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Antineoplastic 4-piperidone-1-phosphonothioates with potential multi-targeted inhibitory properties.
Mohamed S Bekheit1, Siva S Panda2, Benson M Kariuki3
1Department of Pesticide Chemistry, National Research Centre, Dokki, 12622, Giza, Egypt.
Scientific Reports
|November 18, 2025
Summary
New phosphonothioate compounds show potent anticancer activity, outperforming existing drugs against breast, colon, and skin cancer cell lines. These agents also inhibit key cancer-related proteins like MDM2 and topoisomerases, suggesting potential as multi-targeted cancer therapies.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Cancer Biology
Background:
- Developing novel anticancer agents is crucial for overcoming drug resistance and improving patient outcomes.
- Piperidone derivatives have shown promise as scaffolds for anticancer drug discovery.
- Targeting multiple pathways, such as proliferation and DNA repair, may enhance therapeutic efficacy.
Purpose of the Study:
- To synthesize a novel series of 3,5-bis(ylidene)-4-piperidone-1-phosphonothioates.
- To evaluate the antiproliferative activity of these compounds against various human cancer cell lines.
- To investigate the biochemical mechanisms underlying their anticancer effects, including inhibition of MDM2 and topoisomerases.
Main Methods:
- Synthesis of 3,5-bis(ylidene)-4-piperidone-1-phosphonothioates via dehydrochlorination.
- In vitro antiproliferation assays against MCF7, HCT116, and A431 cancer cell lines.
- Biochemical assays to assess inhibition of MDM2, p53 activation, topoisomerase I, and topoisomerase IIα.
- Molecular docking studies to rationalize observed MDM2 inhibitory activity.
Main Results:
- High yields of synthesized phosphonothioate analogs were achieved.
- Compound 20c demonstrated significant antiproliferative activity against MCF7, HCT116, and A431 cells, exceeding that of 5-fluorouracil and sunitinib.
- Compound 20k showed potent inhibition of MDM2, surpassing doxorubicin.
- Compound 20i effectively inhibited topoisomerase I and IIα, comparable to standard drugs.
- Molecular docking studies supported the observed MDM2 inhibition.
Conclusions:
- The synthesized 3,5-bis(ylidene)-4-piperidone-1-phosphonothioates exhibit potent anticancer properties.
- These compounds act through multiple mechanisms, including MDM2 inhibition and topoisomerase targeting.
- The most effective analogs, such as 20c, 20k, and 20i, represent promising candidates for further development as multi-targeted anticancer agents.
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