. In the present study, a series of sulphur-containing ZBG were designed and synthesized in the novel HDAC inhibitors to replace the classical ZBGs of SAHA and BML-210,hydroxamic acids and benzamides, respectively. The HDAC inhibitory activity and the structure-activity relationships of these molecules were analyzed. A sulphur-rich group, diethylcarbamo (dithioperoxo)thioate, was finally identifiedas a novel potent ZBG. Among all the synthesized compounds, 4d was much more potent compared with BML-210, and it showed similar inhibitory effect of SAHA against HDAC isoforms 1 and 2. Therefore, it was chosen as a lead compound.

Key words: Histone deacetylase inhibitor, Zinc binding group, Anticancer

CLC Number:

R914

Supporting:

Wenwen Cheng, Dongmei Zhang, Qiang Zheng, Zhongjun Li, Xiangbao Meng. Design, synthesis and biological evaluation of novel HDAC inhibitors: sulphur-containing zinc binding groups[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(6): 408-421.

References

[1] Roche, J.; Bertrand, P. Inside HDACs with more selective HDAC inhibitors. Eur. J. Med. Chem. 2016, 121, 451-483.

[2] Li, Z.M.; Zhu, W.G. Targeting histone deacetylases for cancer therapy: from molecular mechanisms to clinical implications. Int. J. Biol. Sci. 2014, 10, 757-770.

[3] Hou, J.L.; Li, Z.H.; Fang, Q.H.; Feng, C.R.; Zhang, H.W.; Guo, W.K.; Wang, H.H.; Gu, G.X.; Tian, Y.P.; Liu, P.; Liu, R.H.; Lin, J.P.; Shi, Y.K.; Yin, Z.; Shen, J.; Wang, P.G. Discovery and extensive in vitro evaluations of NK-HDAC-1: a chiral histone deacetylase inhibitor as a promising lead. J. Med. Chem. 2012, 55, 3066-3075.

[4] Patil, V.; Sodji, Q.H.; Kornacki, J.R.; Mrksich, M.; Oyelere, A.K. 3-Hydroxypyridin-2-thione as novel zinc binding group for selective histone deacetylase inhibition. J. Med. Chem. 2013, 56, 3492-3506.

[5] Eckschlager, T.; Plch, J.; Stiborova, M.; Hrabeta, J. Histone deacetylase inhibitors as anticancer drugs. Int. J. Mol. Sci. 2017, 18, E1414.

[6] Shen, S.D.; Kozikowski, A.P. Why hydroxamates May not be the best histone deacetylase inhibitors-what some May have forgotten or would rather forget? Chem. Med. Chem. 2016, 11, 15-21.

[7] Bora-Tatar, G.; Dayangaç-Erden, D.; Demir, A.S.; Dalkara, S.; Yelekçi, K.; Erdem-Yurter, H. Molecular modifications on carboxylic acid derivatives as potent histone deacetylase inhibitors: Activity and docking studies. Bioorg. Med. Chem. 2009, 17, 5219-5228.

[8] Nagaoka, Y.; Maeda, T.; Kawai, Y.; Nakashima, D.; Oikawa, T.; Shimoke, K.; Ikeuchi, T.; Kuwajima, H.; Uesato, S. Synthesis and cancer antiproliferative activity of new histone deacetylase inhibitors: hydrophilic hydroxamates and 2-aminobenzamide-containing derivatives. Eur. J. Med. Chem. 2006, 41, 697-708.

[9] Gu, W.X.; Nusinzon, I.; Smith, R.D. Jr, Horvath, C.M.; Silverman, R.B. Carbonyl- and sulfur-containing analogs of suberoylanilide hydroxamic acid: Potent inhibition of histone deacetylases. Bioorg. Med. Chem. 2006, 14, 3320-3329.

