Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma
Histone deacetylase 6 (HDAC6) is an attractive target for cancer therapeutic intervention. Selective HDAC6 inhibitors is important to minimise the side effects of pan inhibition. Thus, new class of hydroxamic acid-based derivatives were designed on structural basis to perform preferential activity a...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | http://dx.doi.org/10.1080/14756366.2019.1613987 |
| _version_ | 1818025482842537984 |
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| author | Shaymaa E. Kassab Samar Mowafy Aya M. Alserw Joustin A. Seliem Shahenda M. El-Naggar Nesreen N. Omar Mohamed M. Awad |
| author_facet | Shaymaa E. Kassab Samar Mowafy Aya M. Alserw Joustin A. Seliem Shahenda M. El-Naggar Nesreen N. Omar Mohamed M. Awad |
| author_sort | Shaymaa E. Kassab |
| collection | DOAJ |
| description | Histone deacetylase 6 (HDAC6) is an attractive target for cancer therapeutic intervention. Selective HDAC6 inhibitors is important to minimise the side effects of pan inhibition. Thus, new class of hydroxamic acid-based derivatives were designed on structural basis to perform preferential activity against HDAC6 targeting solid tumours. Interestingly, 1-benzylbenzimidazole-2-thio-N-hydroxybutanamide 10a showed impressive preference with submicromolar potency against HDAC6 (IC50 = 510 nM). 10a showed cytotoxic activity with interesting profile against CCHE-45 at (IC50 = 112.76 µM) when compared to standard inhibitor Tubacin (IC50 = 20 µM). Western blot analysis of acetylated-α-tubulin verified the HDAC6 inhibiting activity of 10a. Moreover, the insignificant difference in acetylated-α-tubulin induced by 10a and Tubacin implied the on-target cytotoxic activity of 10a. Docking of 10a in the binding site of HDAC6 attributed the activity of 10a to π-π stacking with the amino acids of the hydrophobic channel of HDAC6 and capture of zinc metal in bidentate fashion. The therapeutic usefulness besides the on-target activity may define 10a as an interesting safe-lead inhibitor for future development. |
| first_indexed | 2024-12-10T04:16:49Z |
| format | Article |
| id | doaj.art-fab1d4b581ff43a6b0a728973da405bc |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-10T04:16:49Z |
| publishDate | 2019-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-fab1d4b581ff43a6b0a728973da405bc2022-12-22T02:02:34ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742019-01-013411062107710.1080/14756366.2019.16139871613987Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinomaShaymaa E. Kassab0Samar Mowafy1Aya M. Alserw2Joustin A. Seliem3Shahenda M. El-Naggar4Nesreen N. Omar5Mohamed M. Awad6Damanhour UniversityMisr International UniversityChildren's Cancer Hospital in EgyptChildren's Cancer Hospital in EgyptChildren's Cancer Hospital in EgyptModern University for Technology and InformationHelwan UniversityHistone deacetylase 6 (HDAC6) is an attractive target for cancer therapeutic intervention. Selective HDAC6 inhibitors is important to minimise the side effects of pan inhibition. Thus, new class of hydroxamic acid-based derivatives were designed on structural basis to perform preferential activity against HDAC6 targeting solid tumours. Interestingly, 1-benzylbenzimidazole-2-thio-N-hydroxybutanamide 10a showed impressive preference with submicromolar potency against HDAC6 (IC50 = 510 nM). 10a showed cytotoxic activity with interesting profile against CCHE-45 at (IC50 = 112.76 µM) when compared to standard inhibitor Tubacin (IC50 = 20 µM). Western blot analysis of acetylated-α-tubulin verified the HDAC6 inhibiting activity of 10a. Moreover, the insignificant difference in acetylated-α-tubulin induced by 10a and Tubacin implied the on-target cytotoxic activity of 10a. Docking of 10a in the binding site of HDAC6 attributed the activity of 10a to π-π stacking with the amino acids of the hydrophobic channel of HDAC6 and capture of zinc metal in bidentate fashion. The therapeutic usefulness besides the on-target activity may define 10a as an interesting safe-lead inhibitor for future development.http://dx.doi.org/10.1080/14756366.2019.1613987preferential hdac6 inhibitoracetylated-α-tubulinon-target activitybenzimidazoleacute promyeloblastic leukemiachoroid plexus carcinomacytotoxicity |
| spellingShingle | Shaymaa E. Kassab Samar Mowafy Aya M. Alserw Joustin A. Seliem Shahenda M. El-Naggar Nesreen N. Omar Mohamed M. Awad Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma Journal of Enzyme Inhibition and Medicinal Chemistry preferential hdac6 inhibitor acetylated-α-tubulin on-target activity benzimidazole acute promyeloblastic leukemia choroid plexus carcinoma cytotoxicity |
| title | Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma |
| title_full | Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma |
| title_fullStr | Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma |
| title_full_unstemmed | Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma |
| title_short | Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma |
| title_sort | structure based design generated novel hydroxamic acid based preferential hdac6 lead inhibitor with on target cytotoxic activity against primary choroid plexus carcinoma |
| topic | preferential hdac6 inhibitor acetylated-α-tubulin on-target activity benzimidazole acute promyeloblastic leukemia choroid plexus carcinoma cytotoxicity |
| url | http://dx.doi.org/10.1080/14756366.2019.1613987 |
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