294659-79-3Relevant academic research and scientific papers
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)
Thompson,Rewcastle,Boushelle,Hartl,Kraker,Lu,Batley,Panek,Hollis Showalter,Denny
, p. 3134 - 3147 (2007/10/03)
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-β 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(CH2)(n)NRR, 7-NHPhO(CH2)(n)NRR, or 7-NHPhN(CH2)4NMe] were the most potent against c-Src (IC50s 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 103-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.
