RESUMO
Fortuneicyclidins A (1) and B (2), a pair of epimeric pyrrolizidine alkaloids containing an unprecedented 7-azatetracyclo[5.4.3.0.02,8]tridecane core, were isolated from the seeds of Cephalotaxus fortunei, along with two biogenetically relative known analogues, 3 and 4. The structures were determined by multiple spectral techniques and chemical derivatization methods. Compound 1 showed inhibitory activity against α-glucosidase.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Cephalotaxus/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Folhas de Planta/química , Alcaloides de Pirrolizidina/farmacologia , Alcanos/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Estrutura Molecular , Alcaloides de Pirrolizidina/química , Alcaloides de Pirrolizidina/isolamento & purificaçãoRESUMO
Novel withangulatin A (WA) derivatives were synthesized and evaluated for antiproliferative activity against four human cancer cell lines (U2OS, MDA-MB-231, HepG2, and A549). Among these derivatives, 10 exhibited the most potent antiproliferative activity, with an IC50 value of 74.0 nM against the human breast cancer cell line MDA-MB-231 and potency that was 70-fold that of WA (IC50 = 5.22 µM). Moreover, 10 caused G2-phase cell cycle arrest in a concentration-dependent manner and induced the apoptosis of MDA-MB-231 cells by increasing intracellular reactive oxygen species (ROS). Compound 10 showed a high selectivity index (SI = 267.03) for breast cancer MDA-MB-231 cells. These results suggest that 10 is a promising anticancer agent.
Assuntos
Antineoplásicos/síntese química , Pregnenos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Potencial da Membrana Mitocondrial , Pregnenos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
To develop novel GLS1 inhibitors as effective therapeutic agents for triple-negative breast cancer (TNBC), 25 derivatives were synthesized from the natural inhibitor withangulatin A (IC50 = 18.2 µM). Bioassay optimization identified a novel and selective GLS1 inhibitor 7 (IC50 = 1.08 µM). In MDA-MB-231 cells, 7 diminished cellular glutamate levels by blocking glutaminolysis pathway, further triggering the generation of reactive oxygen species to induce caspase-dependent apoptosis. Molecular docking indicated that 7 interacted with a new reacting site of allosteric binding pocket by forming various interactions in GLS1. The intraperitoneal administration of 7 at a dose of 50 mg/kg exhibited remarkable therapeutic effects and no apparent toxicity in the MDA-MB-231 xenograft model, indicating its potential as a novel GLS1 inhibitor for treatment of TNBC.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Glutaminase/antagonistas & inibidores , Pregnenos/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glutaminase/metabolismo , Humanos , Estrutura Molecular , Pregnenos/síntese química , Pregnenos/química , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
(20R)-25-Methoxyl-dammarane-3ß,12ß,20-triol (25-OCH3-PPD, AD-1) is a dammarane-type sapogenin showing anti-tumor potential. In the search for new anti-tumor agents with higher potency than our previously identified compound 25-OCH3-PPD, 11 novel sulfamic acid and diacid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 25-OCH3-PPD, compounds 1, 4, and 5 exhibited higher cytotoxic activity on almost all cell lines, together with lower toxicity in the normal cell. In particular, compound 1 exhibited the best anti-tumor activity in the in vitro assays. The water solubility of 25-OCH3-PPD and its derivatives was tested and the results showed that the solubility of 25-OCH3-PPD sulfamic acid and diacid derivatives were better than that of 25-OCH3-PPD in water, which may provide valuable data for the research and development of new anti-tumor agents.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Água/química , Linhagem Celular Tumoral , Ginsenosídeos/química , Células HCT116 , Humanos , Células MCF-7 , Sapogeninas/química , Solubilidade , Ácidos Sulfônicos/química , Triterpenos/química , DamaranosRESUMO
In the search for new anti-tumor agents with higher potency than our previously identified compound 1 (25-OH-PPD, 25-hydroxyprotopanaxadiol), 12 novel sulfamic and succinic acid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 1, compounds 2, 3, and 7 exhibited higher cytotoxic activity on A-549 and BGC-823 cell lines, together with lower toxicity in the normal cell. In particular, compound 2 exhibited the best anti-tumor activity in the in vitro assays, which may provide valuable data for the research and development of new anti-tumor agents.
