title: Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors.
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 5. 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 NCI/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.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Regina
authors.forename: Ruoli
authors.initials: R
authors.lastname: Bai
authors.forename: Whilelmina Maria
authors.initials: WM
authors.lastname: Rensen
authors.forename: Erica
authors.initials: E
authors.lastname: Di Cesare
authors.forename: Antonio
authors.initials: A
authors.lastname: Coluccia
authors.forename: Francesco
authors.initials: F
authors.lastname: Piscitelli
authors.forename: Valeria
authors.initials: V
authors.lastname: Famiglini
authors.forename: Alessia
authors.initials: A
authors.lastname: Reggio
authors.forename: Marianna
authors.initials: M
authors.lastname: Nalli
authors.forename: Sveva
authors.initials: S
authors.lastname: Pelliccia
authors.forename: Eleonora
authors.initials: E
authors.lastname: Da Pozzo
authors.forename: Barbara
authors.initials: B
authors.lastname: Costa
authors.forename: Ilaria
authors.initials: I
authors.lastname: Granata
authors.forename: Amalia
authors.initials: A
authors.lastname: Porta
authors.forename: Bruno
authors.initials: B
authors.lastname: Maresca
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soriani
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Iannitto
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
authors.forename: Junjie
authors.initials: J
authors.lastname: Li
authors.forename: Marlein
authors.initials: M
authors.lastname: Miranda Cona
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Ni
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Giulio
authors.initials: G
authors.lastname: Dondio
authors.forename: Stefania
authors.initials: S
authors.lastname: Vultaggio
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Patrizia
authors.initials: P
authors.lastname: Lavia
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018938:Caco-2 Cells; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D010539:Permeability; D058105:Polymerization; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000098:blood supply / Q000188:drug therapy; D012995:Solubility; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C579726:2-(1H-imidazol-1-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole; C579725:2-(pyridin-4-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole; D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D011725:Pyridines; D017382:Reactive Oxygen Species; D014404:Tubulin; D050257:Tubulin Modulators