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dc.contributor.author | Álvarez Lozano, Raquel | |
dc.contributor.author | Aramburu Villar, Laura | |
dc.contributor.author | Gajate, Consuelo | |
dc.contributor.author | Vicente Blázquez, Alba | |
dc.contributor.author | Mollinedo García, Faustino | |
dc.contributor.author | Medarde Agustín, Manuel | |
dc.contributor.author | Peláez Lamamie de C. Arroyo, Rafael | |
dc.date.accessioned | 2022-01-25T11:22:08Z | |
dc.date.available | 2022-01-25T11:22:08Z | |
dc.date.issued | 2020-03 | |
dc.identifier.issn | 0045-2068 | |
dc.identifier.uri | http://hdl.handle.net/10366/148386 | |
dc.description.abstract | Colchicine site antimitotic agents typically suffer from low aqueous solubilities and are formulated as phosphate prodrugs of phenolic groups. These hydroxyl groups are the aim of metabolic transformations leading to resistance. There is an urgent need for more intrinsically soluble analogues lacking these hydroxyl groups. The 3,4,5-trimethoxyphenyl ring of combretastatin A-4 is a liability in terms of solubility but it is considered essential for high cytotoxic and tubulin polymerization inhibitory (TPI) activity. We have synthesized 36 new analogues of combretastatin A-4 replacing the trimethoxyphenyl moiety with more polar pyridine based moieties, measured their aqueous solubility, and studied their anti-proliferative effects against 3 human cancer cell lines. We show here that pyridine rings can be successful replacements for the trimethoxyphenyl ring, resulting in potent and more soluble analogues. The more straightforward replacement, a 2,6-dimethoxypyridine ring led to inactive analogues, but a 2-methoxy-6-methylsulfanylpyridine moiety led to active analogues when combined with different B rings. This replacement led to potent cytotoxic activity against sensitive human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies. Cell cycle analysis also showed apoptotic responses following treatment. Docking studies suggested binding at the colchicine site of tubulin and provided a good agreement with the observed SAR. A 2-methoxy-6-methylsulfanylpyridine moiety is a good trimethoxyphenyl ring replacement for the development of new colchicine site ligands. | es_ES |
dc.description.sponsorship | We thank the people at Frigoríficos Salamanca S.A. slaughter-house for providing us with the calf brains and “Servicio General de NMR” and “Servicio General de Espectrometría de Masas” of the Universidad de Salamanca for equipment. L.A. acknowledges a predoctoral fellowship from the Junta de Castilla y León. A.V.B acknowledges a predoctoral fellowship from the Spanish Ministerio de Educación, Cultura y Deporte (FPU15/02457). This work was supported by the Consejería de Educación de la Junta de Castilla y León (SA030U16 and SA262P18), co-funded by the EU's European Regional Development Fund-FEDER, and the Spanish Ministry of Science, Innovation and Universities (RTI2018-099474-B-I00 and SAF2017-89672-R). | es_ES |
dc.format.mimetype | application/pdf | |
dc.language.iso | eng | es_ES |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Pyridine derivatives | es_ES |
dc.subject | Combretastatins, isocombretastatins and phenstatins | es_ES |
dc.subject | Solubility | es_ES |
dc.subject | Antimitotic | es_ES |
dc.subject | Docking | es_ES |
dc.title | Potent colchicine-site ligands with improved intrinsic solubility by replacement of the 3,4,5-trimethoxyphenyl ring with a 2-methylsulfanyl-6-methoxypyridine ring | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.relation.publishversion | https://doi.org/10.1016/j.bioorg.2020.103755 | es_ES |
dc.identifier.doi | 10.1016/j.bioorg.2020.103755 | |
dc.relation.projectID | SA030U16 | es_ES |
dc.relation.projectID | SA262P18 | es_ES |
dc.relation.projectID | RTI2018-099474-B-I00 | es_ES |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | es_ES |
dc.journal.title | Bioorganic Chemistry | es_ES |
dc.volume.number | 98 | es_ES |
dc.page.initial | 103755 | es_ES |
dc.type.hasVersion | info:eu-repo/semantics/publishedVersion | es_ES |
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