Hany S Ibrahim1, Wagdy M Eldehna2, Anna Lucia Fallacara3, Esam R Ahmed4, Hazem A Ghabbour5, Mahmoud M Elaasser6, Maurizio Botta3, Sahar M Abou-Seri7, Hatem A Abdel-Aziz8. 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt. 2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt. 3. Department of Biotechnology Chemistry & Pharmaceutical Science, University of Siena, Via Aldo Moro 2, Siena 53100, Italy. 4. Confirmatory Diagnostic Unit, Vacsera Holding Company, Giza, Egypt. 5. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. 6. The Regional Center for Mycology & Biotechnology, Al-Azhar University, Cairo, Egypt. 7. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt. 8. Department of Applied Organic Chemistry Department, National Research Center, Dokki, Cairo 12622, Egypt.
Abstract
AIM: Inhibition of P53-mdm2 interaction will lead to cancer cell apoptosis. This strategy was achieved by reported spiro-oxindole derivatives. MATERIALS & METHODS: Spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitrile derivatives (4a-i and 9a, b) were synthesized and screened for their in vitro anticancer activity. The most active compounds were subjected to P53-MDM2 inhibitory activity, apoptotic and molecular docking studies. RESULTS & DISCUSSION: Compound 4d exhibited potent and broad spectrum of antiproliferative activity with full panel GI50 (MG-MID) value of 3.97 μM. Compounds 4d and 4i inhibited p53-MDM2 protein-protein interaction with IC50 = 52.1 and 95.2 nM, respectively. Compound 4d inhibits the expression of wild p53 in MCF-7 more than mutant p53 in MDA-MB231 at the molecular level. Molecular docking studies illustrated the possible interaction of the target spiro-oxindoles with the p53 binding site on MDM2.
AIM: Inhibition of P53-mdm2 interaction will lead to cancer cell apoptosis. This strategy was achieved by reported spiro-oxindole derivatives. MATERIALS & METHODS:Spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitrile derivatives (4a-i and 9a, b) were synthesized and screened for their in vitro anticancer activity. The most active compounds were subjected to P53-MDM2 inhibitory activity, apoptotic and molecular docking studies. RESULTS & DISCUSSION: Compound 4d exhibited potent and broad spectrum of antiproliferative activity with full panel GI50 (MG-MID) value of 3.97 μM. Compounds 4d and 4i inhibited p53-MDM2 protein-protein interaction with IC50 = 52.1 and 95.2 nM, respectively. Compound 4d inhibits the expression of wild p53 in MCF-7 more than mutant p53 in MDA-MB231 at the molecular level. Molecular docking studies illustrated the possible interaction of the target spiro-oxindoles with the p53 binding site on MDM2.
Authors: Tarfah Al-Warhi; Mahmoud F Abo-Ashour; Hadia Almahli; Ohoud J Alotaibi; Mohammad M Al-Sanea; Ghada H Al-Ansary; Hanaa Y Ahmed; Mahmoud M Elaasser; Wagdy M Eldehna; Hatem A Abdel-Aziz Journal: J Enzyme Inhib Med Chem Date: 2020-12 Impact factor: 5.051
Authors: Sara T Al-Rashood; Ahmed R Hamed; Ghada S Hassan; Hamad M Alkahtani; Abdulrahman A Almehizia; Amal Alharbi; Mohammad M Al-Sanea; Wagdy M Eldehna Journal: J Enzyme Inhib Med Chem Date: 2020-12 Impact factor: 5.051