RESUMEN
The exploration of novel anticancer compounds based on natural cyclopeptides has emerged as a pivotal paradigm in the contemporary advancement of macrocyclic pharmaceuticals. Phakellistatin 13 is a cycloheptapeptide derived from the brown snubby sponge and exhibits remarkable antitumor activity. In this study, we have designed and synthesized a series of chiral cyclopeptides incorporating the rigid isoindolinone moiety at various sites within the natural cycloheptapeptide Phakellistatin 13, with the aim of investigating conformationally constrained cyclopeptides as potential antitumor agents. Cyclopeptide 3, comprising alternating l-/d-amino acid residues, exhibited promising antihepatocellular carcinoma effects. Detailed biological experiments have revealed that Phakellistatin 13 analogs effectively inhibit the proliferation of tumor cells and induce apoptosis and autophagy, while also causing cell cycle arrest through the modulation of the p53 and mitogen-activated protein kinase (MAPK) signaling pathway. This study not only provides valuable insights into chemical structural modifications but also contributes to a deeper understanding of the biological mechanisms underlying the development of natural cyclopeptide-based drugs.
Asunto(s)
Antineoplásicos , Apoptosis , Proliferación Celular , Péptidos Cíclicos , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Humanos , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Autofagia/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismo , AnimalesRESUMEN
Cyclic peptides combine several favorable properties such as good binding affinity, target selectivity and low toxicity that make them an attractive modality for drug development. In an effort to identify what conformation could be accounting for the bioactive disparity of natural and synthetic cyclic peptides, some structurally-constrained analogs of cyclopeptide Axinastatin 3 were prepared by photo-induced single electron transfer (SET) reaction. Detailed stereochemistry study was performed by experimental electronic circular dichroism combined with theoretical calculations. Our study suggested that the cyclopeptide 1 with ßI-turn presented stronger antitumor activity comparing with those without such secondary structures. Moreover, a rare 'π helix unit' (compound 3) was realized because of the constrained cyclic structure, which could be considered an important research object for future study of unique helix secondary structures.
Asunto(s)
Péptidos Cíclicos/farmacología , Animales , Antineoplásicos , Línea Celular , Proliferación Celular/efectos de los fármacos , Teoría Funcional de la Densidad , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Transporte de Electrón , Fibroblastos/efectos de los fármacos , Humanos , Ratones , Modelos Moleculares , Conformación Molecular , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/química , Procesos Fotoquímicos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A cyclic analog of natural peptide Yunnanin A was synthesized via photoinduced single electron transfer reaction (SET) in the paper. The resulting compound exhibited potent bioactivity (with IC50 values 29.25 µg mL-1 against HepG-2 cell lines and 65.01 µg mL-1 against HeLa cell lines), but almost have no toxicity to normal cells (with IC50 values 203.25 µg mL-1 against L929 cell lines), which may be served as a potential antitumor drug for medical treatment. The spatial structure was examined by experimental electronic circular dichroism (ECD) and quantum chemistry calculations. Moreover, the theoretical study suggested that special intramolecular hydrogen bonds and γ, ß-turn secondary structures may be possible sources affecting cyclic peptide's bioactivity.