Cycloartane-type sapogenol derivatives inhibit NFκB activation as chemopreventive strategy for inflammation-induced
Bilge Debeleç-Bütüner1, Mert Burak Öztürk2, Özgür Tağ3
1Ege University, Faculty of Pharmacy, Department of Pharmaceutical Biotechnology, Izmir, Turkey.
Abstract:
Chronic inflammation is associated to 25% of cancer cases according to epidemiological data. Therefore, inhibition of inflammation-induced carcinogenesis can be an efficient therapeutic approach for cancer chemoprevention in drug development studies. It is also determined that anti-inflammatory drugs reduce cancer incidence. Cell culture-based in vitro screening methods are used as a fast and efficient method to investigate the biological activities of the biomolecules. In addition, saponins are molecules that are isolated from natural sources and are known to have potential for tumor inhibition. Studies on the preparation of analogues of cycloartane-type sapogenols (9,19-cyclolanostanes) have so far been limited. Therefore we have decided to direct our efforts toward the exploration of new anti-tumor agents prepared from cycloastragenol and its production artifact astragenol. The semi-synthetic derivatives were prepared mainly by oxidation, condensation, alkylation, acylation, and elimination reactions. After preliminary studies, five sapogenol analogues, two of which were new compounds (2 and 3), were selected and screened for their inhibitory activity on cell viability and NFκB signaling pathway activity in LNCaP prostate cancer cells. We found that the astragenol derivatives 1 and 2 as well as cycloastragenol derivatives 3, 4, and 5 exhibited strong inhibitory activity on NFκB signaling leading the repression of NFκB transcriptional activation and suppressed cell proliferation. The results suggested that these molecules might have significant potential for chemoprevention of prostate carcinogenesis induced by inflammatory NFκB signaling pathway.
Insights
Chronic inflammation contributes to cancer. New semi-synthetic saponol analogues derived from cycloastragenol and astragenol show potential for cancer chemoprevention by inhibiting the NFκB signaling pathway and suppressing cell proliferation.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Natural Products Chemistry
Background:
- Chronic inflammation is linked to 25% of cancer cases, highlighting inflammation-induced carcinogenesis as a target for cancer chemoprevention.
- Anti-inflammatory drugs have demonstrated a reduction in cancer incidence, underscoring the therapeutic potential of targeting inflammation.
- Saponins, natural compounds, are known for their tumor-inhibiting properties, but studies on cycloartane-type sapogenol analogues are limited.
Purpose of the Study:
- To explore novel anti-tumor agents derived from cycloastragenol and its artifact astragenol.
- To synthesize and evaluate semi-synthetic derivatives of sapogenols for their chemopreventive potential.
- To investigate the inhibitory activity of these analogues on cell viability and the NFκB signaling pathway in prostate cancer cells.
Main Methods:
- Preparation of semi-synthetic derivatives of cycloastragenol and astragenol using reactions like oxidation, condensation, alkylation, acylation, and elimination.
- In vitro screening of five selected sapogenol analogues (two novel) for their effects on LNCaP prostate cancer cells.
- Assessment of inhibitory activity on cell viability and the Nuclear Factor kappa B (NFκB) signaling pathway.
Main Results:
- Five sapogenol analogues, including two new compounds, were synthesized and tested.
- Astragenol derivatives 1 and 2, and cycloastragenol derivatives 3, 4, and 5 demonstrated significant inhibitory activity.
- These compounds effectively repressed NFκB transcriptional activation and suppressed prostate cancer cell proliferation.
Conclusions:
- The synthesized sapogenol analogues exhibit potent anti-cancer properties.
- These molecules show promise for the chemoprevention of prostate cancer.
- Targeting the inflammatory NFκB signaling pathway with these novel compounds represents a viable therapeutic strategy.
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