RESUMO
In the present study, a practical method to prepare piperazinyl amides of 18ß-glycyrrhetinic acid was developed. Two main procedures for the construction of important intermediate 8 are discussed. One procedure involves the amidation of 1-Boc-piperazine with 3-acetyl-18ß-glycyrrhetinic acid, prepared by the reaction of 18ß-glycyrrhetinic acid with acetic anhydride without any solvent at 130 °C. The other procedure to prepare compound 8 involves the amidation of 18ß-glycyrrhetinic acid followed by the esterification with acetic anhydride. Finally, compound 8 underwent N-Boc deprotection to prepare product 4. To ascertain the scope of the reaction, another C-3 ester derivative 17 was tested under the optimized reaction conditions. Furthermore, the reasons for the appearance of byproducts were elucidated. Crystallographic data of a selected piperazinyl amide is reported.
RESUMO
Novel 18ß-glycyrrhetinic acid derivatives possessing a carbamate moiety and structurally similar ester derivatives were developed and evaluated for their efficacy as antitumor inhibitors. In the cellular assays, most of the N-substituted carbamate derivatives at the C3-position exhibited potent activities. The results of SAR investigation revealed that the introduction of the morpholine group at the C30-COOH led to a significant loss of the inhibitory potency. Among the ester derivatives, the ester group at C3-position also determined a noticeable reduction in the efficacy. Compound 3j exhibited the most prominent antiproliferative activity against six human cancer cells (A549, HT29, HepG2, MCF-7, PC-3, and Karpas299). Furthermore, compound 3j exerted a moderate inhibiting effect on the ALK. The results of molecular docking analyses suggested that it could bind well to the active site of the receptor ALK, which was consistent with the biological data. These results might inspire further structural optimization of 18ß-glycyrrhetinic acid aiming at the development of potent antitumor agents. The structures 4d, 4g, 4h, 4j, and 4n were studied by X-ray crystallographic analyses.
Assuntos
Quinase do Linfoma Anaplásico/química , Antineoplásicos/química , Ácido Glicirretínico/análogos & derivados , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacologia , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Conformação Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
Six new triterpene saponins, clematomandshurica saponins F-K (1-6), together with a known compound (7), were isolated from the roots and rhizomes of Clematis mandshurica. Their structures were elucidated on the basis of spectroscopic evidence and hydrolysis. Compounds 5-7 exhibited antiproliferative effects against PC-3 human prostate cancer cells with GI50 values of 1.29, 1.50, and 0.71 µM, respectively.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Clematis/química , Saponinas/farmacologia , Triterpenos/farmacologia , Antineoplásicos Fitogênicos/química , Isótopos de Carbono/análise , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , China , Humanos , Hidrólise , Espectroscopia de Ressonância Magnética , Medicina Tradicional Chinesa , Estrutura Molecular , Raízes de Plantas/química , Plantas Medicinais , Rizoma/química , Saponinas/química , Saponinas/isolamento & purificação , Triterpenos/química , Triterpenos/isolamento & purificaçãoRESUMO
Four new oleanene-type triterpenoid saponins together with six known saponins were isolated from the roots of Pulsatilla cernua and their structures were elucidated on the basis of spectroscopic data, including 2D NMR spectra and chemical evidence. Among these one of the aglycones (gypsogenin) is reported for the first time from this genus. Some of these compounds showed significant neuroprotective effects against the cytotoxicity induced by ß-amyloid(25-35) (Aß(25-35)) on human neuroblastoma SH-SY5Y cells.
