title: Synthesis and biological evaluation of new N-alkylcarbazole derivatives as STAT3 inhibitors: preliminary study.
abstract: The signalling pathway of Janus tyrosine Kinases-Signal Transducers and Activators of Transcription (JAK-STAT) is activated by a number of cytokines, hormones (GH, erythropoietin and prolactin), and growth factors. JAK-STAT signalling is involved in regulation of cell proliferation, differentiation and apoptosis. These activities are due to different members of JAK-STAT family consisting of: JAK1, JAK2, JAK3, Tyk2 and STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6. Recent studies suggest a key role for STAT family proteins, in particular for STAT3, in selectively inducing and maintaining a pro-carcinogenic inflammatory microenvironment, that promote tumour cells transformation. Moreover, a striking correlation between cancer development/progression and STAT3 persistent activation exists, probably due to STAT3 promoting of the pro-oncogenic inflammatory pathways, like NF-kB, IL-6 and JAK family kinases. Recent study demonstrated that carbazoles can inhibit STAT3 mediated transcription. From these evidences, STAT3 represents a therapeutic target, so we have synthesized a new set of N-alkylcarbazole derivatives substituted in positions 2, 4 and 6, to evaluate their activity on STAT3. Some of these compounds showed an interesting activity as STAT3 selective inhibitors; in particular, compounds 9a 9b and 9c revealed to inhibit the STAT3 activation for the 50%, 90% and 95%, respectively.
authors.affiliation: Department of Pharmaceutical Science, University of Salerno, Via Ponte Don Melillo 8, 84024 Fisciano (SA), Italy. saturnino@unisa.it
authors.forename: Carmela
authors.initials: C
authors.lastname: Saturnino
authors.forename: Chiara
authors.initials: C
authors.lastname: Palladino
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Napoli
authors.forename: Maria Stefania
authors.initials: MS
authors.lastname: Sinicropi
authors.forename: Antonio
authors.initials: A
authors.lastname: Botta
authors.forename: Marina
authors.initials: M
authors.lastname: Sala
authors.forename: Alessandra
authors.initials: A
authors.lastname: Carcereri de Prati
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Hisanori
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D002227:Carbazoles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human