# Carbazole Derivatives as STAT Inhibitors: An Overview
## 3 STATs Inhibitors
### Carbazoles as STAT Inhibitors  
Psoriasis, a common inflammatory skin disease, is treated, according to its severity, with a large panel of therapies associated with side effects. Coal tar represented an ancient treatment of psoriasis. To assess the potential mechanism of action, [PERSON] et al. in 2006 [31] fractionated coal tar through chromatography determining carbazole as the active compound. STAT3 inhibition resulted in one of the main mechanisms implied in its antiangiogenic activity. Indeed, STAT3 is involved as a signaling pathway in psoriasis. Moreover, carbamazepine (Figure 6) (an anticonvulsant structurally related to carbazole) exhibited great potentiality in patients with generalized psoriasis. For this reason, this research group focused their attention on carbazole **1** included in coal tar. Furthermore, carbazole inhibited IL-15, whose level is increased in psoriasis, and decreased the effects of inducible nitric oxide synthase (iNOS). STAT3, IL-15, and iNOS need rac GTPase activation to exert their activities. Thus, the ability of carbazole to inhibit rac activation has been demonstrated, stating that this could be the origin of its ability to reduce inflammation and counteract angiogenesis [31]. Starting from the assumption that STAT3 is one of the main mediators implied in the immune and angiogenic features of psoriasis, [PERSON] et al. [31] went into the possible actions of carbazole and 2-hydroxycarbazole (a carbazole metabolic by-product) toward the STAT3-mediated transcription. Their data, obtained on RAW264.7 macrophages, indicated that both carbazole and 2-hydroxycarbazole (**11**, Figure 7) could downregulate STAT3-mediated transcription. They assessed the specificity against STAT3, since carbazole possessed no activity on a constitutive promoter. Activity on STAT3 phosphorylation was excluded as a potential carbazole mechanism of action. Indeed, no effect on STAT3 phosphorylation was detected, implicating the existence of an alternative mechanism. A fundamental prerequisite to activate STAT3 is rac activation. In fact, small GTPase rac influences STAT3 transcription, IL-15 production, and iNOS activity. Obtained results outlined that carbazole markedly hampered rac activation by VEGF in HUVEC cells. In 2013, [PERSON] et al. [100] analyzed the molecular mechanism held responsible for the antiproliferative activity of mahanine (**12**, Figure 8) toward several pancreatic cell lines. In fact, natural compounds have been demonstrated to hold a great deal of promise as antineoplastic agents. In particular, the purified carbazole alkaloid mahanine, isolated  
Figure 6: Structure of carbamazepine, an anticonvulsant structurally related to carbazole. Figure 7: Structure of 2-hydroxycarbazole (**11**). from the edible plants _Murraya koenigii_ and _Micromelum minutum_, displayed antimutagenic, antimicrobial, and cytotoxic activities [101]. Furthermore, mahanine triggered the apoptotic process in histicyl lymphoma, promylocytic leukemia, and prostate cancer cells [102; 103; 104]. At first, it was confirmed that mahanine induced apoptosis in an in vitro model of the human pancreatic ductal adenocarcinoma cell line, MIAPCa-2 (IC\({}_{50}\) amounting to 13.9 \(\upmu\)M). Subsequently, the possible effects of mahanine on the molecular chaperone Hsp90 have been studied, starting from the assumption that it presents high expression levels in several tumor cells and regulates different client proteins, including STAT3. The results underlined that mahanine triggers the accumulation of ROS in both a time- and concentration-dependent manner in MIAPCa-2 cells. The main consequence of this activity regards the oxidative insult of Hsp90, mainly involved in maintaining folded proteins in their proper conformation. Immunostaining studies demonstrated the depletion of the two Hsp90 client proteins Akt and STAT3 in orthograft pancreatic adenocarcinoma mouse model treated with mahanine.