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.

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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.