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Effect of two series of isoindolines over HDAC8 activity and expression

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Abstract

This work describes the effect of two series of isoindolines 1(a–g) and 2(a–g) on histone deacetylase 8 (HDAC8) activity by theoretical study (docking method) and experimental assays using a commercial kit, as well as the effect of isoindolines on HDAC8 expression on HeLa cells. The theoretical study show interactions of the isoindolines with two HDAC8 deep pockets; these binding sites were compared to those of HDAC8 inhibitor, Trichostatin A. It was demonstrated experimentally that tested compounds can act as HDAC8 inhibitors. The expression of HDAC8 by Western blot analysis, remain unchanged in HeLa cells treated with the isoindolines with the exception of compound 2b which seems to increase HDAC8 expression. In conclusion, isoindolines act as HDAC8 inhibitors because they do not decrease the protein expression.

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References

  • Barlaam B, Dantzman C (2002) Preparation of isoquinolines and isoindolines as selective estrogen receptor-β ligand. WO 0246164

  • Berger D, Citarella R, Dutia M, Greenberger L, Hallet W, Paul R, Powell D (1999) Novel multidrug resistance reversal agents. J Med Chem 42:2145–2161. doi:10.1021/jm9804477

    Article  CAS  PubMed  Google Scholar 

  • Bhagwat SS, Gayo F, Leah M, Stein BM, Chao Qi, Gangloff AR, McKie JA, Rice KD (2002) Preparation of tetrahydroisoquinolines, tetrahydrobenzazepines, and isoindolines as selective modulators of ER-β estrogen receptors for the treatment of estrogen-related conditions. WO 0224653

  • Chimenti F, Vomero S (1975) Synthesis of N-substituted isoindolines. Farmaco Sci 30:884–890

    CAS  PubMed  Google Scholar 

  • Kukkola PJ, Bilci NA, Ikler T, Savage P, Shetty SS, DelGrande D, Jeng AY (2001) Isoindolines: a new series of potent and selective endothelin-A receptor antagonists. Bioorg Med Chem Lett 11:1737–1740. doi:10.1016/S0960-894x(01)00273-6

    Article  CAS  PubMed  Google Scholar 

  • Kurys BE, Fink DM, Freed BS, Meriman GH (1998) N-(pyridinylamino)isoindolines for treating Alzheimer’s and depression. WO1998029407

  • Lee S, Shinji C, Ogura K, Shimizu M, Maeda S, Sato M, Yoshida M, Hashimoto Y, Miyachi H (2007) Design, synthesis, and evaluation of isoindolinone-hydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Bioorg Med Chem Lett 17:4895–4900. doi:10.1016/j.bmcl.2007.06.038

    Article  CAS  PubMed  Google Scholar 

  • Lin HY, Chen CS, Lin SP, Weng JR, Chen CS (2006) Targeting histone deacetylase in cancer therapy. Med Res Rev 26:397–413. doi:10.1002/med.20056

    Article  CAS  PubMed  Google Scholar 

  • Maier T, Beckers T, Hesslinger C (2009) Preparation of tetrahydroisoquinoline/isoindoline hydroxamic acids as HDAC6 histone deacetylase inhibitors. WO 2009-EP52924

  • Mancilla Percino T, Correa Basurto J, Trujillo Ferrara J, Ramos Morales FR, Acosta Hernández ME, Cruz-Sánchez JS, Saavedra-Vélez M (2010) Molecular modeling study of isoindolines as l-type Ca2+ channel blockers by docking calculations. J Mol Model 16:1377–1382. doi:10.1007/s00894-010-0643-6

    Article  CAS  PubMed  Google Scholar 

  • Mancilla T, Carrillo L, Zamudio L, Beltran HI, Farfan N (2001) Synthesis and characterization of new 2-substituted isoindoline derivatives of α-amino acids. Org Prep Proc Int 33:341–349. doi:10.1080/00304940109356598

