2. Academic Validation
  3. Exploration of carbamide derived pyrimidine-thioindole conjugates as potential VEGFR-2 inhibitors with anti-angiogenesis effect

Exploration of carbamide derived pyrimidine-thioindole conjugates as potential VEGFR-2 inhibitors with anti-angiogenesis effect

  • Eur J Med Chem. 2020 Aug 15:200:112457. doi: 10.1016/j.ejmech.2020.112457.
Sravani Sana 1,  Velma Ganga Reddy 2,  Sonal Bhandari 1,  T Srinivasa Reddy 3,  Ramya Tokala 1,  Akash P Sakla 1,  Suresh K Bhargava 3,  Nagula Shankaraiah 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India.
  • 2 Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO Box 2476, Melbourne, 3001, Australia. Electronic address: ganga.reddy.velma@rmit.edu.au.
  • 3 Centre for Advanced Materials & Industrial Chemistry (CAMIC), School of Science, RMIT University, GPO Box 2476, Melbourne, 3001, Australia.
  • 4 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500 037, India. Electronic address: shankar.niperhyd@gov.in.
PMID: 32422489 DOI: 10.1016/j.ejmech.2020.112457
Abstract

The development of new small molecules from known structural motifs through molecular hybridization is one of the trends in drug discovery. In this connection, we have combined the two pharmacophoric units (pyrimidine and thioindole) in a single entity via molecular hybridization strategy along with introduction of urea functionality at C2 position of pyrimidine to increase the efficiency of H-bonding interactions. Among the synthesized conjugates 12a-aa, compound 12k was found to exhibit significant IC50 values 5.85, 7.87, 6.41 and 10.43 μM against MDA-MB-231 (breast), HepG2 (liver), A549 (lung) and PC-3 (prostate) Cancer cell lines, respectively. All these compounds were further evaluated for their inhibitory activities against VEGFR-2 protein. The results specified that among the tested compounds, 12d, 12e, 12k, 12l, 12p, 12q, 12t and 12u prominently suppressed VEGFR-2, with IC50 values of 310-920 nM in association to the positive control (210 nM). Angiogenesis inhibition was evident by tube formation assay in HUVECs and cell-invasion by transwell assay. The mechanism of cellular toxicity on MDA-MB-231 was found through depolarisation of mitochondrial membrane potential, increased ROS production and subsequent DNA damage resulting in Apoptosis induction. Moreover, clonogenic and wound healing assays designated the inhibition of colony formation and cell migration by 12k in a dose-dependent manner. Molecular docking studies also shown that compound 12k capably intermingled with catalytically active residues GLU-885, ASP-1046 of the VEGFR-2 through hydrogen-bonding interactions.

Keywords

Angiogenesis; Apoptosis; Cytotoxicity; Pyrimidine-thioindole; Urea; VEGFR-2.

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