Abstract
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.
Highlights
Mechanisms and signalling pathways that lead to transformation of normal cell into cancer cell occupy a remarkable space in the experimental oncology researches
We have extended the work to determine the effect of 10a on HL60; an acute promyeloblastic leukemia cell line, as Histone deacetylase 6 (HDAC6) has been observed to be overexpressed in acute myeloid leukemia[76,77]
The present study introduced molecular, structural-based design and identification of new class of benzimidazole-based hydroxamic acid that involves a lead inhibitor with HDAC6 preferential inhibiting activity (HDAC6 IC50 1⁄4 510 nM) and on-target cytotoxic mechanism of action against CCHE-45 children brain cancer cells at (CCHE-45 IC50 1⁄4 112.76 mM)
Summary
Mechanisms and signalling pathways that lead to transformation of normal cell into cancer cell occupy a remarkable space in the experimental oncology researches. This type of biological studies succeeded to identify some important genes[1,2], proteins[3], transcriptional and epigenetic factors[4,5,6] that contribute to the hallmarks of cancer[7]. Epigenetic modifications are associated with changes in gene transcription, and alteration in chromatin structure[8]. HDACs are associated with chromatin condensed form[12], this heterochromatin structure intervenes with gene expression
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