Design, Synthesis, Docking, and Biological Evaluation of Novel Diazide-containing Isoxazole- and Pyrazole-based Histone Deacetylase Probes

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2011 May 10

PMID 21548582

Citations 21

Authors

Raghupathi Neelarapu

Denise L Holzle

Subash Velaparthi

He Bai

Michael Brunsteiner

Sylvie Y Blond

Pavel A Petukhov

Affiliations

Soon will be listed here.

Abstract

The design, synthesis, docking, and biological evaluation of novel potent HDAC3 and HDAC8 isoxazole- and pyrazole-based diazide probes suitable for binding ensemble profiling with photoaffinity labeling (BEProFL) experiments in cells is described. Both the isoxazole- and pyrazole-based probes exhibit low nanomolar inhibitory activity against HDAC3 and HDAC8, respectively. The pyrazole-based probe 3f appears to be one of the most active HDAC8 inhibitors reported in the literature with an IC(50) of 17 nM. Our docking studies suggest that unlike the isoxazole-based ligands the pyrazole-based ligands are flexible enough to occupy the second binding site of HDAC8. Probes/inhibitors 2b, 3a, 3c, and 3f exerted the antiproliferative and neuroprotective activities at micromolar concentrations through inhibition of nuclear HDACs, indicating that they are cell permeable and the presence of an azide or a diazide group does not interfere with the neuroprotection properties, or enhance cellular cytotoxicity, or affect cell permeability.

Citing Articles

Suberoylanilide Hydroxamic Acid Analogs with Heteroaryl Amide Group and Different Chain Length: Synthesis and Effect on Histone Deacetylase.

Micheletti G, Boga C, Drius G, Bordoni S, Calonghi N Molecules. 2024; 29(1).

PMID: 38202821 PMC: 10781187. DOI: 10.3390/molecules29010238.

A Therapeutic Perspective of HDAC8 in Different Diseases: An Overview of Selective Inhibitors.

Fontana A, Cursaro I, Carullo G, Gemma S, Butini S, Campiani G Int J Mol Sci. 2022; 23(17).

PMID: 36077415 PMC: 9456347. DOI: 10.3390/ijms231710014.

Next-generation of selective histone deacetylase inhibitors.

Yang F, Zhao N, Ge D, Chen Y RSC Adv. 2022; 9(34):19571-19583.

PMID: 35519364 PMC: 9065321. DOI: 10.1039/c9ra02985k.

Identification of novel leads as potent inhibitors of HDAC3 using ligand-based pharmacophore modeling and MD simulation.

Kumbhar N, Nimal S, Barale S, Kamble S, Bavi R, Sonawane K Sci Rep. 2022; 12(1):1712.

PMID: 35110603 PMC: 8810932. DOI: 10.1038/s41598-022-05698-7.

Construction of Spirooxindole Analogues Engrafted with Indole and Pyrazole Scaffolds as Acetylcholinesterase Inhibitors.

Islam M, Al-Majid A, Azam M, Verma V, Barakat A, Haukka M ACS Omega. 2021; 6(47):31539-31556.

PMID: 34869980 PMC: 8637602. DOI: 10.1021/acsomega.1c03978.

References

Hockly E, Richon V, Woodman B, Smith D, Zhou X, Rosa E . Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci U S A. 2003; 100(4):2041-6. PMC: 149955. DOI: 10.1073/pnas.0437870100. View

Suzuki T, Nagano Y, Kouketsu A, Matsuura A, Maruyama S, Kurotaki M . Novel inhibitors of human histone deacetylases: design, synthesis, enzyme inhibition, and cancer cell growth inhibition of SAHA-based non-hydroxamates. J Med Chem. 2005; 48(4):1019-32. DOI: 10.1021/jm049207j. View

He B, Velaparthi S, Pieffet G, Pennington C, Mahesh A, Holzle D . Binding ensemble profiling with photoaffinity labeling (BEProFL) approach: mapping the binding poses of HDAC8 inhibitors. J Med Chem. 2009; 52(22):7003-13. PMC: 2789734. DOI: 10.1021/jm9005077. View

de Ruijter A, van Gennip A, Caron H, Kemp S, van Kuilenburg A . Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2002; 370(Pt 3):737-49. PMC: 1223209. DOI: 10.1042/BJ20021321. View

