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  3. Design, synthesis and biological evaluation of novel pyrazolochalcones as potential modulators of PI3K/Akt/mTOR pathway and inducers of apoptosis in breast cancer cells

Design, synthesis and biological evaluation of novel pyrazolochalcones as potential modulators of PI3K/Akt/mTOR pathway and inducers of apoptosis in breast cancer cells

  • Eur J Med Chem. 2017 Oct 20:139:305-324. doi: 10.1016/j.ejmech.2017.07.056.
Anver Basha Shaik 1,  Garikapati Koteswara Rao 2,  G Bharath Kumar 1,  Nibeditha Patel 2,  Vangala Santhosh Reddy 1,  Irfan Khan 1,  Sunitha Rani Routhu 1,  C Ganesh Kumar 1,  Immadi Veena 2,  Kunta Chandra Shekar 1,  Madan Barkume 3,  Shailesh Jadhav 3,  Aarti Juvekar 3,  Jyoti Kode 4,  Manika Pal-Bhadra 5,  Ahmed Kamal 6
Affiliations

Affiliations

  • 1 Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India.
  • 2 Centre for Chemical Biology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India.
  • 3 Anti-Cancer Drug Screening Facility (ACDSF), Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India.
  • 4 Anti-Cancer Drug Screening Facility (ACDSF), Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India. Electronic address: jkode@actrec.gov.in.
  • 5 Centre for Chemical Biology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India. Electronic address: manika@iict.res.in.
  • 6 Medicinal Chemistry and Pharmacology, CSIR - Indian Institute of Chemical Technology, Hyderabad 500007, India. Electronic address: ahmedkamal@iict.res.in.
PMID: 28803046 DOI: 10.1016/j.ejmech.2017.07.056
Abstract

Cancer has been established as the "Emperor of all maladies". In recent years, medicinal chemistry has focused on identifying novel anti-cancer compounds; though discovery of these compounds appears to be a herculean task. In present study, we synthesized forty pyrazolochalcone conjugates and explored their cytotoxic activity against a panel of sixty Cancer cell lines. Fifteen conjugates of the series showed excellent growth inhibition (13b-e, 13h-j, 14c-d, 15 a, 15 c-d, 16b, 16d and 18f; GI50 for MCF-7: 0.4-20 μM). Conjugates 13b, 13c, 13d, 16b and 14d were also evaluated for their cytotoxic activity in human breast Cancer cell line (MCF-7). The promising candidates induced cell cycle arrest, mitochondrial membrane depolarization and Apoptosis in MCF-7 cells at a 2 μM concentration. Furthermore, inhibition of PI3K/Akt/mTOR pathway-regulators such as PI3K, p-PI3K, p-AKT, and mTOR were observed; as well as upregulation of p-GSK3β and tumor-suppressor protein, PTEN. Our study indicates that pyrazolochalcone conjugates could serve as potential leads in the development of tailored Cancer therapeutics.

Keywords

Apoptosis; Cytotoxicity; Molecular modeling; PI3K/Akt/mTOR signaling pathway; Pyrazolochalcones.

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