Novel Spirooxindole–Benzofuran Scaffold: Potential Inhibition Against Hepatocellular Carcinoma by Targeting MDM2‐p53 Interaction
Abstract We synthesized a novel compound library featuring a spirooxindole core structure combined with various heterocycles, including benzofuran, benzothiophene, and thiophene scaffolds. Evaluation using MTT assays against HepG2, 4T1, and MDA‐MB‐231 cells revealed the most potent candidate, spirooxindole hybrid 5c , with an IC50 of 5 ± 0.6 µM against HepG2, inducing G2/M phase cell cycle arrest, inhibition of the wound healing, and induction of ROS. Selected spirooxindole conjugates exhibited significant inhibitory potential against MDM2, with KD values ranging from 0.0531 to 16.8 µM. Notably, the salt of spirooxindole analogue 5q demonstrated the highest inhibitory activity at K D = 53.1 nM. Molecular docking studies revealed excellent accommodation of the designed compounds within the MDM2 receptor. All compounds displayed favorable ADME profiles, suggesting their potential as lead compounds for further optimization.
Authors
- Muhanna K. Al‐Muhanna (ORCID: https://orcid.org/0000-0001-5060-6658)
- Komal Zia (ORCID: https://orcid.org/0000-0003-3554-1934)
- Assem Barakat (ORCID: https://orcid.org/0000-0002-7885-3201)
- Mohammad Shahidul Islam (ORCID: https://orcid.org/0000-0002-4612-5875)
- Fardous F. El‐Senduny (ORCID: https://orcid.org/0000-0002-4572-2061)
- Mohd Sajid Ali (ORCID: https://orcid.org/0000-0003-0191-9708)
- Alexander Dömlingꝉ (ORCID: https://orcid.org/0000-0002-9923-8873)
- Farid A. Badria (ORCID: https://orcid.org/0000-0001-7230-3105)
- Zaheer Ul‐Haq (ORCID: https://orcid.org/0000-0002-8530-8711)
- Abdulmajeed Abdullah Alayyaf (ORCID: https://orcid.org/0009-0000-3377-4115)
Institutions
- King Abdulaziz City for Science and Technology (SA)
- Mansoura University (EG)
- University of Karachi (PK)
- King Saud University (SA)
- International Center for Chemical and Biological Sciences (PK)
- Institute of Molecular and Translational Medicine (CZ)
- Sylvester Comprehensive Cancer Center (US)
- Palacký University Olomouc (CZ)
Publication Details
- Journal
- ChemistrySelect
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1002/slct.202403953
- Citations
- 2
- Primary Topic
- Cancer-related Molecular Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.57
Funders
- King Saud University
- Science and Technology Development Fund
- KWF Kankerbestrijding
- King Abdulaziz City for Science and Technology