We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×

Key structural requirements of benzamide derivatives for histone deacetylase inhibition: design, synthesis and biological evaluation

    Narges Cheshmazar

    Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, 5165665813, Iran

    ,
    Maryam Hamzeh-Mivehroud

    Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, 5165665813, Iran

    Department of Medicinal Chemistry, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, 5166414766, Iran

    ,
    Salar Hemmati

    Drug applied research Center, Tabriz University of Medical Sciences, Tabriz, 5165665811, Iran

    ,
    Hoda Abolhasani

    Cellular & Molecular Research Center, Qom University of Medical Sciences, Qom, Iran

    Department of Pharmacology, School of Medicine, Qom University of Medical Sciences, Qom, Iran

    ,
    Fatemeh Heidari

    Cellular & Molecular Research Center, Qom University of Medical Sciences, Qom, Iran

    ,
    Hojjatollah Nozad Charoudeh

    Anatomical Sciences Department, Faculty of Medicine, Tabriz University of Medical, Tabriz, 5166614766, Iran

    ,
    Matthes Zessin

    Department of Enzymology, Institute of Biochemistry, Martin-Luther-University Halle-Wittenberg, Halle/Saale, 06120, Germany

    ,
    Mike Schutkowski

    Department of Enzymology, Institute of Biochemistry, Martin-Luther-University Halle-Wittenberg, Halle/Saale, 06120, Germany

    ,
    Wolfgang Sippl

    Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Halle/Saale, 06120, Germany

    &
    Siavoush Dastmalchi

    *Author for correspondence:

    E-mail Address: dastmalchi.s@tbzmed.ac.ir

    Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, 5165665813, Iran

    Department of Medicinal Chemistry, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, 5166414766, Iran

    Faculty of Pharmacy, Near East University, PO Box 99138, Nicosia, North Cyprus, Mersin, 10, Turkey

    Published Online:https://doi.org/10.4155/fmc-2023-0122

    Background: Histone deacetylase inhibitors (HDACIs) are important as anticancer agents. Objective: This study aimed to investigate some key structural features of HDACIs via the design, synthesis and biological evaluation of novel benzamide-based derivatives. Methods: Novel structures, designed using a molecular modification approach, were synthesized and biologically evaluated. Results: The results indicated that a subset of molecules with CH3/NH2 at R2 position possess selective antiproliferative activity. However, only those with an NH2 group showed HDACI activity. Importantly, the shorter the molecule length, the stronger HDACI. Among all, 7j was the most potent HDAC1-3 inhibitor and antiproliferative compound. Conclusion: The results of the present investigation could provide valuable structural knowledge applicable for the development of the HDACIs and benzamide-based antiproliferative agents in the future.

