Synthesis and Evaluation of New 6-formyl-oxazolo[3,2-a]pyrimidine derivatives as Potential Src Kinase Inhibitors
| Autor: | François Hallé, Daniel-Henri Caignard, Jean Guillon, Solène Savrimoutou, Stéphane Moreau, Pascal Sonnet |
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| Přispěvatelé: | Chimie Nucléaire Analytique et Bio-environnementale (CNAB), Université Sciences et Technologies - Bordeaux 1 (UB)-Centre National de la Recherche Scientifique (CNRS), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Régulations Naturelles et Artificielles (ARNA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux Ségalen [Bordeaux 2], Institut de Recherches SERVIER (IRS), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, DESSAIVRE, Louise |
| Rok vydání: | 2018 |
| Předmět: |
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
Pyrimidine Kinase Stereochemistry Cycloaddition Malignant transformation Amidine chemistry.chemical_compound chemistry IC50 Tyrosine kinase ComputingMilieux_MISCELLANEOUS [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | 4th International Electronic Conference on Medicinal Chemistry 4th International Electronic Conference on Medicinal Chemistry, Nov 2018, Sciforum.net, France. pp.5566, ⟨10.3390/ecmc-4-05566⟩ |
| DOI: | 10.3390/ecmc-4-05566 |
| Popis: | The tyrosine-protein kinase Src, also known as proto-oncogene c-Src or simply c-Src, is a non-receptor tyrosine kinase protein that has been shown to be involved in the regulation of important cellular processes including migration, survival and proliferation. In fact, Src activation has been associated with multiple cancers, such as colon, breast, pancreas, lung, or brain (Roskoski, R. Jr. Pharmacol. Res. 2015, 94, 9-25; Creedon, H., et al., Crit. Rev. Oncog. 2012, 17, 145-159). There are only few Src inhibitors in clinical development, therefore, there is an urgent need to identify new low molecular weight therapeutics able to inhibit Src and, thus, to modulate aberrant pathways leading to malignant transformation of cells (Lu, X.L., et al., Curr. Med. Chem. 2012, 19, 1821-1829). Heterocyclic compounds attracted a lot of attention because of their wide spread biological activities. Thus, we have previously reported the synthesis of biological active heterocyclic derivatives based on the reactivity of the amidine moiety of 2-amino-2-oxazolines 2 with bis-electrophiles (Massip, S., et al., Bioorg. Med. Chem. 2006, 14, 2697-2719). https://ibb.co/hzkMnJ In a preliminary screening testing our heterocycles library, we have identified a “hit” (compound 1d) derived from various substituted 6-formyl-oxazolo[3,2-a]pyrimidines as a new Src kinase inhibitor (IC50 = 4 µM). These original oxazolo[3,2-a]pyrimidine derivatives 1a-k were synthesized through a Diels-Alder cycloaddition of alkylidene derivatives of 2-amino-2-oxazoline (compounds 3a-k) with acrolein, as an electron-poor dienophile, a reaction previously described by our group (Guillon, J., et al., Synlett 2002, 8, 1249-1252). Versatility given by this reaction allowed us to access a promising family of diversely substituted 6-formyl-oxazolo[3,2-a]pyrimidines with inhibitory effect on Src kinase. Acknowledgments: This work was supported by a grant from Ligue Contre le Cancer (Gironde, Bordeaux, France). |
| Databáze: | OpenAIRE |
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