Design, synthesis, and antitumor activity evaluation of carbazole derivatives with potent HDAC inhibitory activity
Histone deacetylase (HDAC), a key regulator in controlling the acetylation status of histone, are considered to be associated with viability, migration, invasion, proliferation and apoptosis of malignant tumors. The HDAC inhibition is an effective strategy for designing compounds against malignant t...
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| Published in | Medicinal chemistry research Vol. 32; no. 8; pp. 1677 - 1689 |
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| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
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01.08.2023
Springer Nature B.V |
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| Abstract | Histone deacetylase (HDAC), a key regulator in controlling the acetylation status of histone, are considered to be associated with viability, migration, invasion, proliferation and apoptosis of malignant tumors. The HDAC inhibition is an effective strategy for designing compounds against malignant tumors and five compounds have been approved by FDA or NMPA for clinical therapy. In this study, we designed and synthesized a series of novel carbazole-hydroxamate analogues as HDAC inhibitors and evaluated their anti-tumor properties in vitro. Compared with vorinostat, the HDAC semi-inhibitory concentration of compounds
3f
and
3g
decreased 4–13 folds, compounds
8a
and
8c
also showed strong inhibitory HDAC activity, and compound
3g
had a strong inhibitory effect on HDAC 1. The CCK8 assay showed that compounds
3g
displayed good antiproliferative activity on tested tumor cells. Flow cytometric and western blot assay showed that
3g
exerted anti-tumor activities by regulating the level of Ac-HH3 and activating the cleaved caspase 3. Based on these results, carbazole-hydroxamate derivative
3g
might become a potential anti-tumor candidate molecule to further structural optimization research.
Graphical Abstract |
|---|---|
| AbstractList | Histone deacetylase (HDAC), a key regulator in controlling the acetylation status of histone, are considered to be associated with viability, migration, invasion, proliferation and apoptosis of malignant tumors. The HDAC inhibition is an effective strategy for designing compounds against malignant tumors and five compounds have been approved by FDA or NMPA for clinical therapy. In this study, we designed and synthesized a series of novel carbazole-hydroxamate analogues as HDAC inhibitors and evaluated their anti-tumor properties in vitro. Compared with vorinostat, the HDAC semi-inhibitory concentration of compounds
3f
and
3g
decreased 4–13 folds, compounds
8a
and
8c
also showed strong inhibitory HDAC activity, and compound
3g
had a strong inhibitory effect on HDAC 1. The CCK8 assay showed that compounds
3g
displayed good antiproliferative activity on tested tumor cells. Flow cytometric and western blot assay showed that
3g
exerted anti-tumor activities by regulating the level of Ac-HH3 and activating the cleaved caspase 3. Based on these results, carbazole-hydroxamate derivative
3g
might become a potential anti-tumor candidate molecule to further structural optimization research.
Graphical Abstract Histone deacetylase (HDAC), a key regulator in controlling the acetylation status of histone, are considered to be associated with viability, migration, invasion, proliferation and apoptosis of malignant tumors. The HDAC inhibition is an effective strategy for designing compounds against malignant tumors and five compounds have been approved by FDA or NMPA for clinical therapy. In this study, we designed and synthesized a series of novel carbazole-hydroxamate analogues as HDAC inhibitors and evaluated their anti-tumor properties in vitro. Compared with vorinostat, the HDAC semi-inhibitory concentration of compounds 3f and 3g decreased 4–13 folds, compounds 8a and 8c also showed strong inhibitory HDAC activity, and compound 3g had a strong inhibitory effect on HDAC 1. The CCK8 assay showed that compounds 3g displayed good antiproliferative activity on tested tumor cells. Flow cytometric and western blot assay showed that 3g exerted anti-tumor activities by regulating the level of Ac-HH3 and activating the cleaved caspase 3. Based on these results, carbazole-hydroxamate derivative 3g might become a potential anti-tumor candidate molecule to further structural optimization research. |
