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Medicinal Chemistry Research

, Volume 24, Issue 5, pp 1814–1829 | Cite as

Synthesis and biological evaluation of novel 1,2-benzisothiazol-3-one-derived 1,2,3-triazoles as caspase-3 inhibitors

  • Zhenfei Guo
  • Zhihui Yan
  • Xiaowei Zhou
  • Quan Wang
  • Meiqi Lu
  • Wei LiuEmail author
  • Honggang Zhou
  • Cheng Yang
  • Edward J. McClain
Original Research

Abstract

Several series of novel 1,4-disubstituted 1,2,3-triazoles were prepared using the Huisgen cycloaddition reaction and evaluated as inhibitors against caspase-3/-7. The 1,2-benzisothiazol-3-one-derived 1,4-disubstituted 1,2,3-triazoles containing an urea group had dramatically increased inhibitory activity in vitro compared to the others, and the most potent caspase-3 inhibitor was found to be N-((1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)-3-oxobenzoisothiazole-2(3H)-carboxamide 14c with IC50-values of 11.0 ± 1.2 nM. Meanwhile, the compound 14c showed significant protection against apoptosis in human Jurkat T cells, as determined by annexin V-FITC/7-AAD. Moreover, in order to better rationalize the action and the binding mode of these compounds, docking studies were carried out.

Keywords

Caspase-3 inhibitor 1,2,3-Triazoles 1,2-Benzisothiazol-3-one Apoptosis Docking studies 

Notes

Acknowledgment

This work was supported by the National Natural Science Foundation of China (Grant No. 21302139).

