Discovery of anilinopyrimidine-based naphthamide derivatives as potent VEGFR-2 inhibitors

Abstract

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays an important role in tumor angiogenesis, and inhibition of the VEGFR-2 signaling pathway has emerged as an attractive strategy for the treatment of cancer. Herein, we describe the design, synthesis, and biological evaluation of anilinopyrimidine-based naphthamide derivatives as potent VEGFR-2 inhibitors. Among the new derivatives, compound 3k exhibited high VEGFR-2 inhibitory potency in both enzymatic and VEGF-induced HUVEC cellular proliferation assays (IC50 = 0.5 and 9.8 nM, respectively). Kinase selectivity profiling revealed that 3k was a highly selective VEGFR-2 inhibitor. Moreover, 3k effectively inhibited angiogenesis in HUVEC tube formation assay.

Microwave-assisted simple synthesis of 2-anilinopyrimidines by the reaction of 2-chloro-4,6-dimethylpyrimidine with aniline derivatives

“…( Table 1). A similar effect was observed in the phenyl substituted instance (11). In case of products (3) and (4), the high yields of 90 and 92%, respectively, are the consequence of the electronreleasing MeO and HO groups.…”

“…General procedure for the synthesis of compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) The appropriate aniline (1.0 mmol), 2-chloro-4,6dimethylpyrimidine (114 mg, 0.80 mmol), and ethanol (4 mL) were placed in a 5 mL reaction vial, sealed and irradiated at 160 C for 10 min under magnetic stirring. The solid residue was taken up in 30 mL of CH 2 Cl 2 , and the solution washed with 0.25 M Na 2 CO 3 (2 Â 20 mL) and dried over Na 2 SO 4 .…”

“…[1][2][3][4][5][6][7] Recently, a few 2-anilinopyrimidine derivatives have been evaluated as kinase inhibitors having antiproliferative activity against cancer cell lines. [8][9][10][11] The role of this class of compounds in the generation of supramolecular networks for molecular recognition has also been demonstrated. 12 Different methods have been proposed to synthesize anilinopyrimidines: (a) the cyclization between guanidines (generally obtained from isothiourea salts and alkyl(aryl)amines in the presence of strong bases) and b-diketones, ethyl acetoacetate or ethyl cyanoacetate under reuxing for several hours (b) the transition metal-free cross-coupling reactions, (c) the aromatic nucleophilic substitution of halogen pyrimidines or substituted heterocycles having an alkylsulfonyl group with anilines.…”

“…Preparative data and melting points for the synthesized products(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) …”

Design, Microwave-Assisted Synthesis, Antimicrobial and Anticancer Evaluation, and In Silico Studies of Some 2-Naphthamide Derivatives as DHFR and VEGFR-2 Inhibitors

“…Structure–activity relationship studies of the naphthalene ring system suggested that the C-1 and C-2 positions are very much important for the pharmacological effect. 12 Especially, naphthamide derivatives are potent VEGFR-2 inhibitors, for example, amide groups similar to anticancer drugs (sorafenib, sunitinib, pazopanib, axitinib, vandetanib, and regorafenib). Our designed derivatives and anticancer drug millepachine (potent cytotoxicity against a variety of human cancer cells with an IC 50 range of 0.76–4.66 μM), linifanib, and derivatives of Harmange et al, and Lv et al, share three common essential structural features such as a planar naphthalene moiety, the amide group at C-1 and C-2 positions, and the −OR-substituted groups at different positions ( Figure 2 ).…”