Barral K, Moorhouse A, Moses J . Efficient conversion of aromatic amines into azides: a one-pot synthesis of triazole linkages. Org Lett. 2007; 9(9):1809-11. DOI: 10.1021/ol070527h. View

Jain A . Surflex-Dock 2.1: robust performance from ligand energetic modeling, ring flexibility, and knowledge-based search. J Comput Aided Mol Des. 2007; 21(5):281-306. DOI: 10.1007/s10822-007-9114-2. View

Condorelli F, Gnemmi I, Vallario A, Genazzani A, Canonico P . Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells. Br J Pharmacol. 2007; 153(4):657-68. PMC: 2259214. DOI: 10.1038/sj.bjp.0707608. View

Li B, Desai S, Fan L, Spencer D . A novel conditional Akt 'survival switch' reversibly protects cells from apoptosis. Gene Ther. 2002; 9(4):233-44. DOI: 10.1038/sj.gt.3301641. View

Kozikowski A, Tapadar S, Luchini D, Kim K, Billadeau D . Use of the nitrile oxide cycloaddition (NOC) reaction for molecular probe generation: a new class of enzyme selective histone deacetylase inhibitors (HDACIs) showing picomolar activity at HDAC6. J Med Chem. 2008; 51(15):4370-3. PMC: 3913184. DOI: 10.1021/jm8002894. View

10.

Hosoya T, Hiramatsu T, Ikemoto T, Nakanishi M, Aoyama H, Hosoya A . Novel bifunctional probe for radioisotope-free photoaffinity labeling: compact structure comprised of photospecific ligand ligation and detectable tag anchoring units. Org Biomol Chem. 2004; 2(5):637-41. DOI: 10.1039/b316221d. View

11.

Workman P, Clarke P, Raynaud F, van Montfort R . Drugging the PI3 kinome: from chemical tools to drugs in the clinic. Cancer Res. 2010; 70(6):2146-57. PMC: 3242038. DOI: 10.1158/0008-5472.CAN-09-4355. View

12.

Oehme I, Deubzer H, Wegener D, Pickert D, Linke J, Hero B . Histone deacetylase 8 in neuroblastoma tumorigenesis. Clin Cancer Res. 2009; 15(1):91-9. DOI: 10.1158/1078-0432.CCR-08-0684. View

13.

Korner M, Tibes U . Histone deacetylase inhibitors: a novel class of anti-cancer agents on its way to the market. Prog Med Chem. 2008; 46:205-80. DOI: 10.1016/S0079-6468(07)00005-7. View

14.

Bradford M . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54. DOI: 10.1016/0003-2697(76)90527-3. View

15.

Vlahos C, Matter W, Hui K, Brown R . A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem. 1994; 269(7):5241-8. View

16.

Mann B, Johnson J, Cohen M, Justice R, Pazdur R . FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist. 2007; 12(10):1247-52. DOI: 10.1634/theoncologist.12-10-1247. View

17.

Witt O, Deubzer H, Milde T, Oehme I . HDAC family: What are the cancer relevant targets?. Cancer Lett. 2008; 277(1):8-21. DOI: 10.1016/j.canlet.2008.08.016. View

18.

Estiu G, West N, Mazitschek R, Greenberg E, Bradner J, Wiest O . On the inhibition of histone deacetylase 8. Bioorg Med Chem. 2010; 18(11):4103-10. PMC: 3245874. DOI: 10.1016/j.bmc.2010.03.080. View

19.

Oehme I, Deubzer H, Lodrini M, Milde T, Witt O . Targeting of HDAC8 and investigational inhibitors in neuroblastoma. Expert Opin Investig Drugs. 2009; 18(11):1605-17. DOI: 10.1517/14728220903241658. View

20.

Acharya M, Sparreboom A, Venitz J, Figg W . Rational development of histone deacetylase inhibitors as anticancer agents: a review. Mol Pharmacol. 2005; 68(4):917-32. DOI: 10.1124/mol.105.014167. View