and E

and E.F. of cancer-associated PI3K/AKT, ERK, and p38 signaling pathways. L., and its analogs have shown anti-cancer properties by suppressing tumor initiation and progression [6,7], through the modulation of multiple signaling pathways and the inhibition of cell proliferation, invasion, metastasis, and angiogenesis [8]. Curcumin has exhibited chemopreventive and chemotherapeutic activity also in PCa. In vitro, it reduces the expression of androgen receptors (AR), which appears to enhance the progression of PCa to the hormone refractory state CRPC [9]. Experiments performed on LNCaP, PC3, and DU145, metastatic PCa cells from lymph node, bone, and brain, respectively, showed that curcumin impacts on K-Ras(G12C) inhibitor 12 cell proliferation by decreasing the expression Klf2 of epidermal growth factor receptor (EGFR) and cell cycle cyclins. Moreover, curcumin anti-proliferative activity has been associated to increased expression of the cyclin dependent inhibitors (CDKs) p21, p27, and p16, both in vitro and in vivo. Curcumin targets numerous signaling pathways, among which the PI3K/AKT network, generally constitutively activated in PCa (for a review see [10]). Interestingly, curcumin has been recently found to affect malignancy associated fibroblast (CAF)-driven PCa invasion, promoted by prostate tumorCstromal conversation, through the inhibition of the MAOA/mTOR/HIF-1 signaling pathway [11]. These data pointed at curcumin as a protective molecule against the epithelial to mesenchymal transition (EMT), a highly complex process allowing the cells to escape from the primary tumor and disseminate at distant sites. Despite the confirmed efficacious anti-proliferative properties of curcumin against malignancy cells in vitro and in vivo, there is currently no approved health claim for this molecule [12]. The main controversial dark side of this polyphenol is usually its apparent instability in physiological environment. This limits a possible successful and controlled application in clinics and does not allow to fully understand which mechanisms are activated by the molecule and which by its metabolites. It is therefore crucial to identify stable derivatives and characterize their molecular basis of action against cancer cell proliferation and metastatization. Recently, Nelson et al. [13] pinpointed the main concerns in selecting curcumin as pharmaceutical lead compound. However, a wide slice of the scientific community does not completely agree with this lapidary verdict [14,15,16,17]. In this landscape, we devoted research efforts to develop new stable curcumin analogs based on phtalimide (K3F). Phthalimide-based drugs firstly K-Ras(G12C) inhibitor 12 appeared in the late 1950s and Thalidomide, the most notable one, was prescribed to K-Ras(G12C) inhibitor 12 pregnant women as a sedative and anti-emetic agent. The benefits of this compound were soon darkened by the discovery of its teratogenicity that forced its withdrawal from market. Today, Thalidomide is used in the treatment of erythema nodosum leprosum, multiple myeloma, myelodysplastic syndrome, and shows promising properties in the treatment of autoimmune disorders [18]. Recently, the identification of the basis for its teratogenicity has allowed the development of new thalidomide derivatives without teratogenic activity [19]. Early clinical trials showed that thalidomide has clinical anti-tumor activity in hormone-refractory PCa [20], therefore the development of analogues and/or its administration in conjunction with other anti-cancer agents are under exploration in order to improve its efficacy and reduce toxicity. Here, we describe the synthesis, chemical and pharmacokinetic characterization, and anti-proliferative activity of new phthalimide-based curcumin derivatives on human PCa cells. 2. Results 2.1. Synthesis and Characterization The synthesis of curcumin-like structures is commonly performed by one-pot Pabon reaction [21] K-Ras(G12C) inhibitor 12 or its modifications [22]. The reaction proceeds through the complexation of boron by acetyl-acetone (acac), or another -diketone, in order to protect the methylenic carbon and activate the side methyl groups as nucleophiles. In a further step, Knoevenagel condensation takes place with vanillin or other selected benzaldehydes. Finally, when the reaction is accomplished in N,N-dimethylformamide.

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