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

Abstract

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.

Differential Functionalization of 1,6‐Naphthyridin‐2(1H)‐ones through Sequential One‐Pot Suzuki–Miyaura Cross‐Couplings

“…Because of this broad range of biological activities, various strategies to provide functionalized 1,6‐naphthyridin‐2(1 H )‐ones efficiently are still needed. 7‐Substituted 3‐aryl‐1,6‐naphthyridin‐2(1 H )‐ones5a,5c–5g are of particular value, but few methods are available to produce highly functionalized 3,7‐disubstituted 1,6‐naphthyridin‐2(1 H )‐ones. Indeed, Thompson and co‐workers have reported the selective inhibition of c‐Src kinase in a nanomolar range for such compounds 5a…”

Synthesis and Activity of Novel 5‐Substituted Pyrrolo[2,3‐d]pyrimidine Analogues as pp60c‐Src Tyrosine Kinase Inhibitors

“…The pp60 c-Src has been implicated in the development of leukemia, breast, and colon cancer [9]. In addition, the inhibitors of pp60 c-Src tyrosine kinase particularly have been identified as potential therapeutics for osteoporosis [10]. In the few past years, much progress has been made about different kinase inhibitors with utility in oncology; they often lack selectivity or show weak cellular potency.…”

Theoretical Studies of QSAR and Molecular Design on a Novel Series of Ethynyl‐3‐Quinolinecarbonitriles as Src Inhibitors

“…Src has been recognized as an attractive therapeutic target for the discovery of antitumor drugs (7,8), and thus the development of novel c‐Src‐targeting agents is very significant. So far, various classes of Src kinase inhibitors have been synthesized (9–12), and they have spanned a variety of structural classes, in which the three most advanced compounds, i.e., the anilinoquinazoline AZD0530 (13), the thiazolecarboxamide BMS‐354825 (14), and the quinolinecarbonitrile SKI‐606 (15,16) (Figure 1) are undergoing clinical evaluation .…”