dc.creator | Fratta, Simone | es |
dc.creator | Biniecka, Paulina | es |
dc.creator | Moreno Vargas, Antonio José | es |
dc.creator | Carmona Asenjo, Ana Teresa | es |
dc.creator | Nahimana, Aimable | es |
dc.creator | Duchosal, Michel A. | es |
dc.creator | Piacente, Francesco | es |
dc.creator | Bruzzone, Santina | es |
dc.creator | Caffa, Irene | es |
dc.creator | Nencioni, Alessio | es |
dc.creator | Robina Ramírez, Inmaculada | es |
dc.date.accessioned | 2023-05-15T14:25:27Z | |
dc.date.available | 2023-05-15T14:25:27Z | |
dc.date.issued | 2023 | |
dc.identifier.citation | Fratta, S., Biniecka, P., Moreno Vargas, A.J., Carmona Asenjo, A.T., Nahimana, A., Duchosal, M.A.,...,Robina Ramírez, I. (2023). Synthesis and Structure-activity Relationship of New Nicotinamide Phosphoribosyltransferase Inhibitors with Antitumor Activity on Solid and Haematological Cancer. European Journal of Medicinal Chemistry, 250, 115170. https://doi.org/10.1016/j.ejmech.2023.115170. | |
dc.identifier.issn | 0223-5234 | es |
dc.identifier.issn | 1768-3254 | es |
dc.identifier.uri | https://hdl.handle.net/11441/146032 | |
dc.description.abstract | Cancer cells are highly dependent on Nicotinamide phosphoribosyltransferase (NAMPT) activity for proliferation, therefore NAMPT represents an interesting target for the development of anti-cancer drugs. Several compounds, such as FK866 and CHS828, were identified as potent NAMPT inhibitors with strong anti-cancer activity, although none of them reached the late stages of clinical trials. We present herein the preparation of three libraries of new inhibitors containing (pyridin-3-yl)triazole, (pyridin-3-yl)thiourea and (pyridin-3/4-yl)cyanoguanidine as cap/connecting unit and a furyl group at the tail position of the compound. Antiproliferative activity in vitro was evaluated on a panel of solid and haematological cancer cell lines and most of the synthesized compounds showed nanomolar or sub-nanomolar cytotoxic activity in MiaPaCa-2 (pancreatic cancer), ML2 (acute myeloid leukemia), JRKT (acute lymphobalistic leukemia), NMLW (Burkitt lymphoma), RPMI8226 (multiple myeloma) and NB4 (acute myeloid leukemia), with lower IC50 values than those reported for FK866. Notably, compounds 35a, 39a and 47 showed cytotoxic activity against ML2 with IC50 = 18, 46 and 49 pM, and IC50 towards MiaPaCa-2 of 0.005, 0.455 and 2.81 nM, respectively. Moreover, their role on the NAD+ synthetic pathway was demonstrated by the NAMPT inhibition assay. Finally, the intracellular NAD+ depletion was confirmed in vitro to induced ROS accumulation that cause a time-dependent mitochondrial membrane depolarization, leading to ATP loss and cell death. | es |
dc.description.sponsorship | European Union No671881 | es |
dc.description.sponsorship | Ministerio de Ciencia e Innovación PID2020-116460RB-100 | es |
dc.description.sponsorship | Associazione Italiana per la Ricerca sul Cancro IG#22098 | es |
dc.description.sponsorship | Italian Ministry of Health PE-2016-02362694, PE-2016-02363073 | es |
dc.format | application/pdf | es |
dc.format.extent | 20 p. | es |
dc.language.iso | eng | es |
dc.publisher | Elsevier | es |
dc.relation.ispartof | European Journal of Medicinal Chemistry, 250, 115170. | |
dc.rights | Atribución 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject | Cancer | es |
dc.subject | Cyanoguanidines | es |
dc.subject | Cytotoxic agents | es |
dc.subject | Furan | es |
dc.subject | NAD+ | es |
dc.subject | NAMPT inhibitors | es |
dc.title | Synthesis and Structure-activity Relationship of New Nicotinamide Phosphoribosyltransferase Inhibitors with Antitumor Activity on Solid and Haematological Cancer | es |
dc.type | info:eu-repo/semantics/article | es |
dcterms.identifier | https://ror.org/03yxnpp24 | |
dc.type.version | info:eu-repo/semantics/publishedVersion | es |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es |
dc.contributor.affiliation | Universidad de Sevilla. Departamento de Química orgánica | es |
dc.relation.projectID | No671881 | es |
dc.relation.projectID | PID2020-116460RB-100 | es |
dc.relation.projectID | IG#22098 | es |
dc.relation.projectID | PE-2016-02362694 | es |
dc.relation.projectID | PE-2016-02363073 | es |
dc.relation.publisherversion | https://doi.org/10.1016/j.ejmech.2023.115170 | es |
dc.identifier.doi | 10.1016/j.ejmech.2023.115170 | es |
dc.journaltitle | European Journal of Medicinal Chemistry | es |
dc.publication.volumen | 250 | es |
dc.publication.initialPage | 115170 | es |
dc.contributor.funder | European Union (UE). H2020 | es |
dc.contributor.funder | Ministerio de Ciencia e Innovación (MICIN). España | es |
dc.contributor.funder | Associazione Italiana per la Ricerca sul Cancro (AIRC) | es |
dc.contributor.funder | Italian Ministry of Health | es |