RESUMEN
In this study of creating new molecules from clinical trial agents, an approach of Combretastatin structural modulation with the installation of NP-privileged motifs was considered, and a series of trimethoxyphenyl-2-aminoimidazole with functionalized quinolines and isoquinolines was investigated. An exciting method of quinoline C3-H iodination coupled with imidazopyridine-C3-H arylation and hydrazine-mediated fused-ring cleavage enabled synthesizing a class of compounds with two specific unsymmetric aryl substitutions. Interestingly, three compounds (6, 11, and 13) strongly inhibited HeLa cell proliferation with a half-maximal inhibitory concentration (10-46 nM). Among the compounds, compound 6 (QTMP) showed stronger antiproliferative ability than CA-4 (a clinical trial agent) in various cancer cell lines, including cervical, lung, breast, highly metastatic breast, and melanoma cells. QTMP inhibited the assembly of purified tubulin, depolymerized microtubules of A549 lung carcinoma cells, produced defective spindles, and arrested the cells in the G2/M phase. Further, QTMP binds to the colchicine site in tubulin with a dissociation constant of 5.0 ± 0.6 µM. QTMP displayed higher aqueous stability than CA-4 at 37 °C. Further, in silico analysis of QTMP indicated excellent drug-like properties, including good aqueous solubility, balanced hydrophilicity-lipophilicity, and high GI-absorption ability. The results together suggest that QTMP has anticancer potential.
Asunto(s)
Antineoplásicos , Tubulina (Proteína) , Humanos , Tubulina (Proteína)/metabolismo , Estructura Molecular , Relación Estructura-Actividad , Moduladores de Tubulina/farmacología , Células HeLa , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Proliferación Celular , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
KF-mediated nucleophilic activation of TMSCN as a functional isonitrile equivalent establishes an efficient and chemoselective Ugi-type multicomponent reaction of a heterocyclic amidine and aldehyde with TMSCN in water. In this approach, the use of isocyanide is circumvented, known competing reactions are virtually eliminated, pure products are obtained by a non-chromatographic method, and therapeutically relevant and diverse N-fused 3-aminoimidazoles can be prepared from a wide variety of aldehydes and heterocyclic amidines. This reaction coupling with cascade cyclization provides various privileged tetracyclic heteroaromatic scaffolds.