Synthesis and biological activity of salinomycin conjugates with floxuridine

• Published in: European journal of medicinal chemistry 2015-03, Vol.93, p.33-41
• Main Authors: Huczyński, Adam, Antoszczak, Michał, Kleczewska, Natalia, Lewandowska, Marta, Maj, Ewa, Stefańska, Joanna, Wietrzyk, Joanna, Janczak, Jan, Celewicz, Lech
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Conjugation; Drug Design; Floxuridine - chemistry; Floxuridine - pharmacology; Humans; Hybrid compound; Methicillin-Resistant Staphylococcus aureus - drug effects; Molecular Structure; Pyrans - chemistry; Pyrans - pharmacology; Staphylococcus epidermidis - drug effects; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.01.045

As part of our program to develop anticancer agents, we have synthesized new compounds, which are conjugates between well-known anticancer drug, floxuridine and salinomycin which is able to selectivity kill cancer stem cells. The conjugates were obtained in two ways i.e. by copper(I) catalysed click Huisgen cycloaddition reaction performed between 3′-azido-2′,3′-dideoxy-5-fluorouridine and salinomycin propargyl amide, and by the ester synthesis starting from salinomycin and floxuridine under mild condition. The compounds obtained were characterized by spectroscopic methods and evaluated for their in vitro cytotoxicity against seven human cancer cell lines as well as antibacterial activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE). The conjugate obtained by esterification reaction showed a significantly higher antiproliferative activity against the drug-resistant cancer cells and lower toxicity than those of salinomycin and floxuridine towards normal cells, as well as standard anticancer drugs, such as cisplatin and doxorubicin. The conjugate compound revealed also moderate activity against MRSA and MRSE bacterial strains. Very high activity of floxuridine and 5-fluorouracil against MRSA and MRSE has been also observed. [Display omitted] •Novel salinomycin conjugates with floxuridine were synthesized.•Obtained compounds showed potent antiproliferative activity against human tumour cells.•One of the conjugates showed very high selectivity index•The conjugates showed antibacterial activity.