2. Academic Validation
  3. Design, synthesis and anticancer evaluation of novel arylhydrazones of active methylene compounds

Design, synthesis and anticancer evaluation of novel arylhydrazones of active methylene compounds

  • Int J Biol Macromol. 2023 Nov 10;254(Pt 3):127909. doi: 10.1016/j.ijbiomac.2023.127909.
Akshaya Murugesan 1,  Saravanan Konda Mani 2,  Shabnaz Koochakkhani 3,  Kumar Subramanian 4,  Jayalakshmi Kandhavelu 4,  Ramesh Thiyagarajan 5,  Atash V Gurbanov 6,  Kamran T Mahmudov 6,  Meenakshisundaram Kandhavelu 7
Affiliations

Affiliations

  • 1 Department of Biotechnology, Lady Doak College, Madurai Kamaraj University, Thallakulam, Madurai 625002, India; Molecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University and BioMediTech, P.O. Box 553, 33101 Tampere, Finland.
  • 2 Department of Biotechnology, Bharath Institute of Higher Education & Research, Chennai 600 073, Tamilnadu, India.
  • 3 Molecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University and BioMediTech, P.O. Box 553, 33101 Tampere, Finland.
  • 4 Oncology Division, Faculty of Health Sciences, University of the Witwatersrand, Parktown, Johannesburg, South Africa.
  • 5 Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
  • 6 Centro de Química Estrutural, Institute of Molecular Sciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal; Excellence Center, Baku State University, Z. Xalilov Str. 23, Az 1148 Baku, Azerbaijan.
  • 7 Molecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University and BioMediTech, P.O. Box 553, 33101 Tampere, Finland. Electronic address: meenakshisundaram.kandhavelu@tuni.fi.
PMID: 37951450 DOI: 10.1016/j.ijbiomac.2023.127909
Abstract

Nerve growth factor (NGF) and its receptor, tropomyosin kinase receptor kinase type A (TrkA) is emerging as an important target for Glioblastoma (GBM) treatment. TrkA is the Cancer biomarker majorly involved in tumor invasion and migration into nearby normal tissue. However, currently, available Trk inhibitors exhibit many adverse effects in Cancer patients, thus demanding a novel class of ligands to regulate Trk signaling. Here, we exploited the role of TrkA (NTRK1) expression from the 651 datasets of brain tumors. RNA sequence analysis identified overexpression of NTRK1 in GBM, recurrent GBM as well in Oligoastrocytoma patients. Also, TrkA expression tends to increase over the higher grades of GBM. TrkA protein targeting hydrazone derivatives, R48, R142, and R234, were designed and their mode of interaction was studied using molecular docking and dynamic simulation studies. Ligands' stability and binding assessment reveals R48, 2 2-(2-(2-hydroxy-4-nitrophenyl) hydrazineylidene)-1-phenylbutane-1,3-dione, as a potent ligand that interacts well with TrkA's hydrophobic residues, Ile, Phe, Leu, Ala, and Val. R48- TrkA exhibits stable binding potentials with an average RMSD value <0.8 nm. R48 obeyed Lipinski's rule of five and possessed the best oral bioavailability, suggesting R48 as a potential compound with drug-likeness properties. In-vitro analysis also revealed that R48 exhibited a higher cytotoxicity effect for U87 GBM cells than TMZ with the IC50 value of 68.99 μM. It showed the lowest percentage of cytotoxicity to the non-cancerous TrkA expressing MEF cells. However, further SiRNA analysis validates the non-specific binding of R48, necessitating structural alteration for the development of R48-based TrkA Inhibitor for GBM therapeutics.

Keywords

Glioblastoma; Hydrazone derivatives; Molecular docking; TrkA inhibitor.

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