Design, Synthesis, Chemical and Biochemical Insights Into Novel Hybrid Spirooxindole-Based p53-MDM2 Inhibitors With Potential Bcl2 Signaling Attenuation

Yasmine M Abdel Aziz; Gehad Lotfy; Mohamed M Said; El Sayed H El Ashry; El Sayed H El Tamany; Saied M Soliman; Marwa M Abu-Serie; Mohamed Teleb; Sammer Yousuf; Alexander Dömling; Luis R Domingo; Assem Barakat

doi:10.3389/fchem.2021.735236

Design, Synthesis, Chemical and Biochemical Insights Into Novel Hybrid Spirooxindole-Based p53-MDM2 Inhibitors With Potential Bcl2 Signaling Attenuation

Front Chem. 2021 Dec 14:9:735236. doi: 10.3389/fchem.2021.735236. eCollection 2021.

Affiliations

¹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt.
² Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt.
³ Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia, Egypt.
⁴ Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
⁶ H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
⁷ Department of Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, Netherlands.
⁸ Department of Organic Chemistry, University of Valencia, Valencia, Spain.
⁹ Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.

Abstract

The tumor resistance to p53 activators posed a clinical challenge. Combination studies disclosed that concomitant administration of Bcl2 inhibitors can sensitize the tumor cells and induce apoptosis. In this study, we utilized a rapid synthetic route to synthesize two novel hybrid spirooxindole-based p53-MDM2 inhibitors endowed with Bcl2 signaling attenuation. The adducts mimic the thematic features of the chemically stable potent spiro [3H-indole-3,2'-pyrrolidin]-2(1H)-ones p53-MDM2 inhibitors, while installing a pyrrole ring via a carbonyl spacer inspired by the natural marine or synthetic products that efficiently inhibit Bcl2 family functions. A chemical insight into the two synthesized spirooxindoles including single crystal x-ray diffraction analysis unambiguously confirmed their structures. The synthesized spirooxindoles 2a and 2b were preliminarily tested for cytotoxic activities against normal cells, MDA-MB 231, HepG-2, and Caco-2 via MTT assay. 2b was superior to 5-fluorouracil. Mechanistically, 2b induced apoptosis-dependent anticancer effect (43%) higher than that of 5-fluorouracil (34.95%) in three studied cancer cell lines, activated p53 (47%), downregulated the Bcl2 gene (1.25-fold), and upregulated p21 (2-fold) in the treated cancer cells. Docking simulations declared the possible binding modes of the synthesized compounds within MDM2.

Keywords: Bcl 2; human homolog of mouse double minute 2 (MDM2); p53; protein–protein interaction (PPI); spirooxindole.