Synthesis and biological evaluation of new N-alkylcarbazole derivatives as STAT3 inhibitors: Preliminary study

• Published in: European journal of medicinal chemistry 2013-02, Vol.60, p.112-119
• Main Authors: Saturnino, Carmela, Palladino, Chiara, Napoli, Mariagrazia, Sinicropi, Maria Stefania, Botta, Antonio, Sala, Marina, Carcereri de Prati, Alessandra, Novellino, Ettore, Suzuki, Hisanori
• Format: Article
• Language: English
• Subjects: Antitumoral; Carbazoles; Carbazoles - chemical synthesis; Carbazoles - chemistry; Carbazoles - pharmacology; Cytotoxicity; Dose-Response Relationship, Drug; Humans; Inhibitors; Molecular Structure; STAT3; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - metabolism; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.11.004

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. 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. 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. These compounds showed an interesting activity as STAT3 selective inhibitors. [Display omitted] ► Synthesis of anti-tumoral compounds based on STAT3 inhibition. ► New substituted N-alkylcarbazole derivatives active on STAT3. ► Compounds able to suppress the STAT3 phosphorylation and nuclear translocation.