RESUMEN
4-Aminoquinolines were prepared in a three-step synthesis starting from substituted anthranilonitriles. The condensation on 1,1,1-trichloro-4-ethoxybut-3-enone proceeded efficiently either neat or in refluxing EtOH. Cyclization in superacidic trifluoromethanesulfonic acid provided unstable intermediate, which upon treatment with NaOEt in ethanol, afforded the expected esters. Theoretical investigations pointed out a monoprotonated nitrilium as the reactive species during the cyclization process.
RESUMEN
Marine organisms have proven to be a promising source of new compounds with activity against tumor cell lines. Granulatimide and isogranulatimide are marine alkaloids that have been shown to inhibit checkpoint kinase 1 (Chk1), a key protein in the DNA damage response and an emerging target for anticancer therapeutics. Here, we describe the synthesis and preliminary evaluation of amido and amino analogues of isogranulatimide. The new derivatives were prepared in three steps from 2-imidazol-1-yl-1H-indol-5-ylamine. Two of the compounds synthesized exhibited more potent in vitro antiproliferative activity (single-digit micromolar concentration range), by at least one log of magnitude, than the natural product isogranulatimide when evaluated in six human tumor cell lines: non-small-cell lung cancer (A549), colon cancer (LoVo), breast cancer (MCF7), oligodendroglioma (Hs683), glioblastoma (U373), and melanoma (SKMEL28). The mechanism of action of these derivatives remains to be elucidated, given that they did not significantly inhibit Chk1, however these compounds are easily synthesized and exhibit potent anticancer activity and are thus worthy of further study.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Productos Biológicos/química , Productos Biológicos/farmacología , Proliferación Celular/efectos de los fármacos , Imidazoles/química , Imidazoles/farmacología , Indoles/química , Indoles/farmacología , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Aminación , Antineoplásicos/síntesis química , Productos Biológicos/síntesis química , Línea Celular Tumoral , Humanos , Imidazoles/síntesis química , Indoles/síntesis química , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
The two marine alkaloids granulatimide and isogranulatimide have been shown to inhibit the checkpoint kinase 1 (Chk1), a promising target for cancer treatment. A molecular docking study allowing the design of new potential Chk1 inhibitors based on the natural products skeleton and the synthetic work to an amino-target platform to prepare them are described.
Asunto(s)
Alcaloides/farmacología , Diseño de Fármacos , Imidazoles/farmacología , Indoles/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Alcaloides/síntesis química , Alcaloides/química , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Relación Dosis-Respuesta a Droga , Imidazoles/síntesis química , Imidazoles/química , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
A series of nanometric isoreticular and/or functionalized analogues of the mesoporous environmentally-friendly iron(III) polycarboxylates MIL-100/101 have been successfully synthesized. Their exceptional pore size, of up to 68 Å, together with their relatively good stability in solvents, makes them promising candidates for heterogeneous catalysis or inclusion of large molecules, among others.