Multi-target rational design and synthesis of novel diphenyl-tethered pyrazolopyrimidines targeting EGFR and topoisomerase II with potential DNA intercalation and apoptosis induction

[Display omitted] •Novel pyrazolopyrimidines were designed as multitarget-directed drug candidates.•GI % against fifteen human cancer cell lines was recorded.•Cytotoxicity against HNO97, MDA-MB-468, FaDu, and HeLa were measured.•Compound 6l decreased EGFR protein concentration by a 6.10-fold change,...

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Published in:Bioorganic chemistry 2024-04, Vol.145, p.107223-107223, Article 107223
Main Authors: Gaber, Ahmed A, Abo Elmaaty, Ayman, Sharaky, Marwa, Mosa, Aliaa A., Yahya Abdullah Alzahrani, Abdullah, Shaaban, Saad, Eldehna, Wagdy M., Al-Karmalawy, Ahmed A.
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Apoptosis
Biphenyl Compounds
Cell Proliferation
DNA
DNA intercalation
DNA Topoisomerases, Type II - metabolism
Drug Screening Assays, Antitumor
EGFR
ErbB Receptors - metabolism
Etoposide - pharmacology
Humans
Molecular Docking Simulation
Molecular Structure
Multi-target rationale
Pyrazolopyrimidine
Structure-Activity Relationship
TOPO II
Topoisomerase II Inhibitors
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Summary:[Display omitted] •Novel pyrazolopyrimidines were designed as multitarget-directed drug candidates.•GI % against fifteen human cancer cell lines was recorded.•Cytotoxicity against HNO97, MDA-MB-468, FaDu, and HeLa were measured.•Compound 6l decreased EGFR protein concentration by a 6.10-fold change, compared to imatinib.•Compounds 6a and 6l exhibited IC50 values of 17.89 and 19.39 μM, respectively, against TOPO II.•DNA fragmentation images described the great potential of 6a and 6l in inducing DNA degradation.•Protein expression analysis for caspases 3, 7, 8, and 9, Bax, p53, MMP2, MMP9, and BCL-2 was conducted.•Cell cycle analysis and molecular docking were performed. Herein, we envisioned the design and synthesis of novel pyrazolopyrimidines (confirmed by elemental analysis, 1H and 13C NMR, and mass spectra) as multitarget-directed drug candidates acting as EGFR/TOPO II inhibitors, DNA intercalators, and apoptosis inducers. The target diphenyl-tethered pyrazolopyrimidines were synthesized starting from the reaction of phenyl hydrazine and ethoxymethylenemalononitrile to give aminopyrazole-carbonitrile 2. The latter hydrolysis with NaOH and subsequent reaction with 4-chlorobenzaldhyde afforded the corresponding pyrazolo[3,4-d]pyrimidin-4-ol 4. Chlorination of 4 with POCl3 and sequential reaction with different amines afforded the target compounds in good yields (up to 73 %). The growth inhibition % of the new derivatives (6a-m) was investigated against different cancer and normal cells and the IC50 values of the most promising candidates were estimated for HNO97, MDA-MB-468, FaDu, and HeLa cancer cells. The frontier derivatives (6a, 6i, 6k, 6l, and 6m) were pursued for their EGFR inhibitory activity. Compound 6l decreased EGFR protein concentration by a 6.10-fold change, compared to imatinib as a reference standard. On the other side, compounds (6a, 6i, 6k, 6l, and 6m) underwent topoisomerase II (TOPO II) inhibitory assay. In particular, compounds 6a and 6l exhibited IC50s of 17.89 and 19.39 μM, respectively, surpassing etoposide with IC50 of 20.82 μM. Besides, the DNA fragmentation images described the great potential of both candidates 6a and 6l in inducing DNA degradation at lower concentrations compared to etoposide and doxorubicin. Moreover, compound 6l, with the most promising EGFR/TOPO II inhibition and DNA intercalation, was selected for further investigation for its apoptosis induction ability by measuring caspases 3, 7, 8, and 9, Bax, p53, MMP2,
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2024.107223