Synthesis and Antiproliferative Activity of Thiazolyl-bis-pyrrolo[2,3-b]pyridines and Indolyl-thiazolyl-pyrrolo[2,3-c]pyridines, Nortopsentin Analogues

Marine Drugs

Anna Carbone²  Barbara Parrino²  Gloria Di Vita²  Alessandro Attanzio²  Virginia Spanò²  Alessandra Montalbano²  Paola Barraja²  Luisa Tesoriere²  Maria Antonia Livrea²  Patrizia Diana²  Girolamo Cirrincione¹ 

[1] Biological, Chemical and Pharmaceutical Sciences and Technologies Department, STEBICEF, Università degli Studi di Palermo, via Archirafi 32, 90123 Palermo, Italy;

关键词: marine alkaloids;    bis-indolyl alkaloids;    nortopsentins;    thiazolyl-bis-pyrrolo[2;    3-b]pyridines;    indolyl-thiazolyl-pyrrolo[2;    3-c]pyridines;    apoptosis;    autophagic death;    antiproliferative activity;   

DOI  :  10.3390/md13010460

来源: mdpi

【 摘 要 】

Two new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and indole units were both substituted by 7-azaindole moieties or one indole unit was replaced by a 6-azaindole portion, were efficiently synthesized. Compounds belonging to both series inhibited the growth of HCT-116 colorectal cancer cells at low micromolar concentrations, whereas they did not affect the viability of normal-like intestinal cells. A compound of the former series induced apoptosis, evident as externalization of plasma membrane phosphatidylserine (PS), and changes of mitochondrial trans-membrane potential, while blocking the cell cycle in G2/M phase. In contrast, a derivative of the latter series elicited distinct responses in accordance with the dose. Thus, low concentrations (GI₃₀) induced morphological changes characteristic of autophagic death with massive formation of cytoplasmic acid vacuoles without apparent loss of nuclear material, and with arrest of cell cycle at the G1 phase, whereas higher concentrations (GI₇₀) induced apoptosis with arrest of cell cycle at the G1 phase.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.