HDAC and NF-κB mediated cytotoxicity induced by novel N-Chloro β-lactams and benzisoxazole derivatives

Novel N-chloro â-Lactam and benzisoxazole derivatives were successfully synthesized with excellent yields (92–96%) under simple and mild reaction conditions. The β-lactams as a class acquired importance since the discovery of penicillin which contains β-lactam unit as an essential structural feature...

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Bibliographic Details
Published in:	Chemico-biological interactions Vol. 246; pp. 69 - 76
Main Authors:	Rajashekar Reddy, C.B., Rajasekhara Reddy, Sabbasani, Suthindhiran, Krish, Sivakumar, Arumugam
Format:	Journal Article
Language:	English
Published:	Ireland Elsevier Ireland Ltd 25-02-2016
Subjects:	Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - metabolism Antineoplastic Agents - pharmacology Benzisoxazole derivatives beta-Lactams - chemical synthesis beta-Lactams - chemistry beta-Lactams - metabolism beta-Lactams - pharmacology Catalysis Catalytic Domain Derivatives of N-Chloro β-lactams HDAC inhibition HEK293 Cells Hemolysis - drug effects Histone Deacetylase Inhibitors - chemical synthesis Histone Deacetylase Inhibitors - chemistry Histone Deacetylase Inhibitors - metabolism Histone Deacetylase Inhibitors - pharmacology Histone Deacetylases - chemistry Histone Deacetylases - metabolism Humans In-silico studies Isoxazoles - chemical synthesis Isoxazoles - chemistry Isoxazoles - metabolism Isoxazoles - pharmacology Models, Molecular Molecular Docking Simulation NF-kappa B - metabolism NF-κB inhibition Stereoisomerism Derivatives of N-Chloro β-lactams HDAC inhibition NF-κB inhibition In-silico studies Benzisoxazole derivatives
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Summary:	Novel N-chloro â-Lactam and benzisoxazole derivatives were successfully synthesized with excellent yields (92–96%) under simple and mild reaction conditions. The β-lactams as a class acquired importance since the discovery of penicillin which contains β-lactam unit as an essential structural feature of its molecule, this interest continued unabated because of the therapeutic importance of β-lactam antibiotics. In silico studies of the compounds with cancer drug target enzymes showed the inhibition of HDAC (Histone Deacetylase) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) significantly. The compounds were then investigated for the inhibitory potential against the same enzymes in vitro. NF-κB inhibition was investigated by trans activation assay using HEK293/NF-κB-luc cells. Overall, the synthesized compounds induce the cancer cell toxicity by restraining the NF-κB transcription factor mediated by HDAC inhibition and thus the compounds act as dual inhibitors. [Display omitted] •Synthesized the novel N-chloro β-lactams and benzisoxazole compounds with an excellent yields.•Cancer drug target enzymes showed significantly inhibitions on both HDAC and NFkB.•Developed compounds were not shown cytotoxicity against normal cells.•The results indicate that the compound could be used as a dual inhibitor for both HDAC and NFkB.
ISSN:	0009-2797 1872-7786
DOI:	10.1016/j.cbi.2016.01.010