3-[4-(1H-indol-3-yl)-1,3-thiazol-2-yl]-1H-pyrrolo[2,3-b]pyridines, nortopsentin analogues with antiproliferative activity

• Published in: Marine drugs 2015-04, Vol.13 (4), p.1901-1924
• Main Authors: Parrino, Barbara, Carbone, Anna, Di Vita, Gloria, Ciancimino, Cristina, Attanzio, Alessandro, Spanò, Virginia, Montalbano, Alessandra, Barraja, Paola, Tesoriere, Luisa, Livrea, Maria Antonia, Diana, Patrizia, Cirrincione, Girolamo
• Format: Article
• Language: English
• Subjects: 3-[4-(1H-indol-3-yl)-1,3-thiazol-2-yl]-1H-pyrrolo[2,3-b]pyridines; Alkaloids - chemical synthesis; Alkaloids - chemistry; Alkaloids - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antiproliferative activity; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Design; G2 Phase - drug effects; Halogenation; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; indolyl alkaloids; Marine; marine alkaloids; Membrane Potential, Mitochondrial - drug effects; Methylation; Mitochondria - drug effects; Mitochondria - pathology; Molecular Structure; Neoplasms - drug therapy; Neoplasms - pathology; nortopsentin analogues; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Resting Phase, Cell Cycle - drug effects; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md13041901

A new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and the indole unit bound to position 2 of the thiazole ring was substituted by a 7-azaindole moiety, was efficiently synthesized. Two of the new nortopsentin analogues showed good antiproliferative effect against the totality of the NCI full panel of human tumor cell lines (~60) having GI50 values ranging from low micromolar to nanomolar level. The mechanism of the antiproliferative effect of these derivatives, investigated on human hepatoma HepG2 cells, was pro-apoptotic, being associated with externalization of plasma membrane phosphatidylserine and mitochondrial dysfunction. Moreover, the compounds induced a concentration-dependent accumulation of cells in the subG0/G1phase, while confined viable cells in G2/M phase.