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Evaluation of the anticancer activity of singly and doubly modified analogues of C20-epi-salinomycin
Dominika Czerwonka1, Magdalena Mielczarek-Puta2, Michał Antoszczak1
1Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61‒614, Poznań, Poland.
Abstract:
In developed countries, cancer is the second leading cause of death, with colon and prostate cancer belonging to the group of most often diagnosed types of neoplastic diseases. The search for new treatment strategies against these types of cancer is thus of top current interest. In this context, salinomycin (SAL), a naturally occurring polyether ionophore, has been identified recently as a very promising anticancer drug candidate towards several tumour cells. In the present work, a broad library of 24 derivatives of C20-epi-salinomycin (2), including C1 singly, C20 singly and C1/C20 doubly modified analogue structures, was screened to identify compounds with improved activity against colon and prostate cancer cells. Our study demonstrated that the growth inhibitory potency of the parent compound on both primary and metastatic colon cancer cells was similar to that of the semisynthetic products derived from SAL, and simultaneously the SAL analogues showed more potent toxic action on metastatic prostate cancer cells than that of the chemically unmodified ionophore. In contrast to the widely used oncological drug doxorubicin, some of the SAL derivatives demonstrated promising anticancer activity with no toxic effects on non-tumour cells, and with more favourable cytotoxicity than that of a reference agent 5-fluorouracil. Mechanistically, the SAL analogues induced late apoptosis in colon cancer cells and necrosis in prostate cancer cells, as well as reduced secretion of interleukin 6 (IL-6) in these cells.
Insights
Salinomycin derivatives show potent anticancer activity against colon and prostate cancer cells. Some analogues exhibit improved efficacy and reduced toxicity compared to existing treatments, offering new therapeutic strategies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- Cancer is a leading cause of death globally, with colon and prostate cancers being highly prevalent.
- Salinomycin (SAL), a natural ionophore, has emerged as a promising anticancer agent.
- Developing novel therapeutic strategies for colon and prostate cancers is a critical area of research.
Purpose of the Study:
- To synthesize and screen a library of 24 C20-epi-salinomycin derivatives for enhanced anticancer activity.
- To evaluate the efficacy of SAL analogues against colon and prostate cancer cell lines.
- To compare the cytotoxicity of SAL derivatives with existing chemotherapeutic agents.
Main Methods:
- Synthesis of a library of 24 C1 and/or C20 modified salinomycin analogues.
- In vitro screening of compounds against primary and metastatic colon and prostate cancer cells.
- Comparative analysis of cytotoxicity against non-tumour cells and established drugs like doxorubicin and 5-fluorouracil.
Main Results:
- Salinomycin analogues demonstrated potent growth inhibition in colon cancer cells, comparable to the parent compound.
- SAL derivatives exhibited enhanced toxicity against metastatic prostate cancer cells compared to unmodified salinomycin.
- Several SAL derivatives displayed significant anticancer activity with no observed toxicity to non-tumour cells, outperforming doxorubicin and 5-fluorouracil.
Conclusions:
- C20-epi-salinomycin derivatives represent a promising class of compounds for colon and prostate cancer therapy.
- These analogues offer a potentially safer and more effective alternative to current treatments.
- Further investigation into the mechanisms, including apoptosis induction and IL-6 reduction, is warranted.
