title: New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer.
abstract: We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway.
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.forename: Ruoli
authors.initials: R
authors.lastname: Bai
authors.forename: Antonio
authors.initials: A
authors.lastname: Coluccia
authors.forename: Valeria
authors.initials: V
authors.lastname: Famiglini
authors.forename: Sveva
authors.initials: S
authors.lastname: Pelliccia
authors.forename: Sara
authors.initials: S
authors.lastname: Passacantilli
authors.forename: Carmela
authors.initials: C
authors.lastname: Mazzoccoli
authors.forename: Vitalba
authors.initials: V
authors.lastname: Ruggieri
authors.forename: Lorenza
authors.initials: L
authors.lastname: Sisinni
authors.forename: Alessio
authors.initials: A
authors.lastname: Bolognesi
authors.forename: Whilelmina Maria
authors.initials: WM
authors.lastname: Rensen
authors.forename: Andrea
authors.initials: A
authors.lastname: Miele
authors.forename: Marianna
authors.initials: M
authors.lastname: Nalli
authors.forename: Romina
authors.initials: R
authors.lastname: Alfonsi
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
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: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Patrizia
authors.initials: P
authors.lastname: Lavia
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D051379:Mice; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D058105:Polymerization; D011485:Protein Binding; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C000594994:(1-(3-aminophenyl)-1H-pyrrol-3-yl)(3,4,5-trimethoxyphenyl)methanone; C000594995:1-(3-(3-(3,4,5-trimethoxybenzoyl)-1H-pyrrol-1-yl)phenyl)guanidine; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D006146:Guanidines; D053823:Hedgehog Proteins; D011758:Pyrroles; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine