Article ; Online: Synthesis and biological activity of thiophene bioisosteres of natural styryl lactone goniofufurone and related compounds.
European journal of medicinal chemistry
2024 Volume 269, Page(s) 116340
Abstract: Ten 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 ... ...
| Abstract | Ten 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 suggest that analogue 3 achieves strong cytotoxicity without causing DNA fragmentation. This is clearly indicated by the relatively low incidence of micronuclei, as well as the SAR analysis of all biological effects. |
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| MeSH term(s) | Humans ; Structure-Activity Relationship ; Thiophenes/pharmacology ; Cell Proliferation ; Antineoplastic Agents/chemistry ; Cell Line, Tumor ; Lactones/chemistry ; Drug Screening Assays, Antitumor ; Molecular Structure ; Apoptosis |
| Chemical Substances | 7-goniofufurone (136778-39-7) ; Thiophenes ; Antineoplastic Agents ; Lactones |
| Language | English |
| Publishing date | 2024-03-21 |
| Publishing country | France |
| Document type | Journal Article |
| ZDB-ID | 188597-2 |
| ISSN | 1768-3254 ; 0009-4374 ; 0223-5234 |
| ISSN (online) | 1768-3254 |
| ISSN | 0009-4374 ; 0223-5234 |
| DOI | 10.1016/j.ejmech.2024.116340 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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