title: Luotonin-A based quinazolinones cause apoptosis and senescence via HDAC inhibition and activation of tumor suppressor proteins in HeLa cells.
abstract: A series of novel quinazolinone hybrids were synthesized by employing click chemistry and evaluated for anti-proliferative activities against MCF-7, HeLa and K562 cell lines. Among these cell lines, HeLa cells were found to respond effectively to these quinazolinone hybrids with IC50 values ranging from 5.94 to 16.45 μM. Some of the hybrids (4q, 4r, 4e, 4k, 4t, 4w) with promising anti-cancer activity were further investigated for their effects on the cell cycle distribution. FACS analysis revealed the G1 cell cycle arrest nature of these hybrids. Further to assess the senescence inducing ability of these compounds, a senescence associated β-gal assay was performed. The senescence inducing nature of these compounds was supported by the effect of hybrid (4q) on p16 promoter activity, the marker for senescence. Moreover, cells treated with most effective compound (4q) show up-regulation of p53, p21 and down-regulation of HDAC-1, HDAC-2, HDAC-5 and EZH2 mRNA levels. Docking results suggest that, the triazole nitrogen showed Zn(+2) mediated interactions with the histidine residue of HDACs.
authors.affiliation: Organic Chemistry Division II, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
authors.forename: Ramineni
authors.initials: R
authors.lastname: Venkatesh
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India.
authors.forename: M Janaki
authors.initials: MJ
authors.lastname: Ramaiah
authors.affiliation: Organic Chemistry Division II, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
authors.forename: Hanmant K
authors.initials: HK
authors.lastname: Gaikwad
authors.affiliation: Centre for Molecular Modeling, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India.
authors.forename: Sridhara
authors.initials: S
authors.lastname: Janardhan
authors.affiliation: Organic Chemistry Division II, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
authors.forename: Rajashaker
authors.initials: R
authors.lastname: Bantu
authors.affiliation: Organic Chemistry Division II, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India. Electronic address: lnagarapuiict@yahoo.com.
authors.forename: Lingaiah
authors.initials: L
authors.lastname: Nagarapu
authors.affiliation: Centre for Molecular Modeling, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India.
authors.forename: G Narahari
authors.initials: GN
authors.lastname: Sastry
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India.
authors.forename: A Raksha
authors.initials: AR
authors.lastname: Ganesh
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India.
authors.forename: Manikapal
authors.initials: M
authors.lastname: Bhadra
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D057930:Click Chemistry; D000071221:Enhancer of Zeste Homolog 2 Protein; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000737:chemistry / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000737:chemistry / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells / Q000187:drug effects; D061986:MCF-7 Cells / Q000187:drug effects; D062105:Molecular Docking Simulation; D063151:Polycomb Repressive Complex 2 / Q000737:chemistry / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry*; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011809:Quinones / Q000737:chemistry*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D011758:Pyrroles; D052999:Quinazolinones; D011809:Quinones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C480761:luotonin A; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; C404500:HDAC5 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases
keywords: Click chemistry; Docking studies; HDACs; Quinazolinone hybrids; Senescence