    Papers of special note have been highlighted as: • of interest

    References

    • 1. Motofei Ion G. Biology of cancer; from cellular cancerogenesis to supracellular evolution of malignant phenotype. Cancer Invest. 36(5), 309–317 (2018).
    • 2. Takeshima H, Ushijima T. Accumulation of genetic and epigenetic alterations in normal cells and cancer risk. NPJ Precis. Oncol. 3(1), 1–8 (2019).
    • 3. Akram MD, Iqbal M, Daniyal M et al. Awareness and current knowledge of breast cancer. Biol. Res. 50(1), 1–23 (2017).
    • 4. Audia J, Campbell R. Histone modifications and cancer. Csh. Perspect. Biol. 8(4), a019521 (2016).
    • 5. Verza F, Das U, Fachin A et al. Roles of histone deacetylases and inhibitors in anticancer therapy. Cancers 12(6), 1664 (2020).
    • 6. Kozikowski A, Butler K. Chemical origins of isoform selectivity in histone deacetylase inhibitors. Curr. Pharm. Design 14(6), 505–528 (2008).
    • 7. Mottamal M, Zheng SH, Huang Tien L et al. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules 20(3), 3898–3941 (2015).
    • 8. Dai W, Zhou J, Jin B et al. Class III-specific HDAC inhibitor Tenovin-6 induces apoptosis, suppresses migration and eliminates cancer stem cells in uveal melanoma. Sci. Rep. 6(1), 1–14 (2016).
    • 9. Yoon S, Eom G. HDAC and HDAC inhibitor: from cancer to cardiovascular diseases. Chonnam. Med. J. 52(1), 1–11 (2016).
    • 10. Mrakovcic M, Kleinheinz J, Fröhlich L. p53 at the crossroads between different types of HDAC inhibitor-mediated cancer cell death. Inte. J. Mol. Sci. 20(10), 2415 (2019).
    • 11. Hamze A. How do we improve histone deacetylase inhibitor drug discovery? Exp. Opin. Drug. Dis. 15(5), 527–529 (2020).
    • 12. Cheshmazar N, Hamzeh-Mivehroud M, Charoudeh Hojjatollah N et al. Current trends in development of HDAC-based chemotherapeutics. Life Sci. 308, 120946 (2022).
    • 13. Melesina J, Simoben C, Praetorius L et al. Strategies to design selective histone deacetylase inhibitors. Chem. Med. Chem. 16(9), 1336–1359 (2021). • Important review that describes the design strategies of selective histone deacetylase inhibitors (HDACIs).
    • 14. Patel V, Shirbhate E, Tiwari P et al. Multi-targeted HDAC inhibitors as anticancer agents: current status and future prospective. Curr. Med. Chem. 30(24), 2762–2795 (2023). • Interesting review that summarizes the the design strategies of multitargeted HDACIs.
    • 15. He J, Wang S, Liu X et al. Synthesis and biological evaluation of HDAC inhibitors with a novel zinc binding group. Front Chem. 8, 256 (2020). • Describes the design of potent HDACIs with novel zinc-binding groups.
    • 16. Yao D, Li CH, Jiang J et al. Design, synthesis and biological evaluation of novel HDAC inhibitors with improved pharmacokinetic profile in breast cancer. Eur. J. Med. Chem. 205, 112648 (2020). • Interesting study on the design and synthesis of novel HDAIs with an improved pharmacokinetic profile.
    • 17. Nepali K, Liou J. Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends. J. Biomed. Sci. 28(1), 1–58 (2021).
    • 18. Stojkovska J, Zvicer J, Milivojević M et al. Validation of a novel perfusion bioreactor system in cancer research. Hem. Ind. 74(3), 187–196 (2020).
    • 19. Cheshmazar N, Hemmati S, Hamzeh-Mivehroud M et al. Development of new inhibitors of HDAC1-3 Enzymes aided by in silico design strategies. J. Chem. Inf. Model. 62(10), 2387–2397 (2022).
    • 20. Marek M, Shaik T, Heimburg T et al. Characterization of histone deacetylase 8 (HDAC8) selective inhibition reveals specific active site structural and functional determinants. J. Med. Chem. 61(22), 10000–10016 (2018).
    • 21. Zessin M, Kutil Z, Meleshin M et al. One-atom substitution enables direct and continuous monitoring of histone deacylase activity. Biochemistry 58(48), 4777–4789 (2019).
    • 22. Heimburg T, Kolbinger F, Zeyen P et al. Structure-based design and biological characterization of selective histone deacetylase 8 (HDAC8) inhibitors with anti-neuroblastoma activity. J. Med. Chem. 60(24), 10188–10204 (2017).
    • 23. Mosdam T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxic assay. J. Immunol. Methods 65, 55–63 (1983).
    • 24. Liu T, Wan Y, Xiao Y et al. Dual-target inhibitors based on HDACs: novel antitumor agents for cancer therapy. J. Med. Chem. 63(17), 8977–9002 (2020).
    • 25. Finnin M, Donigian J, Cohen A et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401(6749), 188–193 (1999).
    • 26. Gfeller D, Grosdidier A, Wirth M et al. SwissTargetPrediction: a web server for target prediction of bioactive small molecules. Nucleic. Acids Res. 42(W1), W32–W38 (2014).
    • 27. Hu J, Wang Y, Li Y et al. Structure-based optimization of a series of selective BET inhibitors containing aniline or indoline groups. Eur. J. Med. Chem. 150, 156–175 (2018).
    • 28. Bressi J, Jennings A, Skene R et al. Exploration of the HDAC2 foot pocket: synthesis and SAR of substituted N-(2-aminophenyl) benzamides. Bioorg. Med. Chem. Lett. 20(10), 3142–3145 (2010).
    • 29. Vannini A, Volpari C, Filocamo G et al. Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc. Natl Acad. Sci. USA 101(42), 15064–15069 (2004).
    • 30. Molsoft L. Drug-Likeness and molecular property prediction (2018). www.molsoft.com/mprop/
    • 31. Ghose A, Viswanadhan V, Wendoloski J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem. 1(1), 55–68 (1999).
    • 32. Veber D, Johnson S, Cheng H et al. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 45(12), 2615–2623 (2002).
    • 33. Egan W, Merz K, Baldwin JJ. Prediction of drug absorption using multivariate statistics. J. Med. Chem. 43(21), 3867–3877 (2000).
    • 34. Muegge I, Heald S, Brittelli D. Simple selection criteria for drug-like chemical matter. J. Med. Chem. 44(12), 1841–1846 (2001).