2. Academic Validation
  3. Luotonin-A based quinazolinones cause apoptosis and senescence via HDAC inhibition and activation of tumor suppressor proteins in HeLa cells

Luotonin-A based quinazolinones cause apoptosis and senescence via HDAC inhibition and activation of tumor suppressor proteins in HeLa cells

  • Eur J Med Chem. 2015 Apr 13:94:87-101. doi: 10.1016/j.ejmech.2015.02.057.
Ramineni Venkatesh 1,  M Janaki Ramaiah 2,  Hanmant K Gaikwad 1,  Sridhara Janardhan 3,  Rajashaker Bantu 1,  Lingaiah Nagarapu 4,  G Narahari Sastry 3,  A Raksha Ganesh 2,  Manikapal Bhadra 2
Affiliations

Affiliations

  • 1 Organic Chemistry Division II, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India.
  • 2 Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India.
  • 3 Centre for Molecular Modeling, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500607, India.
  • 4 Organic Chemistry Division II, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India. Electronic address: lnagarapuiict@yahoo.com.
PMID: 25757092 DOI: 10.1016/j.ejmech.2015.02.057
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.

Keywords

Click chemistry; Docking studies; HDACs; Quinazolinone hybrids; Senescence.

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