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Differential Effect of Wortmannolone Derivatives on MDA-MB-231 Breast Cancer Cells
Ulyana Munoz Acuña1,2, Robert W Curley2, Nighat Fatima3,4
1Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH, U.S.A.
Background/Aim:
The survival rate of women diagnosed with triple-negative breast-cancer (TNBC) remains low. Hence, this study aimed at the chemical and biological optimization of furanosteroid derivatives for the treatment of this type of malignancy using TNBC cells.
Materials And Methods:
Semi-synthetic analogs of wortmannolone (1-6) that negatively affected the aberrant pathways in tumor cells were evaluated in hormone-independent breast cancer cells using western blot and cell-cycle analysis.
Results:
Wortmannolone derivatization generated NF-ĸB inhibitors as new lead structures for further development. Compound (3) was found to be the most significantly active lead.
Conclusion:
Structure-activity analysis in the present study showed that acetylation of the hydroxyl groups and substitution on C3 and C17 of wortmannolone enhanced biological activity. Alpha-substitution of the acetyl group in C3 on ring A (compound 3) resulted in ROS inducing effect; however, presence of an acetyl group in β-position of C3 displayed the highest NF-ĸB p65 inhibitory activity (0.60 μM).
Insights
Researchers optimized furanosteroid derivatives to treat triple-negative breast cancer (TNBC). Compound 3, a wortmannolone derivative, showed significant NF-κB p65 inhibitory activity, offering a promising lead for TNBC treatment.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) has a poor prognosis.
- Novel therapeutic strategies are urgently needed for TNBC treatment.
Purpose of the Study:
- To chemically and biologically optimize furanosteroid derivatives.
- To evaluate these derivatives for their potential in treating triple-negative breast cancer.
Main Methods:
- Synthesis of semi-synthetic wortmannolone analogs.
- Evaluation of compounds in hormone-independent breast cancer cells.
- Western blot and cell-cycle analysis were employed.
Main Results:
- Wortmannolone derivatization yielded novel NF-κB inhibitors.
- Compound 3 emerged as the most active lead compound.
- Structure-activity relationship analysis indicated key modifications for enhanced activity.
Conclusions:
- Acetylation and substitution at C3/C17 of wortmannolone improved biological activity.
- Alpha-substitution at C3 induced a ROS effect, while beta-substitution showed potent NF-κB p65 inhibition (0.60 μM).
- These optimized furanosteroids represent promising candidates for further TNBC drug development.