We report 31 new compounds designed, synthesized and evaluated on Bcr-Abl, BTK and FLT3-ITD as part of our program to develop 2,6,9-trisubstituted purine derivatives as inhibitors of oncogenic kinases. The design was inspired by the chemical structures of well-known kinase inhibitors and our previously developed purine derivatives. The synthesis of these purines was simple and used a microwave reactor for the final step. Kinase assays showed three inhibitors with high selectivity for each protein that were identified: 4f (IC50 = 70 nM for Bcr-Abl), 5j (IC50 = 0.41 μM for BTK) and 5b (IC50 = 0.38 μM for FLT-ITD). The 3D-QSAR analysis and molecular docking studies suggested that two fragments are potent and selective inhibitors of these three kinases: a substitution at the 6-phenylamino ring and the length and volume of the alkyl group at N-9. The N-7 and the N-methyl-piperazine moiety linked to the aminophenyl ring at C-2 are also requirements for obtaining the activity. Furthermore, most of these purine derivatives were shown to have a significant inhibitory effect in vitro on the proliferation of leukaemia and lymphoma cells (HL60, MV4-11, CEM, K562 and Ramos) at low concentrations. Finally, we show that the selected purines (4i, 5b and 5j) inhibit the downstream signalling of the respective kinases in cell models. Thus, this study provides new evidence regarding how certain chemical modifications of purine ring substituents provide novel inhibitors of target kinases as potential anti-leukaemia drugs.
An attention to the novel synthetic route for the polycyclic quinolines (3 & 5) from cyclic-diketones, cyclohexan-1,2-dione (2) / cyclohexan-1,3-dione (4) with oaminoarylketones (1) in the presence of SiO 2 /H 2 SO 4 yielded via Friedlӓnder synthetic method. The catalytic efficiency of the SiO 2 /H 2 SO 4 was discussed through their utilization in the synthesis of biologically active substituted polycyclic quinoline derivatives (3 & 5) and the mechanism has been proposed. The SiO 2 /H 2 SO 4 was found as a effective catalyst for the Friedlӓnder reaction and gave considerable isolated yield of the targeted products under the mild reaction condition. The synthesized polycyclic quinolines (3 & 5) were characterized through diverse analytical techniques like FT-IR, NMR spectroscopy and single crystal X-ray diffraction studies.
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