References

  1. Castro RE, Santos MM, Gloria PM, Ribeiro CJ, Ferreira DM, Xavier JM, Moreira R, Rodrigues CM (2010) Cell death targets and potential modulators in Alzheimer’s disease. Curr Pharm Des 16:2851–2864CrossRefPubMedGoogle Scholar
  2. Chen YH, Zhang YH, Zhang HJ et al (2006) Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors. J Med Chem 49:1613–1623CrossRefPubMedGoogle Scholar
  3. Chu W, Zhang J, Zeng C, Rothfuss J, Tu Z, Chu Y, Reichert DE, Welch MJ, Mach RH (2005) N-benzylisatin sulfonamide analogues as potent caspase-3 inhibitors: synthesis, in vitro activity, and molecular modeling studies. J Med Chem 48:7637–7647CrossRefPubMedGoogle Scholar
  4. Chu W, Rothfuss J, d’Avignon A, Zeng C, Zhou D, Hotchkiss RS, Mach RH (2007) Isatin sulfonamide analogs containing a Michael addition acceptor: a new class of caspase 3/7 inhibitors. J Med Chem 50:3751–3755CrossRefPubMedGoogle Scholar
  5. Chu W, Rothfuss J, Zhou D, Mach RH (2011) Synthesis and evaluation of isatin analogs as caspase-3 inhibitors: introduction of a hydrophilic group increases potency in a whole cell assay. Bioorg Med Chem Lett 21:2192–2197CrossRefPubMedCentralPubMedGoogle Scholar
  6. da Silva FD, de Souza MCBV, Frugulhetti IIP et al (2009) Synthesis, HIV-RT inhibitory activity and SAR of 1-benzyl-1H-1,2,3-triazole derivatives of carbohydrates. Eur J Med Chem 44:373–383CrossRefGoogle Scholar
  7. Dalvie DK, Kalgutkar AS, Khojasteh-Bakht SC, Obach RS, O’Donnell JP (2002) Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem Res Toxicol 15:269–299CrossRefPubMedGoogle Scholar
  8. Du JQ, Wu J, Zhang HJ, Zhang YH et al (2008) Isoquinoline-1,3,4-trione derivatives inactivate caspase-3 by generation of reactive oxygen species. J Biol Chem 283:30205–30215CrossRefPubMedCentralPubMedGoogle Scholar
  9. Fleischer A, Ghadiri A, Dessauge F, Duhamel M, Rebollo MP, AlvarezFranco F, Rebollo A (2006) Modulating apoptosis as a target for effective therapy. Mol Immunol 43:1065–1079CrossRefPubMedGoogle Scholar
  10. Gill C, Jadhav G, Shaikh M, Kale R, Ghawalkar A, Nagargoje D, Shiradkar M (2008) Clubbed [1,2,3] triazoles by fluorine benzimidazole: a novel approach to H37Rv inhibitors as a potential treatment for tuberculosis. Bioorg Med Chem Lett 18:6244–6247CrossRefPubMedGoogle Scholar
  11. Holla BS, Mahalinga M, Karthikeyan MS, Poojary B, Akberali PM, Kumari NS (2005) Synthesis, characterization and antimicrobial activity of some substituted 1,2,3-triazoles. Eur J Med Chem 40:1173–1178CrossRefPubMedGoogle Scholar
  12. Howley B, Fearnhead HO (2008) Caspases as therapeutic targets. J Cell Mol Med 12:1502–1516CrossRefPubMedCentralPubMedGoogle Scholar
  13. Jagasia R, Holub JM, Bollinger M, Kirshenbaum K, Finn MG (2009) Peptide cyclization and cyclodimerization by Cu-I-mediated azide-alkyne cycloaddition. J Org Chem 74:2964–2974CrossRefPubMedCentralPubMedGoogle Scholar
  14. Kravchenko DV, Kysil VM, Tkachenko SE, Maliarchouk S, Okun IM, Ivachtchenko AV (2005a) Pyrrolo[3,4-c]quinoline-1,3-diones as potent caspase-3 inhibitors. Synthesis and SAR of 2-substituted 4-methyl-8-(morpholine-4-sulfonyl)-pyrrolo[3,4-c]quinoline-1,3-diones. Eur J Med Chem 40:1377–1383CrossRefPubMedGoogle Scholar
  15. Kravchenko DV, Kuzovkova YA, Kysil VM, Tkachenko SE, Maliarchouk S, Okun IM, Balakin KV, Ivachtchenko AV (2005b) Synthesis and structure-activity relationship of 4-substituted 2-(2-acetyloxyethyl)-8-(morpholine-4-sulfonyl)pyrrolo[3,4-c]quinoline-1,3-diones as potent caspase-3 inhibitors. J Med Chem 48:3680–3683CrossRefPubMedGoogle Scholar
  16. Lee D, Long SA, Murray JH et al (2001) Potent and selective nonpeptide inhibitors of caspases 3 and 7. J Med Chem 44:2015–2026CrossRefPubMedGoogle Scholar
  17. Limpachayaporn P, Schäfers M, Schober O, Kopka K, Haufe G (2013) Synthesis of new fluorinated, 2-substituted 5-pyrrolidinylsulfonyl isatin derivatives as caspase-3 and caspase-7 inhibitors: nonradioactive counterparts of putative PET-compatible apoptosis imaging agents. Bioorg Med Chem 21:2025–2036CrossRefPubMedGoogle Scholar
  18. Linton SD, Karanewsky DS, Ternansky RJ et al (2002) Acyl dipeptides as reversible caspase inhibitors. Part 1: initial lead optimization. Bioorg Med Chem Lett 12:2969–2971CrossRefPubMedGoogle Scholar
  19. Liu DZ, Tian Z, Yan ZH, Wu LX, Ma Y, Wang Q, Liu W, Zhou HG, Yang C (2013) Design, synthesis and evaluation of 1,2-benzisothiazol-3-one derivatives as potent caspase-3 inhibitors. Bioorg Med Chem 21:2960–2967CrossRefPubMedGoogle Scholar
  20. Majer P, Randad RS (1994) A safe and efficient method for preparation of N, N′-unsymmetrically disubstituted ureas utilizing triphosgene. J Org Chem 59:1937–1938CrossRefGoogle Scholar
  21. Meldal M, Tornoe CW (2008) Cu-catalyzed azide-alkyne cycloaddition. Chem Rev 108:2952–3015CrossRefPubMedGoogle Scholar
  22. Ng SL, Yang PY, Chen KYT, Srinivasan R, Yao SQ (2008) Click synthesis of small-molecule inhibitors targeting caspases. Org Biomol Chem 6:844–847CrossRefPubMedGoogle Scholar
  23. Ni CZ, Li C, Wu JC, Spada AP, Ely KR (2003) Conformational restrictions in the active site of unliganded human caspase-3. J Mol Recognit 16:121–124CrossRefPubMedGoogle Scholar
  24. Nicholson DW, Ali A, Thornberry NA et al (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37–41CrossRefPubMedGoogle Scholar
  25. Pagliai F, Pirali T, Del Grosso E, Di Brisco R, Tron GC, Sorba G, Genazzani AA (2006) Rapid synthesis of triazole-modified resveratrol analogues via click chemistry. J Med Chem 49:467–470CrossRefPubMedGoogle Scholar
  26. Podichetty AK, Wagner S, Faust A, Schafers M, Schober O, Kopka K, Haufe G (2009) Fluorinated isatin derivatives. Part 3. New side-chain fluoro-functionalized pyrrolidinyl sulfonyl isatins as potent caspase-3 and-7 inhibitors. Future Med Chem 1:969–989CrossRefPubMedGoogle Scholar
  27. Porter AG, Janicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6:99–104CrossRefPubMedGoogle Scholar
  28. Schmidt MF, El-Dahshan A, Keller S, Rademann J (2009) Selective identification of cooperatively binding fragments in a high-throughput ligation assay enables development of a picomolar caspase-3 inhibitor. J Angew Chem Int Ed 48:6346–6349CrossRefGoogle Scholar
  29. Taylor RC, Cullen SP, Martin SJ (2008) Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Biol 9:231–241CrossRefPubMedGoogle Scholar
  30. Xing Y, Zhou Z, Agula ZhongZ, Ma Y, Zhao Y, Xiao X, Wang SQ (2012) Protocatechuic aldehyde inhibits lipopolysaccharide-induced human umbilical vein endothelial cell apoptosis via regulation of caspase-3. Phytother Res 26:1334–1341CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Zhenfei Guo
    • 2
  • Zhihui Yan
    • 2
  • Xiaowei Zhou
    • 2
  • Quan Wang
    • 3
  • Meiqi Lu
    • 3
  • Wei Liu
    • 1
    Email author
  • Honggang Zhou
    • 4
  • Cheng Yang
    • 4
    • 5
  • Edward J. McClain
    • 6
  1. 1.College of SciencesTianjin University of Science and TechnologyTianjinChina
  2. 2.College of BiotechnologyTianjin University of Science and TechnologyTianjinChina
  3. 3.College of Life SciencesNanKai UniversityTianjinChina
  4. 4.College of PharmacyNanKai UniversityTianjinChina
  5. 5.High Throughput Molecular Drug Discovery CenterTianjin International Joint Academy of Biotechnology and Medicine, TEDATianjinChina
  6. 6.C. Eugene Bennett Department of ChemistryWest Virginia UniversityMorgantownUSA

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