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  3. Derivatives of D(-)-glutamine-based MMP-2 inhibitors as an effective remedy for the management of chronic myeloid leukemia-Part-III: Synthesis, biological screening and in silico binding interaction analysis

Derivatives of D(-)-glutamine-based MMP-2 inhibitors as an effective remedy for the management of chronic myeloid leukemia-Part-III: Synthesis, biological screening and in silico binding interaction analysis

  • Bioorg Chem. 2025 Jan:154:108057. doi: 10.1016/j.bioorg.2024.108057.
Sanjib Das 1,  Tarun Patel 2,  Ambati Himaja 2,  Sanjeev Regula 2,  Suvankar Banerjee 3,  Asit Kumar De 4,  Insaf Ahmed Qureshi 5,  Shovanlal Gayen 6,  Balaram Ghosh 7,  Nilanjan Adhikari 8,  Tarun Jha 9
Affiliations

Affiliations

  • 1 Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India; School of Pharmacy, Sister Nivedita University, DG Block (New Town), Action Area 1, 1/2, Newtown, Chakpachuria, Kolkata 700156, India.
  • 2 Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad, India.
  • 3 Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India.
  • 4 Department of Chemistry, Jadavpur University, Kolkata, India.
  • 5 Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, 500 046, Telangana, India.
  • 6 Laboratory of Drug Design and Discovery, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, 700032, India. Electronic address: shovanlal.gayen@gmail.com.
  • 7 Epigenetic Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad, India. Electronic address: balaram@hyderabad.bits-pilani.ac.in.
  • 8 Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India. Electronic address: nilanjan_juphar@rediffmail.com.
  • 9 Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India. Electronic address: tjupharm@yahoo.com.
PMID: 39708552 DOI: 10.1016/j.bioorg.2024.108057
Abstract

Tyrosine kinase inhibitors (TKIs) have markedly improved the overall survival rate of patients with chronic myeloid leukemia (CML), enabling them to achieve a normal life expectancy. However, toxicity, relapse, and drug resistance continue to pose major challenges in the clinical treatment of CML. The progression of leukemia is directly connected to higher expression levels and enzymatic actions of matrix metalloproteinase-2 (MMP-2). It is also associated with increased expression and enzymatic actions of matrix metalloproteinase-9 (MMP-9). From this perspective, MMP-2 and MMP-9 offers a promising strategy for developing novel therapeutic molecules that could be effective in treating CML. This study is the Part-III of D(-)-glutamine-based MMP-2 inhibitors series for the management of chronic myeloid leukemia. Fourteen newly synthesized p-tosyl-D(-)-glutamine derivatives were examined in cell culture-based antileukemic assays and also evaluated for their ability to inhibit MMPs. The lead compounds 5g and 5j demonstrated the most promising antileukemic potential. Compounds 5g and 5j are safe for normal cells and effectively block gelatinases (MMP-2 and MMP-9). The best active molecule 5g induced significant Apoptosis. Compound 5g reduced MMP-2 levels in the K562 cell line. It also had strong antiangiogenic effects in the ACHN cell line. The strongest MMP-2 Inhibitor, 5g, had stable binding at the MMP-2 active site, which is linked to its effective inhibition of MMP-2. In conclusion, these p-tosyl-D(-)-glutamine derivatives are promising MMP-2 inhibitors. They have strong anti-CML effects and should be studied more for future CML treatment.

Keywords

Angiogenesis; Apoptosis; Binding mode of interaction; Chronic myeloid leukemia; MMP-2 inhibitors.

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