title: Design and synthesis of 2-heterocyclyl-3-arylthio-1H-indoles as potent tubulin polymerization and cell growth inhibitors with improved metabolic stability.
abstract: New arylthioindoles (ATIs) were obtained by replacing the 2-alkoxycarbonyl group with a bioisosteric 5-membered heterocycle nucleus. The new ATIs 5, 8, and 10 inhibited tubulin polymerization, reduced cell growth of a panel of human transformed cell lines, and showed higher metabolic stability than the reference ester 3. These compounds induced mitotic arrest and apoptosis at a similar level as combretastatin A-4 and vinblastine and triggered caspase-3 expression in a significant fraction of cells in both p53-proficient and p53-defective cell lines. Importantly, ATIs 5, 8, and 10 were more effective than vinorelbine, vinblastine, and paclitaxel as growth inhibitors of the P-glycoprotein-overexpressing cell line NCI/ADR-RES. Compound 5 was shown to have medium metabolic stability in both human and mouse liver microsomes, in contrast to the rapidly degraded reference ester 3, and a pharmacokinetic profile in the mouse characterized by a low systemic clearance and excellent oral bioavailability.
authors: Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
authors: Giuseppe
authors: G
authors: La Regina
authors: Ruoli
authors: R
authors: Bai
authors: Willeke
authors: W
authors: Rensen
authors: Antonio
authors: A
authors: Coluccia
authors: Francesco
authors: F
authors: Piscitelli
authors: Valerio
authors: V
authors: Gatti
authors: Alessio
authors: A
authors: Bolognesi
authors: Antonio
authors: A
authors: Lavecchia
authors: Ilaria
authors: I
authors: Granata
authors: Amalia
authors: A
authors: Porta
authors: Bruno
authors: B
authors: Maresca
authors: Alessandra
authors: A
authors: Soriani
authors: Maria Luisa
authors: ML
authors: Iannitto
authors: Marisa
authors: M
authors: Mariani
authors: Angela
authors: A
authors: Santoni
authors: Andrea
authors: A
authors: Brancale
authors: Cristiano
authors: C
authors: Ferlini
authors: Giulio
authors: G
authors: Dondio
authors: Mario
authors: M
authors: Varasi
authors: Ciro
authors: C
authors: Mercurio
authors: Ernest
authors: E
authors: Hamel
authors: Patrizia
authors: P
authors: Lavia
authors: Ettore
authors: E
authors: Novellino
authors: Romano
authors: R
authors: Silvestri
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D007211:Indoles; D011758:Pyrroles; D013876:Thiophenes; D050257:Tubulin Modulators; D053148:Caspase 3