One-pot Three-Component Synthesis, In vitro Anticancer Activity and p53-MDM2 Protein-Protein Interaction Inhibition of Novel Spiro-Oxindoline-Based Pyrazolo[3,4-b]Pyridines
M. Odeh, D., Allam, H., R. Mahmoud, W., M. Odeh, M., Abdel Aziz, H., R. Mohammed, E. (2024). One-pot Three-Component Synthesis, In vitro Anticancer Activity and p53-MDM2 Protein-Protein Interaction Inhibition of Novel Spiro-Oxindoline-Based Pyrazolo[3,4-b]Pyridines. EKB Journal Management System, 67(3), 495-513. doi: 10.21608/ejchem.2023.228742.8415
Dana M. Odeh; Heba Allam; Walaa R. Mahmoud; Mohanad M. Odeh; Hatem Abdel Aziz; Eman R. Mohammed. "One-pot Three-Component Synthesis, In vitro Anticancer Activity and p53-MDM2 Protein-Protein Interaction Inhibition of Novel Spiro-Oxindoline-Based Pyrazolo[3,4-b]Pyridines". EKB Journal Management System, 67, 3, 2024, 495-513. doi: 10.21608/ejchem.2023.228742.8415
M. Odeh, D., Allam, H., R. Mahmoud, W., M. Odeh, M., Abdel Aziz, H., R. Mohammed, E. (2024). 'One-pot Three-Component Synthesis, In vitro Anticancer Activity and p53-MDM2 Protein-Protein Interaction Inhibition of Novel Spiro-Oxindoline-Based Pyrazolo[3,4-b]Pyridines', EKB Journal Management System, 67(3), pp. 495-513. doi: 10.21608/ejchem.2023.228742.8415
M. Odeh, D., Allam, H., R. Mahmoud, W., M. Odeh, M., Abdel Aziz, H., R. Mohammed, E. One-pot Three-Component Synthesis, In vitro Anticancer Activity and p53-MDM2 Protein-Protein Interaction Inhibition of Novel Spiro-Oxindoline-Based Pyrazolo[3,4-b]Pyridines. EKB Journal Management System, 2024; 67(3): 495-513. doi: 10.21608/ejchem.2023.228742.8415

One-pot Three-Component Synthesis, In vitro Anticancer Activity and p53-MDM2 Protein-Protein Interaction Inhibition of Novel Spiro-Oxindoline-Based Pyrazolo[3,4-b]Pyridines

Egyptian Journal of Chemistry
Volume 67, Issue 3, March 2024, Page 495-513  XML PDF (1.23 MB)
Document Type: Original Article
DOI: 10.21608/ejchem.2023.228742.8415
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Authors
Dana M. Odeh1; Heba Allam email orcid 2; Walaa R. Mahmoud3; Mohanad M. Odeh4; Hatem Abdel Azizorcid 5; Eman R. Mohammed3
1Department of pharmaceutical chemistry, Faculty of pharmacy, Cairo university
2Faculty of Pharmacy, Cairo University
3Faculty of Pharmacy, Cairo University, Cairo, Egypt.
4Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University
5Applied Organic Chem, NRC
Abstract
Two series of spiro-indoline-pyrazolo[3,4-b]pyridines 6a-f and 7a-f were synthesized via a one-pot three-component reaction of indoline-2,3-diones, 3-oxo-3-arylpropanenitriles and 1,3-diphenyl-1H-pyrazol-5-amine. Preliminary anti-cancer activity evaluation of 6a-f and 7a-f on 60 cancer cell lines was performed at the (NCI/USA). Compounds 7b-f were selected by the NCI for 5-dose assay, revealing very promising activity against almost the full panel with GI50 range 6.05-49.70, 14.60-53.20, 2.99-38.70, 2.47-16.80 and 3.40-20.70 μM, respectively, and GI50 (MG-MID) Full panel = 18.11, 22.93, 13.19, 6.04, 12.20 μM, respectively. The inhibitory activity of p53-MDM2 protein-protein interaction for 7b-f in MCF7 cell line showed that 7f was the most potent compound with IC50 = 3.05 ± 0.12 µM and 2.7-folds increase in activity when compared with nutlin-1 (IC50 = 8.21 ± 0.25 µM). Furthermore, compound 7b increased the level of p53 and p21 by 3.86- and 1.78-folds in leukemia MOLT4 cancer cell line, similarly 7e and 7f increased the level of p53 by 2.53- and 2.98-folds, respectively, whereas p21 increased by 2.74- and 2.43-folds in cancer cells of non-small cell lung cancer HOP92, respectively. Compounds 7b, 7e and 7f induced a significant level of early and late apoptosis on MCF7. Compounds 7b-f revealed good binding mode in the cleft of p53 on MDM2 in their molecular docking studies
Keywords
Spiro-indolines; pyrazolo[3; 4-b]pyridines; anticancer; p53-MDM2; apoptosis
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