title: HDAC and NF-κB mediated cytotoxicity induced by novel N-Chloro β-lactams and benzisoxazole derivatives.
abstract: 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.
authors.affiliation: Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632014, India.
authors.forename: C B
authors.initials: CB
authors.lastname: Rajashekar Reddy
authors.affiliation: Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632014, India. Electronic address: sekharareddy@vit.ac.in.
authors.forename: Sabbasani
authors.initials: S
authors.lastname: Rajasekhara Reddy
authors.affiliation: School of Biosciences and Technology, VIT University, Vellore 632014, India.
authors.forename: Krish
authors.initials: K
authors.lastname: Suthindhiran
authors.affiliation: School of Biosciences and Technology, VIT University, Vellore 632014, India.
authors.forename: Arumugam
authors.initials: A
authors.lastname: Sivakumar
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002384:Catalysis; D020134:Catalytic Domain; D057809:HEK293 Cells; D006461:Hemolysis / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000378:metabolism*; D013237:Stereoisomerism; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D007555:Isoxazoles; D016328:NF-kappa B; D047090:beta-Lactams; D006655:Histone Deacetylases
keywords: Benzisoxazole derivatives; Derivatives of N-Chloro β-lactams; HDAC inhibition; In-silico studies; NF-κB inhibition