One-pot synthesis of spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitriles as p53-MDM2 interaction inhibitors

Hany S Ibrahim; Wagdy M Eldehna; Anna Lucia Fallacara; Esam R Ahmed; Hazem A Ghabbour; Mahmoud M Elaasser; Maurizio Botta; Sahar M Abou-Seri; Hatem A Abdel-Aziz

doi:10.4155/fmc-2018-0288

One-pot synthesis of spiro(indoline-3,4'-pyrazolo[3,4-b]pyridine)-5'-carbonitriles as p53-MDM2 interaction inhibitors

Future Med Chem. 2018 Dec;10(24):2771-2789. doi: 10.4155/fmc-2018-0288. Epub 2018 Dec 10.

Authors

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

Affiliations

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.

PMID: 30526032
DOI: 10.4155/fmc-2018-0288

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.

Keywords: P53-MDM2 interaction inhibitor; anticancer activities; apoptosis; molecular docking; spiro-oxindole.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
MCF-7 Cells
Models, Molecular
Molecular Structure
Nitriles / chemical synthesis
Nitriles / chemistry
Nitriles / pharmacology*
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-mdm2 / metabolism
Structure-Activity Relationship
Tumor Suppressor Protein p53 / antagonists & inhibitors*
Tumor Suppressor Protein p53 / metabolism

Substances

Antineoplastic Agents
Nitriles
Tumor Suppressor Protein p53
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2