[10] Wang, L.; Zhang, J.Y.; Kim, B.; Peng, J.J.; Berry, S.N.; Ni, Y.; Su, D.D.; Lee, J.; Yuan, L.; Chang, Y.T. Boronic acid: A bio-inspired strategy to increase the sensitivity and selectivity of fluorescent NADH probe. J. Am. Chem. Soc. 2016, 138, 10394-10397.

[11] Suzuki, T.; Matsuura, A.; Kouketsu, A.; Hisakawa, S.; Nakagawa, H.; Miyata, N. Design and synthesis of non-hydroxamate histone deacetylase inhibitors: identification of a selective histone acetylating agent. Bioorg. Med. Chem. 2005, 13, 4332-4342.

[12] De-Vreese, R.; D'hooghe, M. Synthesis and applications of benzohydroxamic acid-based histone deacetylase inhibitors. Eur. J. Med. Chem. 2017, 135, 174-195.

[13] Wang, J.J.; Shen, Y.K.; Hu, W.P.; Hsieh, M.C.; Lin, F.L.; Hsu, M.K.; Hsu, M.H. Design, synthesis, and biological evaluation of pyrrolo[2, 1-c][1, 4]benzodiazepine and indole conjugates as anticancer agents. J. Med. Chem. 2006, 49, 1442-1449.

[14] Obermoser, V.; Urban, M.E.; Murgueitio, M.S.; Wolber, G.; Kintscher, U.; Gust, R. New telmisartan-derived PPARγ agonists: Impact of the 3D-binding mode on the pharmacological profile. Eur. J. Med. Chem. 2016, 124, 138-152.

[15] Wang, R.B.; Chen, C.S.; Zhang, X.J.; Zhang, C.D.; Zhong, Q.; Chen, G.L.; Zhang, Q.; Zheng, S.L.; Wang, G.D.; Chen, Q.H. Structure-activity relationship and pharmacokinetic studies of 1,5-diheteroarylpenta-1,4-Dien-3-ones: A class of promising curcumin-based anticancer agents. J. Med. Chem. 2015, 58, 4713-4726.

[16] Giannini, G.; Vesci, L.; Battistuzzi, G.; Vignola, D.; Milazzo, F.M.; Guglielmi, M.B.; Barbarino, M.; Santaniello, M.; Fantò, N.; Mor, M.; Rivara, S.; Pala, D.; Taddei, M.; Pisano, C.; Cabri, W. ST7612AA1, a thioacetate-ω(γ-lactam carboxamide) derivative selected from a novel generation of oral HDAC inhibitors. J. Med. Chem. 2014, 57, 8358-8377.

[17] Zhang, S.J.; Hu, W.X. Synthesis, antiproliferation, and docking studies of N-phenyl-lipoamide and 8-mercapto-N-phenyloctanamide derivatives: effects of C6 position thiol moiety. Med. Chem. Res. 2012, 21, 3312-3320.

[18] Cilibrasi, V.; Tsang, K.; Morelli, M.; Solfa, F.; Wiggins, H.L.; Jones, A.T.; Westwell, A.D. Synthesis of substituted carbamo(dithioperoxo)thioates as potential BCA2-inhibitory anticancer agents. Tetrahedron Lett. 2015, 56, 2583-2585.

[19] Villadsen, J.S.; Stephansen, H.M.; Maolanon, A.R.; Harris, P.; Olsen, C.A. Total synthesis and full histone deacetylase inhibitory profiling of Azumamides A-E as well as β²- epi-Azumamide E and β³-epi-Azumamide E. J. Med. Chem. 2013, 56, 6512-6520.

[20] Wang, J.J.; Shen, Y.K.; Hu, W.P.; Hsieh, M.C.; Lin, F.L.; Hsu, M.K.; Hsu, M.H. Design, synthesis, and biological evaluation of pyrrolo[2,1-c][1,4]benzodiazepine and indole conjugates as anticancer agents. J. Med. Chem. 2006, 49, 1442-1449.