Abstract
Despite the increased success rates of histone deacetylases inhibitors (HDACi) as potent anticancer agents, many metabolic obstacles face the hydroxamic acid-based HDAC inhibitors, which inspired us to develop non-hydroxamate HDAC inhibitors. Based on the established knowledge of the SAR of the reported HDAC inhibitors and based on the knowledge that salicylaldimine moiety is an established chelating agent, a series of salicylaldimine based HDAC inhibitors were designed, synthesized and biologically evaluated. The compound 14 in the present study showed considerable HDAC inhibition and potential antiproliferative activities on NCI cell lines rendering it as a good start for optimization that introduces a new class of non-hydroxamate HDAC inhibitors as potential anticancer agents.
Highlights
Histone deacetylases inhibitors (HDACi) proved their potent cytotoxic effects and their capability in a reversal of resistance in many cancer cell lines by regulating the expression of a number of tumor suppressor genes that are involved in apoptosis of cancer cells [1]
The overexpression of HDACs is directly linked to the poor prognosis of the cancer patient because they are responsible for removal of an acetyl group from the histones allowing interaction between negatively charged DNA and positively charged histone proteins, which lead to transcriptional silencing of tumor suppressor genes and apoptotic genes
We have explored the reported chelating agent salicylaldimine [17] and other imine analogs 2-thiophene imine and 2-pyridine imine to be the zinc-binding group (ZBG) [18,19] which connected via phenyl linker to different surface recognition caps containing urea, sulfonamides, piperazine and benzthiazole to form novel non-hydroxamate HDAC inhibitors targeting the cancer cells
Summary
Histone deacetylases inhibitors (HDACi) proved their potent cytotoxic effects and their capability in a reversal of resistance in many cancer cell lines by regulating the expression of a number of tumor suppressor genes that are involved in apoptosis of cancer cells [1]. We have explored the reported chelating agent salicylaldimine [17] and other imine analogs 2-thiophene imine and 2-pyridine imine to be the ZBGs [18,19] which connected via phenyl linker to different surface recognition caps containing urea, sulfonamides, piperazine and benzthiazole to form novel non-hydroxamate HDAC inhibitors targeting the cancer cells. The use of hydrophobic moieties as capping group such as naphthyl in compounds 15, 16, 17 and 6-methoxy benzothiazole as in compound 21 (Fig. 10) rendered the caps more surface binder with extra interaction with HIS651 These findings from molecular docking by autodock vina directed us to proceed in the chemical synthesis of the designed compounds and their further biological evaluation
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