2. Academic Validation
  3. Design, synthesis and biological evaluation of 1, 4-dihydro indeno[1,2-c] pyrazole linked oxindole analogues as potential anticancer agents targeting tubulin and inducing p53 dependent apoptosis

Design, synthesis and biological evaluation of 1, 4-dihydro indeno[1,2-c] pyrazole linked oxindole analogues as potential anticancer agents targeting tubulin and inducing p53 dependent apoptosis

  • Eur J Med Chem. 2018 Jan 20:144:104-115. doi: 10.1016/j.ejmech.2017.12.010.
Irfan Khan 1,  Koteswara Rao Garikapati 2,  Anver Basha Shaik 3,  Venkata Krishna Kanth Makani 4,  Abdul Rahim 1,  Mohd Adil Shareef 1,  V Ganga Reddy 1,  Manika Pal-Bhadra 5,  Ahmed Kamal 6,  C Ganesh Kumar 7
Affiliations

Affiliations

  • 1 Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India; Academy of Scientific and Innovative Research, New Delhi 110 025, India.
  • 2 Academy of Scientific and Innovative Research, New Delhi 110 025, India; Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
  • 3 Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India.
  • 4 Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
  • 5 Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India. Electronic address: manika@iict.res.in.
  • 6 Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India; Academy of Scientific and Innovative Research, New Delhi 110 025, India. Electronic address: ahmedkamal@iict.res.in.
  • 7 Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India; Academy of Scientific and Innovative Research, New Delhi 110 025, India. Electronic address: cgkumar@iict.res.in.
PMID: 29268127 DOI: 10.1016/j.ejmech.2017.12.010
Abstract

A series of 1, 4-dihydroindeno-[1,2-c] pyrazole linked oxindole conjugates have been synthesized by using Knoevenagel condensation method and further evaluated for their antiproliferative activity against HeLa, A549 and MDA-MB-231 human Cancer cell lines along with HEK-293 (normal human embryonic kidney cells). Among the derivatives, compounds 12a, 12b, and 12d showed excellent cytotoxicity with IC50 values ranging between 1.33 to 4.33 μM. Furthermore, detailed biological assays showed that there was accumulation of mitotic cells in G2/M phase, disruption of microtubule network and increase in the G2/M checkpoint proteins (Cyclin B1 and CDK1). Moreover, compound 12d with IC50 value of 1.33 μM showed significant upregulation of tumor suppressor proteins like p53, p21 and pro-apoptotic Bax. The molecular docking analysis demonstrated that these congeners occupy the colchicine binding pocket of the tubulin.

Keywords

1, 4-dihydroindeno-[1, 2-c] pyrazole; Apoptosis; Knoevenagel condensation; Oxindoles; p53.

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