    Article  CAS  Google Scholar 

  • Mancilla T, Correa-Basurto J, Alavés Carbajal KS, Sánchez Escalante ETJ, Trujillo Ferrara J (2007) Theoretical study of isoindolines to identify them as cyclooxigenase-1 and -2 inhibitors by docking simulation. J Mex Chem Soc 51:95–102 ISSN1870-249X

    Google Scholar 

  • Mertens A, Zilch H, Koenig B, Schaefer W, Poll T, Kampe W, Seidel H, Leser U, Leinert H (1993) Selective non-nucleoside HIV-1 reverse transcriptase inhibitors. New 2,3-dihydrothiazolo(2,3-a)isoindol-5(9bH)-ones and related compounds with anti-HIV-1 activity. J Med Chem 36:2526–2535. doi:10.1021/jm00069a011

    Article  CAS  PubMed  Google Scholar 

  • Muller GW, Stirling DI, Chen RS, Man H (1999a) Preparation of 2-(2,6-dioxo-3-fluoropiperidin-3-yl) isoindolines for reducing inflammatory cytokine levels. US 98-42274

  • Muller GW, Stirling DI, Chen RS, Man H (1999b) Preparation of 2-(2, 6-dioxo-3-fluoropiperidin-3-yl) isoindolines and their use to reduce tumor necrosis factor α levels. WO 98-US24453

  • Muller GW, Stirling DI, Man H (2008) Pharmaceutically active isoindoline derivatives. TW 2001-90128385

  • Robarge MJ, Chen RS, Muller GW, Man H (2001) Isoindoline derivates as TNF-inhibitors. EP2168958

  • Schrump DS (2009) Cytotoxicity mediated by histone deacetylase inhibitors in cancer cells: mechanisms and potential clinical implications. Clin Cancer Res 15:3947–3957. doi:10.1158/1078-0432.CCR-08-2787

    Article  CAS  PubMed  Google Scholar 

  • Shinji C, Nakamura T, Maeda S, Yoshida M, Hashimoto Y, Miyachi H (2005) Design and synthesis of phthalimide-type histone deacetylase inhibitors. Bioorg Med Chem Lett 15:4427–4431. doi:10.1016/j.bmcl.2005.07.048

    Article  CAS  PubMed  Google Scholar 

  • Trejo Muñoz CR, Mancilla Percino T, Mera Jiménez E, Correa-J, Trujillo Ferrara JG (2012) Partition coefficient determination of a series of isoindolines-2-substituted and its correlation with their antiproliferative activity on HeLa cells. Med Chem Res. http://link.springer.com/article/10.1007%2Fs00044-012-0399-x. Accessed 06 April 2013

  • Witt O, Hedwig ED, Milde T, Oehme I (2009) HDAC family: what are the cancer relevant targets? Cancer Lett 277:8–21. doi:10.1016/j.canlet.2008.08.016

    Article  CAS  PubMed  Google Scholar 

  • MDL Information Systems Inc. (2002) ISIS/Draw, v.2.3 and 2.5. MDL Information Systems, Inc (now Symyx Technologies, Inc.), San Leandro

  • Buggy JJ, Sideris ML, Mak P, Lorimer DD, McIntosh B, Clark JM (2000) Cloning and characterization of a novel human histone deacetylase, HDAC8. Biochem J 350:199–205. doi:10.1074/jbc.M908988199

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Estiu G, West N, Mazitschek R, Greenberg E, Bradner JE (2010) On the inhibition of histone deacetylase 8. Bioorg Med Chem 18:4103–4110. doi:10.1016/j.bmc.2010.03.080

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Zakrzewski VG, Montgomery JA, Stratmann RE, Burant JC, Dapprich S, Millam JM, Daniels AD, Kudin KN, Strain MC, Farkas O, Tomasi J, Barone V, Cossi M, Cammi R, Mennucci B, Pomelli C, Adamo C, Clifford S, Ochterski J, Peterson GA, Ayala PY, Cui Q, Morokuma K, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Cioslowski J, Ortiz JV, Baboul AG, Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Gomperts R, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Andres JL, Gonzalez C, Head-Gordon M, Replogle ES, Pople JA (1998) Gaussian 98, Revision A.9, Gaussian, Inc, Pittsburgh, PA

