RESUMO
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.
RESUMO
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.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Imidazóis/química , Imidazóis/farmacologia , Indóis/química , Indóis/farmacologia , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Aminação , Antineoplásicos/síntese química , Produtos Biológicos/síntese química , Linhagem Celular Tumoral , Humanos , Imidazóis/síntese química , Indóis/síntese química , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologiaRESUMO
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.
Assuntos
Alcaloides/farmacologia , Desenho de Fármacos , Imidazóis/farmacologia , Indóis/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Alcaloides/síntese química , Alcaloides/química , Quinase 1 do Ponto de Checagem , Relação Dose-Resposta a Droga , Imidazóis/síntese química , Imidazóis/química , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
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.
