New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized S. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCl/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.
Toward Highly Potent Cancer Agents by Modulating the C-2 Group of the Arylthioindole Class of Tubulin Polymerization Inhibitors / LA REGINA, Giuseppe; Ruoli, Bai; Whilelmina Maria, Rensen; DI CESARE, Erica; Coluccia, Antonio; Piscitelli, Francesco; Famiglini, Valeria; Alessia, Reggio; Nalli, Marianna; Pelliccia, Sveva; Eleonora Da, Pozzo; Barbara, Costa; Ilaria, Granata; Amalia, Porta; Bruno, Maresca; Soriani, Alessandra; Iannitto, MARIA LUISA; Santoni, Angela; Junjie, Li; M. m., Cona; Feng, Chen; Yicheng, Ni; Andrea, Brancale; Giulio, Dondio; Stefania, Vultaggio; Mario, Varasi; Ciro, Mercurio; Claudia, Martini; Ernest, Hamel; Patrizia, Lavia; Ettore, Novellino; Silvestri, Romano. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 56:1(2013), pp. 123-149. [10.1021/jm3013097]
Toward Highly Potent Cancer Agents by Modulating the C-2 Group of the Arylthioindole Class of Tubulin Polymerization Inhibitors
LA REGINA, GIUSEPPE;DI CESARE, ERICA;COLUCCIA, Antonio;PISCITELLI, FRANCESCO;FAMIGLINI, VALERIA;NALLI, Marianna;PELLICCIA, SVEVA;SORIANI, Alessandra;IANNITTO, MARIA LUISA;SANTONI, Angela;SILVESTRI, Romano
2013
Abstract
New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized S. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCl/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