| Author | Zheng, Chengyun Sun, Likun Chen, Chen Zhang, Liang Han, Leiqiang |
| Author_xml | – sequence: 1 givenname: Likun surname: Sun fullname: Sun, Likun organization: Department of Hematology, The Second Hospital of Shandong University – sequence: 2 givenname: Leiqiang surname: Han fullname: Han, Leiqiang organization: Department of Medicine, The Second Hospital of Shandong University – sequence: 3 givenname: Liang surname: Zhang fullname: Zhang, Liang organization: School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences) – sequence: 4 givenname: Chen orcidid: 0000-0002-5136-0351 surname: Chen fullname: Chen, Chen email: chenlwchen@163.com organization: School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences) – sequence: 5 givenname: Chengyun surname: Zheng fullname: Zheng, Chengyun email: sdeyzcy@email.sdu.edu.cn organization: Department of Hematology, The Second Hospital of Shandong University |
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| Cites_doi | 10.3390/ijms222111701 10.1021/acs.jmedchem.1c02225 10.1093/jmcb/mjz019 10.1021/acs.jmedchem.2c00866 10.1016/j.bmcl.2017.12.051 10.1016/j.ejmech.2022.114634 10.1016/j.ejmech.2017.03.064 10.1016/j.ejmech.2020.112844 10.1016/j.biopha.2021.112577 10.1016/j.ejmech.2015.02.059 10.1021/acs.jmedchem.0c01454 10.1002/med.21505 10.1021/jo0708846 10.1038/icb.2011.100 10.1016/j.pharmthera.2020.107721 10.1016/S1875-5364(18)30003-7 10.1016/j.ejmech.2021.114049 |
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| References_xml | – reference: BajboujKAl-AliARamakrishnanRKSaber-AyadMHamidQHistone modification in NSCLC: molecular mechanisms and therapeutic targetsInt J Mol Sci202122117011:CAS:528:DC%2BB3MXisFWlsLnK10.3390/ijms222111701347691318584007 – reference: HuangLFengZ-LWangY-TLinL-GAnticancer carbazole alkaloids and coumarins from Clausena plants: a reviewChin J Nat Med20171588181:CAS:528:DC%2BB3cXislSrtL%2FE10.1016/S1875-5364(18)30003-729329644 – reference: ChenCHouXWangGPanWYangXZhangYDesign, synthesis and biological evaluation of quinoline derivatives as HDAC class I inhibitorsEur J Med Chem201713311231:CAS:528:DC%2BC2sXlvVCit7s%3D10.1016/j.ejmech.2017.03.06428371677 – reference: VelascoDCastellanosSLópezMLópez-CalahorraFBrillasEJuliáLRed organic light-emitting radical adducts of carbazole and tris(2,4,6-trichlorotriphenyl)methyl radical that exhibit high thermal stability and electrochemical amphotericityJ Org Chem2007727523321:CAS:528:DC%2BD2sXpvFOit7s%3D10.1021/jo070884617824646 – reference: PunpaiSSaenkhamAJarintananFJongrungruangchokSChoowongkomonKSuksamrarnSHDAC inhibitor cowanin extracted from G. fusca induces apoptosis and autophagy via inhibition of the PI3K/Akt/mTOR pathways in Jurkat cellsBiomed Pharmacother20221471125771:CAS:528:DC%2BB38XhtVyht7vL10.1016/j.biopha.2021.11257735078092 – reference: LiuMGaoSLiangTQiuXYangXFangHDiscovery of novel Src homology-2 domain-containing phosphatase 2 and histone deacetylase dual inhibitors with potent antitumor efficacy and enhanced antitumor immunityJ Med Chem20226512200181:CAS:528:DC%2BB38XitlGrs7rN10.1021/acs.jmedchem.2c0086636097406 – reference: Khan O, La Thangue NB. HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol. 2012;90:85–94. https://doi.org/10.1038/icb.2011.100. – reference: Abu-ZhayiaERMachourFEAyoubNHDAC-dependent decrease in histone crotonylation during DNA damageJ Mol Cell Biol201911804610.1093/jmcb/mjz019308646656821229 – reference: ChenCChuHWangAYinHGaoYLiuSDiscovery of 2,5-diphenyl-1,3,4-thiadiazole derivatives as HDAC inhibitors with DNA binding affinityEur J Med Chem20222411146341:CAS:528:DC%2BB38XitFSlurbM10.1016/j.ejmech.2022.11463435939996 – reference: KunadisELakiotakiEKorkolopoulouPPiperiCTargeting post-translational histone modifying enzymes in glioblastomaPharmacol Ther20212201077211:CAS:528:DC%2BB3cXit1OqtbrP10.1016/j.pharmthera.2020.10772133144118 – reference: