Synthesis and biological activity of thiophene bioisosteres of natural styryl lactone goniofufurone and related compounds

Eur J Med Chem. 2024 Mar 21;269:116340. doi: 10.1016/j.ejmech.2024.116340. Online ahead of print.ABSTRACTTen new thiophene derivatives related to goniofufurone have been obtained by multistep synthesis starting from d-glucose. The critical step of the synthesis was the Grignard reaction of 2-thienyl magnesium bromide with a protected dialdose, yielding the C-5 epimeric thiophene derivatives 9 and 10. The mixture was oxidized to the 5-keto derivative 11, which after deprotection was converted to the corresponding keto-lactone 14. Stereoselective reduction of 14 afforded the thiophene mimic of goniofufurone 3. Esterification of 3 with cinnamic or 4-fluorocinnamic acid gave hybrids 5-7. Synthesized analogues were evaluated for their in vitro cytotoxicity against several tumour cell lines. The vast majority of them showed better activity than lead 1. In the culture of K562 cells, compound 3 was more active than the commercial antitumour drug doxorubicin. Structural features of analogues important for their antiproliferative activities were identified by SAR analysis. Pro-apoptotic potential examination of compound 3 on the K562 cell line was performed using flow cytometry, double fluorescence staining and apoptotic morphology screening. Results show that this derivative induces cell membrane disruptions attributable to apoptosis and induces the apoptotic morphology, but decreasing simultaneously the population of cells in the subG1 phase of the cell cycle. The results further sug...

Source: European Journal of Medicinal Chemistry - March 25, 2024 Category: Chemistry Authors: Mirjana Popsavin Sanja Djoki ć Ivana Kova čević Sla đana M Stanisavljević Vesna Koji ć Marko V Rodi ć Lidija Aleksi ć Jelena Kesi ć Bojana Sre ćo Zelenović Velimir Popsavin Dimitar S Jakimov Source Type: research