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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Optimized spirooxindole-pyrazole hybrids targeting the p53-MDM2 interplay induce apoptosis and synergize with
Mohammad Shahidul Islam1, Abdullah Mohammed Al-Majid1, Essam Nageh Sholkamy2
1Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia.
Abstract:
Recently, cancer research protocols have introduced clinical-stage spirooxindole-based MDM2 inhibitors. However, several studies reported tumor resistance to the treatment. This directed efforts to invest in designing various combinatorial libraries of spirooxindoles. Herein, we introduce new series of spirooxindoles via hybridization of the chemically stable core spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one and the pyrazole motif inspired by lead pyrazole-based p53 activators, the MDM2 inhibitor BI-0252 and promising molecules previously reported by our group. Single crystal X-ray diffraction analysis confirmed the chemical identity of a representative derivative. Fifteen derivatives were screened for cytotoxic activities via MTT assay against a panel of four cancer cell lines expressing wild-type p53 (A2780, A549, HepG2) and mutant p53 (MDA-MB-453). The hits were 8h against A2780 (IC50 = 10.3 µM) and HepG2 (IC50 = 18.6 µM), 8m against A549 (IC50 = 17.7 µM), and 8k against MDA-MB-453 (IC50 = 21.4 µM). Further MTT experiments showed that 8h and 8j potentiated doxorubicin activity and reduced its IC50 by at least 25% in combinations. Western blot analysis demonstrated that 8k and 8m downmodulated MDM2 in A549 cells. Their possible binding mode with MDM2 were simulated by docking analysis.
Insights
New spirooxindole-pyrazole hybrids show promise as cancer therapeutics, overcoming resistance to MDM2 inhibitors. These compounds exhibit cytotoxic activity and potentiate chemotherapy, offering new avenues for cancer treatment.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Drug Discovery
Background:
- Clinical use of spirooxindole-based MDM2 inhibitors is hindered by tumor resistance.
- Development of novel combinatorial libraries is crucial to overcome treatment resistance.
Purpose of the Study:
- To design and synthesize novel spirooxindole-pyrazole hybrids as potential MDM2 inhibitors.
- To evaluate the cytotoxic and synergistic effects of these compounds against various cancer cell lines.
Main Methods:
- Synthesis of spirooxindole-pyrazole hybrids.
- Cytotoxicity screening using MTT assay against wild-type and mutant p53 cancer cell lines.
- Combination studies with doxorubicin and Western blot analysis for MDM2 modulation.
- Molecular docking simulations for binding mode analysis.
Main Results:
- Fifteen derivatives were synthesized and screened.
- Compounds 8h, 8m, and 8k demonstrated significant cytotoxic activity against tested cancer cell lines.
- Derivatives 8h and 8j enhanced doxorubicin efficacy, reducing its IC50 by at least 25%.
- Compounds 8k and 8m were shown to downregulate MDM2 expression in A549 cells.
Conclusions:
- The novel spirooxindole-pyrazole hybrids represent a promising class of anticancer agents.
- These compounds exhibit potential in overcoming resistance to MDM2 inhibitors and enhancing chemotherapy efficacy.
- Further investigation into their therapeutic potential is warranted.
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