VaidyaGNRanaPVenkateshAChatterjeeDRContractorDSatputeDPParadigm shift of “classical” HDAC inhibitors to “hybrid” HDAC inhibitors in therapeutic interventionsEur J Med Chem20212091128441:CAS:528:DC%2BB3cXit1Grsb%2FF10.1016/j.ejmech.2020.11284433143937 – reference: GłuszyńskaABiological potential of carbazole derivativesEur J Med Chem201594405261:CAS:528:DC%2BC2MXktVertro%3D10.1016/j.ejmech.2015.02.05925794500 – reference: CuiHHongQWeiRLiHWanCChenXDesign and synthesis of HDAC inhibitors to enhance the therapeutic effect of diffuse large B-cell lymphoma by improving metabolic stability and pharmacokinetic characteristicsEur J Med Chem20222291140491:CAS:528:DC%2BB38Xhs1Cksw%3D%3D10.1016/j.ejmech.2021.11404934954594 – reference: LiangTZhouYElhassanRMHouXYangXFangHHDAC–Bax multiple ligands enhance Bax-dependent apoptosis in Hela cellsJ Med Chem20206312083991:CAS:528:DC%2BB3cXhvFyiu77N10.1021/acs.jmedchem.0c0145433021789 – reference: Hesham HM, Lasheen DS, Abouzid KAM. Chimeric HDAC inhibitors: comprehensive review on the HDAC-based strategies developed to combat cancer. Med Res Rev. 2018;38:2058–109. https://doi.org/10.1002/med.21505. – reference: HumphriesPSBersotRKincaidJMaberyEMcCluskieKParkTCarbazole-containing amides and ureas: discovery of cryptochrome modulators as antihyperglycemic agentsBioorg Med Chem Lett20182829371:CAS:528:DC%2BC1cXitlSrtQ%3D%3D10.1016/j.bmcl.2017.12.05129292223 – reference: ChenCLiXZhaoHLiuMDuJZhangJDiscovery of DNA-targeting HDAC inhibitors with potent antitumor efficacy in vivo that trigger antitumor immunityJ Med Chem2022653667831:CAS:528:DC%2BB38XjtlCmu78%3D10.1021/acs.jmedchem.1c0222535152694 – volume: 22 start-page: 11701 year: 2021 ident: 3084_CR2 publication-title: Int J Mol Sci doi: 10.3390/ijms222111701 – volume: 65 start-page: 3667 year: 2022 ident: 3084_CR16 publication-title: J Med Chem doi: 10.1021/acs.jmedchem.1c02225 – volume: 11 start-page: 804 year: 2019 ident: 3084_CR4 publication-title: J Mol Cell Biol doi: 10.1093/jmcb/mjz019 – volume: 65 start-page: 12200 year: 2022 ident: 3084_CR8 publication-title: J Med Chem doi: 10.1021/acs.jmedchem.2c00866 – volume: 28 start-page: 293 year: 2018 ident: 3084_CR13 publication-title: Bioorg Med Chem Lett doi: 10.1016/j.bmcl.2017.12.051 – volume: 241 start-page: 114634 year: 2022 ident: 3084_CR14 publication-title: Eur J Med Chem doi: 10.1016/j.ejmech.2022.114634 – volume: 133 start-page: 11 year: 2017 ident: 3084_CR15 publication-title: Eur J Med Chem doi: 10.1016/j.ejmech.2017.03.064 – volume: 209 start-page: 112844 year: 2021 ident: 3084_CR9 publication-title: Eur J Med Chem doi: 10.1016/j.ejmech.2020.112844 – volume: 147 start-page: 112577 year: 2022 ident: 3084_CR6 publication-title: Biomed Pharmacother doi: 10.1016/j.biopha.2021.112577 – volume: 94 start-page: 405 year: 2015 ident: 3084_CR12 publication-title: Eur J Med Chem doi: 10.1016/j.ejmech.2015.02.059 – volume: 63 start-page: 12083 year: 2020 ident: 3084_CR5 publication-title: J Med Chem doi: 10.1021/acs.jmedchem.0c01454 – ident: 3084_CR10 doi: 10.1002/med.21505 – volume: 72 start-page: 7523 year: 2007 ident: 3084_CR17 publication-title: J Org Chem doi: 10.1021/jo0708846 – ident: 3084_CR1 doi: 10.1038/icb.2011.100 – volume: 220 start-page: 107721 year: 2021 ident: 3084_CR3 publication-title: Pharmacol Ther doi: 10.1016/j.pharmthera.2020.107721 – volume: 15 start-page: 881 year: 2017 ident: 3084_CR11 publication-title: Chin J Nat Med doi: 10.1016/S1875-5364(18)30003-7 – volume: 229 start-page: 114049 year: 2022 ident: 3084_CR7 publication-title: Eur J Med Chem doi: 10.1016/j.ejmech.2021.114049 |
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| SubjectTerms | Acetylation Anticancer properties Antitumor activity Antitumor agents Apoptosis Biochemistry Biomedical and Life Sciences Biomedicine Bioorganic Chemistry Carbazole Carbazoles Caspase-3 Flow cytometry Histone deacetylase Histones Inorganic Chemistry Medicinal Chemistry Optimization Original Article Pharmacology/Toxicology Tumor cells Tumors |
| Title | Design, synthesis, and antitumor activity evaluation of carbazole derivatives with potent HDAC inhibitory activity |
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