title: Novel iodoacetamido benzoheterocyclic derivatives with potent antileukemic activity are inhibitors of STAT5 phosphorylation.
abstract: Signal Transducer and Activator of Transcription 5 (STAT5) protein, a component of the STAT family of signaling proteins, is considered to be an attractive therapeutic target because of its involvement in the progression of acute myeloid leukemia. In an effort to discover potent molecules able to inhibit the phosphorylation-activation of STAT5, twenty-two compounds were synthesized and evaluated on the basis of our knowledge of the activity of 2-(3',4',5'-trimethoxybenzoyl)-3-iodoacetamido-6-methoxy benzo[b]furan derivative 1 as a potent STAT5 inhibitor. Most of these molecules, structurally related to compound 1, were characterized by the presence of a common 3',4',5'-trimethoxybenzoyl moiety at the 2-position of different benzoheterocycles such as benzo[b]furan, benzo[b]thiophene, indole and N-methylindole. Effects on biological activity of the iodoacetamido group and of different moieties (methyl and methoxy) at the C-3 to C-7 positions were examined. In the series of benzo[b]furan derivatives, moving the iodoacetylamino group from the C-4 to the C-5 or C-6 positions did not significantly affect antiproliferative activity. Compounds 4, 15, 20 and 23 blocked STAT5 signals and induced apoptosis of K562 BCR-ABL positive cells. For compound 23, the trimethoxybenzoyl moiety at the 2-position of the benzo[b]furan core was not essential for potent inhibition of STAT5 activation.
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy. Electronic address: rmr@unife.it.
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Prencipe
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Carlota
authors.initials: C
authors.lastname: Lopez-Cara
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rondanin
authors.affiliation: Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Ferrara, 44121 Ferrara, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Simoni
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, MD 21702, USA.
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica, Università di Palermo, 90125 Palermo, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Grimaudo
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica, Università di Palermo, 90125 Palermo, Italy.
authors.forename: Rosaria Maria
authors.initials: RM
authors.lastname: Pipitone
authors.affiliation: Dipartimento di Scienze per la Promozione della Salute e Materno Infantile, Area di Farmacologia, Università di Palermo, 90125 Palermo, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Meli
authors.affiliation: Centro Interdipartimentale di Ricerca in Oncologia Clinica e Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Malattie Infettive, Università di Palermo, 90125 Palermo, Italy.
authors.forename: Manlio
authors.initials: M
authors.lastname: Tolomeo
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001577:Benzophenones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C582797:3-iodoacetylamino-6-methoxybenzofuran-2-yl(3,5-trimethoxyphenyl)methanone; D000970:Antineoplastic Agents; D001572:Benzofurans; D001577:Benzophenones; D050799:STAT5 Transcription Factor
keywords: Apoptosis; BCR/ABL expressing leukemia; In vitro antiproliferative activity; STAT5 inhibitors; Structure-activity relationship