Synthesis and structure-activity relationships of 7-substituted 3-(2, 6-dichlorophenyl)-1,6-naphthyridin-2(1H)-ones as selective inhibitors of pp60(c-src)
| Autor: | William A. Denny, Robert L. Panek, Brian L. Batley, Andrew M. Thompson, Stacey L. Boushelle, Gina H. Lu, H. D. Hollis Showalter, Gordon W. Rewcastle, Brian G. Hartl, Alan J. Kraker |
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| Rok vydání: | 2000 |
| Předmět: |
Denticity
Stereochemistry Proto-Oncogene Proteins pp60(c-src) Antineoplastic Agents Ring (chemistry) Chemical synthesis Muscle Smooth Vascular Receptor Platelet-Derived Growth Factor beta chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery Side chain Tumor Cells Cultured Structure–activity relationship Animals Humans Receptor Fibroblast Growth Factor Type 1 Enzyme Inhibitors Naphthyridines Phosphorylation Cells Cultured Bicyclic molecule Chemistry Receptor Protein-Tyrosine Kinases Receptors Fibroblast Growth Factor Lactam Molecular Medicine Selectivity Cell Division |
| Zdroj: | Journal of medicinal chemistry. 43(16) |
| ISSN: | 0022-2623 |
| Popis: | 7-substituted 3-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-ones are potent inhibitors of protein tyrosine kinases, with some selectivity for c-Src. The compounds were prepared by condensing 4, 6-diaminonicotinaldehyde with 2,6-dichlorophenylacetonitrile and selectively converting the 2- and 7-amino groups of the product to hydroxy and fluoro groups, respectively, by prolonged diazotization in 50% aqueous fluoboric acid. N-Methylation, followed by treatment with aliphatic diamines, aromatic amines, or their derived lithium anions, gave the desired compounds. Selected isomeric 1, 8-naphthyridin-2(1H)-ones were also prepared in order to evaluate the relative contributions of both ring A aza atoms of the related pyrido[2,3-d]pyrimidin-7(8H)-ones to the inhibitory activity. The compounds were evaluated for their ability to prevent phosphorylation of a model substrate by c-Src, FGF-1 receptor, and PDGF-beta receptor enzymes. Overall, there was a high degree of correlation of the activities against the different kinases, with c-Src being generally the most sensitive to structural changes. 1, 6-Naphthyridin-2(1H)-one analogues bearing basic aliphatic side chains [7-NH(CH(2))(n)()NRR, 7-NHPhO(CH(2))(n)()NRR, or 7-NHPhN(CH(2))(4)NMe] were the most potent against c-Src (IC(50)s of 10-80 nM), showing good selectivity with respect to PDGFR (10-300-fold) but less with respect to FGFR. The 1, 6-naphthyridin-2(1H)-ones showed broadly similar activity to the analogous pyrido[2,3-d]pyrimidin-7(8H)-ones, whereas the 1, 8-naphthyridin-2(1H)-ones were at least 10(3)-fold less potent. These results, indicating that the 3-aza atom in the pyrido[2, 3-d]pyrimidin-7(8H)-ones is mandatory, whereas the 1-aza atom is not, support the published binding model for these compounds to c-Src (J. Med. Chem. 1998, 41, 1752), where the 3-aza and 2-NH atoms form a bidentate H-bond donor-acceptor motif that interacts with Met341 and the 1-aza atom is not involved in specific binding interactions. |
| Databáze: | OpenAIRE |
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