“Design, Synthesis, and Biological Evaluation of Novel Oxindole-Based Derivatives as Potent and Selective Antileukemic Agents.”
Abstract
Acute lymphoblastic leukemia (ALL) is an aggressive hematological malignancy that requires rapid therapeutic intervention. In this study, a series of oxindole-based derivatives ( 5a-t ) was designed, synthesized, and evaluated for antiproliferative activity. Initial single-dose screening at the NCI-DTP identified five compounds for full five-dose evaluation. Among these, compound 5t emerged as the most potent analogue, demonstrating broad antiproliferative activity across the NCI-60 panel with GI 50 (MG-MID) values ranging from 9.05–45.24 μM and exhibiting pronounced selectivity toward leukemia cell lines. Compound 5t showed superior cytotoxicity against CCRF-CEM cells while displaying markedly lower toxicity toward normal fibroblasts (BJ and MRC-5), yielding selectivity indices >17, thereby outperforming ibrutinib. Kinase profiling revealed that 5t functions as a multi-kinase inhibitor, potently targeting JAK3, VEGFR2, and FGFR1, with sustained inhibition observed at low micromolar concentrations. Mechanistic studies further demonstrated dose-dependent S-phase accumulation, accompanied by a slight increase in the G2/M DNA-content fraction in CCRF-CEM cells, accompanied by a near-complete shutdown of bulk RNA and DNA synthesis by the most potent analogue 5o . Complementary molecular modeling supported stable binding of 5t to JAK3 and VEGFR2, while in silico ADME predictions indicated favorable oral drug-like properties. Collectively, these findings identify as a viable candidate for further preclinical evaluation for the development of new therapeutic agents against ALL.
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BibTeX
@article{mustafa2026design,
title = {{“Design, Synthesis, and Biological Evaluation of Novel Oxindole-Based Derivatives as Potent and Selective Antileukemic Agents.”}},
author = {Muhamad Mustafa and Aya Soudi and Petr Dzubak and Sona Gurska and Ivo Frydrych and Marian Hajduch and Burak Tüzün and Ibrahim Salem and Tarek Ibrahim and Michael Smietana and Jean-Yves Winum and Omar Aly and Taha F.S. Ali and El-Shimaa M.N. Abdelhafez},
journal = {European Journal of Medicinal Chemistry Reports},
year = {2026},
month = oct,
doi = {10.1016/j.ejmcr.2026.100376},
url = {https://hal.science/hal-05794570v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - “Design, Synthesis, and Biological Evaluation of Novel Oxindole-Based Derivatives as Potent and Selective Antileukemic Agents.”
AU - Muhamad Mustafa
AU - Aya Soudi
AU - Petr Dzubak
AU - Sona Gurska
AU - Ivo Frydrych
AU - Marian Hajduch
AU - Burak Tüzün
AU - Ibrahim Salem
AU - Tarek Ibrahim
AU - Michael Smietana
AU - Jean-Yves Winum
AU - Omar Aly
AU - Taha F.S. Ali
AU - El-Shimaa M.N. Abdelhafez
PY - 2026
DA - 2026/10/12
JO - European Journal of Medicinal Chemistry Reports
DO - 10.1016/j.ejmcr.2026.100376
UR - https://hal.science/hal-05794570v1
AB - Acute lymphoblastic leukemia (ALL) is an aggressive hematological malignancy that requires rapid therapeutic intervention. In this study, a series of oxindole-based derivatives ( 5a-t ) was designed, synthesized, and evaluated for antiproliferative activity. Initial single-dose screening at the NCI-DTP identified five compounds for full five-dose evaluation. Among these, compound 5t emerged as the most potent analogue, demonstrating broad antiproliferative activity across the NCI-60 panel with GI 50 (MG-MID) values ranging from 9.05–45.24 μM and exhibiting pronounced selectivity toward leukemia cell lines. Compound 5t showed superior cytotoxicity against CCRF-CEM cells while displaying markedly lower toxicity toward normal fibroblasts (BJ and MRC-5), yielding selectivity indices >17, thereby outperforming ibrutinib. Kinase profiling revealed that 5t functions as a multi-kinase inhibitor, potently targeting JAK3, VEGFR2, and FGFR1, with sustained inhibition observed at low micromolar concentrations. Mechanistic studies further demonstrated dose-dependent S-phase accumulation, accompanied by a slight increase in the G2/M DNA-content fraction in CCRF-CEM cells, accompanied by a near-complete shutdown of bulk RNA and DNA synthesis by the most potent analogue 5o . Complementary molecular modeling supported stable binding of 5t to JAK3 and VEGFR2, while in silico ADME predictions indicated favorable oral drug-like properties. Collectively, these findings identify as a viable candidate for further preclinical evaluation for the development of new therapeutic agents against ALL.
SN - 2772-4174
ER -