title: New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity, and Repression of Hedgehog-Dependent Cancer.
abstract: We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4-7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20-50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer.
authors.affiliation: †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.forename: Giuseppe
authors.initials: G
authors.lastname: La Regina
authors.affiliation: ‡Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
authors.forename: Ruoli
authors.initials: R
authors.lastname: Bai
authors.affiliation: †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.forename: Antonio
authors.initials: A
authors.lastname: Coluccia
authors.affiliation: †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.forename: Valeria
authors.initials: V
authors.lastname: Famiglini
authors.affiliation: §Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, I-80131 Napoli, Italy.
authors.forename: Sveva
authors.initials: S
authors.lastname: Pelliccia
authors.affiliation: †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.forename: Sara
authors.initials: S
authors.lastname: Passacantilli
authors.affiliation: ∥Laboratorio di Ricerca Pre-Clinica e Traslazionale, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Centro di Riferimento Oncologico della Basilicata, Via Padre Pio 1, I-85028 Rionero in Vulture, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Mazzoccoli
authors.affiliation: ∥Laboratorio di Ricerca Pre-Clinica e Traslazionale, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Centro di Riferimento Oncologico della Basilicata, Via Padre Pio 1, I-85028 Rionero in Vulture, Italy.
authors.forename: Vitalba
authors.initials: V
authors.lastname: Ruggieri
authors.affiliation: ⊥Institute of Molecular Biology and Pathology, Sapienza Università di Roma, Consiglio Nazionale delle Ricerche (CNR), Via degli Apuli 4, I-00185 Roma, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Verrico
authors.affiliation: ⊥Institute of Molecular Biology and Pathology, Sapienza Università di Roma, Consiglio Nazionale delle Ricerche (CNR), Via degli Apuli 4, I-00185 Roma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Miele
authors.affiliation: †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.forename: Ludovica
authors.initials: L
authors.lastname: Monti
authors.affiliation: †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.forename: Marianna
authors.initials: M
authors.lastname: Nalli
authors.affiliation: #Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Viale Regina Elena 291, I-00161 Roma, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Alfonsi
authors.affiliation: #Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Viale Regina Elena 291, I-00161 Roma, Italy.|∇Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, I-00161 Roma, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.affiliation: #Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Viale Regina Elena 291, I-00161 Roma, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.affiliation: #Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Viale Regina Elena 291, I-00161 Roma, Italy.
authors.forename: Biancamaria
authors.initials: B
authors.lastname: Ricci
authors.affiliation: #Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Viale Regina Elena 291, I-00161 Roma, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Soriani
authors.affiliation: ⊥Institute of Molecular Biology and Pathology, Sapienza Università di Roma, Consiglio Nazionale delle Ricerche (CNR), Via degli Apuli 4, I-00185 Roma, Italy.|#Department of Molecular Medicine, Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza Università di Roma, Viale Regina Elena 291, I-00161 Roma, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
authors.affiliation: ○Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via S.M. Costantinopoli 16, I-80138 Naples, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.affiliation: ○Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Via S.M. Costantinopoli 16, I-80138 Naples, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Porto
authors.affiliation: ◆Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, I-56126 Pisa, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Da Pozzo
authors.affiliation: ◆Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, I-56126 Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.affiliation: ¶Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.affiliation: §Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, I-80131 Napoli, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.affiliation: §Dipartimento di Farmacia, Università di Napoli Federico II, Via Domenico Montesano 49, I-80131 Napoli, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: △European Institute of Oncology, Via Adamello 16, I-20139 Milano, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Vultaggio
authors.affiliation: △European Institute of Oncology, Via Adamello 16, I-20139 Milano, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
authors.affiliation: ☆DAC SRL, Genextra Group, Via Adamello 16, I-20139 Milano, Italy.
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
authors.affiliation: ▲APHAD Srl, Via della Resistanza 65, I-20090 Buccinasco, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bigogno
authors.affiliation: ▲APHAD Srl, Via della Resistanza 65, I-20090 Buccinasco, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Dondio
authors.affiliation: ‡Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.affiliation: ⊥Institute of Molecular Biology and Pathology, Sapienza Università di Roma, Consiglio Nazionale delle Ricerche (CNR), Via degli Apuli 4, I-00185 Roma, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Lavia
authors.affiliation: †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.forename: Romano
authors.initials: R
authors.lastname: Silvestri
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008938:Mitosis / Q000187:drug effects*; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000276:immunology / Q000473:pathology*; D014404:Tubulin / Q000737:chemistry / Q000187:drug effects*
chemical_list: D053823:Hedgehog Proteins; D007211:Indoles; D014404:Tubulin; C542223:2-phenylindole