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

Document Type : Original Article

Authors

1 Department of pharmaceutical chemistry, Faculty of pharmacy, Cairo university

2 Faculty of Pharmacy, Cairo University

3 Faculty of Pharmacy, Cairo University, Cairo, Egypt.

4 Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, The Hashemite University

5 Applied 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

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History

  • Receive Date: 11 August 2023
  • Revise Date: 19 August 2023
  • Accept Date: 30 August 2023

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