  • Humprey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38. doi:10.1016/0236-7855(96)00018-5

    Article  Google Scholar 

  • Jing H, Hongli L, Yan C (2006) Effects of trichostatin A on HDAC8 expression, proliferation and cell cycle of Molt-4 cells. J Huazhong Univ Sci Technol 26:531–533

    Article  Google Scholar 

  • Montero A, Beierle JM, Olsen CA, Ghadiri MR (2009) Design, synthesis, biological evaluation, and structural characterization of potent histone deacetylase inhibitors based on cyclic alpha/beta-tetrapeptide architectures. J Am Chem Soc 131:3033–3041. doi:10.1021/ja809508f

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662. doi:10.1002/(SICI)1096-987x(19981115

    Article  CAS  Google Scholar 

  • Oehme I, Deubzer HE, Wegener D, Pickert D, Linke JP, Hero B, Kopp-Schneider A, Westermann F, Ulrich SM, von Deimling A, Fischer M, Witt O (2009) Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res 15:91–99. doi:10.1517/14728220903241658

    Article  CAS  PubMed  Google Scholar 

  • Somoza JR, Skene RJ, Katz BA, Mol C, Ho JD, Jennings AJ, Luong C, Arvai A, Buggy JJ, Chi E, Tang J, Sang BC, Verner E, Wynands R, Leahy EM, Dougan DR, Snell G, Navre M, Knuth MW, Swanson RV, McRee DE, Tari WE (2004) Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure 12:1325–1334. doi:10.1016/j.str.2004.04.012

    Article  CAS  PubMed  Google Scholar 

  • Vannini A, Volpari C, Filocamo G, Casavola EC, Brunetti M, Renzoni D, Chakravarty P, de Francesco Paolini, Gallinari P, Steinkühler Ch, di Marco S (2004) Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. PNAS 101:15064–15069. doi:10.1073/pnas.0404603101

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are grateful to CONACYT for scholarship No. 215133 to CRTM, SIP-COFAA/IPN, CONACYT (132353), and ICyTDF for financial support, to Brenda Trejo for language help corrections.

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Authors and Affiliations

  1. Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina del Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, C.P. 11340, Mexico, D. F., Mexico

    Cynthia R. Trejo Muñoz, Elvia Mera Jiménez, José Correa-Basurto & José G. Trujillo-Ferrara

  2. Departamento de Química y, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, C.P. 07000, Mexico, D. F., Mexico

    Cynthia R. Trejo Muñoz & Teresa Mancilla Percino

  3. Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, C.P. 07000, Mexico, D. F., Mexico

    José Alfredo Díaz Gandarilla & Patricia Talamás Rohana

  4. Unidad de Investigación Médica en Farmacología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, C.P. 06720, Mexico, D. F., Mexico

    Rodolfo Pinto-Almazán & Christian Guerra-Araiza

  5. Unidad de Investigación HRAE Ixtapaluca, Carretera Federal México-Puebla, km 34.5, C.P. 56530, Ixtapaluca, Edo. De México, Mexico

    Rodolfo Pinto-Almazán

Authors
  1. Cynthia R. Trejo Muñoz
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  2. Elvia Mera Jiménez
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  3. Rodolfo Pinto-Almazán
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  4. José Alfredo Díaz Gandarilla
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  5. José Correa-Basurto
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  6. José G. Trujillo-Ferrara
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  7. Christian Guerra-Araiza
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  8. Patricia Talamás Rohana
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  9. Teresa Mancilla Percino
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Correspondence to Teresa Mancilla Percino.

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Trejo Muñoz, C.R., Jiménez, E.M., Pinto-Almazán, R. et al. Effect of two series of isoindolines over HDAC8 activity and expression. Med Chem Res 23, 3227–3234 (2014). https://doi.org/10.1007/s00044-013-0903-y

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  • DOI: https://doi.org/10.1007/s00044-013-0903-y

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