Please use this identifier to cite or link to this item: http://hdl.handle.net/10603/291962
Title: Design synthesis and biological characterization of isoform selective histone deacetylase HDAC inhibitors
Researcher: Trivedi Prakruti
Guide(s): BALARAM GHOSH
Keywords: Clinical Pre Clinical and Health
Pharmacology and Pharmacy
Pharmacology and Toxicology
University: Birla Institute of Technology and Science
Completed Date: 2018
Abstract: Histone deacetylases (HDACs) have been found as a potential target for anticancer therapy. newlineA number of HDAC inhibitors have been used pre-clinically and clinically as anticancer newlineagents. Structural modifications of prototype HDAC inhibitors with different chemical newlinemoiety enhance efficiency and selectivity of compounds. With this approach, we have newlinedesigned and synthesized three series of compounds and evaluated their HDAC inhibition newlineefficiency and anticancer activity. newlineFirst, we have designed and synthesized compound 12a by combining the scaffolds of CI- newline994 and BG45. Moreover, the structure of compound 12a was optimized and a series of 2- newlineaminobenzamide derivatives were synthesized further. These compounds were tested for newlinetheir HDAC inhibitory activity and found to be efficient HDAC inhibitors. Compound 26c newlineshowed around 12-fold HDAC3 selectivity over pan HDACs, more than the prototype newlineHDAC3 inhibitor BG-45. Most of these compounds exhibited antiproliferative activity in newlineboth B16F10 and HeLa cell lines. Particularly, compound 26c exhibited better antitumor newlineefficacy in the cell lines compared to both prototype inhibitors CI-994 and BG45. It was newlinealso found to promote apoptosis as well as induced significant cell growth arrest in the newlineG2/M phase of cell cycle in B16F10 melanoma cells. newlineSecond, we have modified the structure of hydroxamate drug SAHA by incorporating newlinepiperidine and piperazine moiety with alkyl side chain in linker region. These derivatives newlinewere further modified in cap region with different hydrophobic and bulky groups and a newlineseries of derivatives were synthesized. These compounds were screened for their HDAC newlinevi newlineinhibitory activity using HeLa nuclear extract and found to be efficient HDAC inhibitors. newlineFurther they were tested on human recombinant HDAC3 and human recombinant HDAC8 newlineand they exhibited efficient inhibition of HDAC8 while minimum inhibition of HDAC3. newlineThese compounds were found to show potent anticancer activity on B16F10, HeLa, A-549, newlineMCF-7 and Jurkat E6 cells. Promising three compounds 5e, 16c a
Pagination: 230p.
URI: http://hdl.handle.net/10603/291962
Appears in Departments:Pharmacy

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