The JAK2/STAT3 pathway is frequently upregulated in both blood cancers and solid tumors as compared to normal cells and plays an essential role in transmitting signals involved with cell growth, differentiation, and apoptosis. Inhibitors of the pathway are considered attractive targets for the prevention and therapy of cancer. Curcumin, isolated from the rhizome of Curcuma longa, has previously been shown to inhibit both JAK2 and STAT3, while displaying little toxicity in vivo. As a drug, however, curcumin is severely limited due to poor bioavailability and rapid metabolism. Therefore, the aim of this study has been to develop curcumin derivatives as potential therapeutic agents. Analogs were designed to increase JAK/STAT selectivity, increase potency, and improve pharmacological profiles. FLLL31 and FLLL32, analogs synthesized early in the process, are two of our most extensively studied analogs and demonstrate selective inhibition of JAK2/STAT3 in a variety of in vitro assays. FLLL32 was also shown to decrease tumor growth in vivo, although with limited success, presumably due to poor water solubility. Our computational models also suggested the possibility of enhancing binding to STAT3 through the synthesis of non-symmetric analogs designed to target the hot spots of the SH2 domain. With this in mind, an efficient route to a series of non-symmetric curcumin analogs for SAR studies was achieved through two analogous acylation procedures. A water soluble pro-drug, FLLL100P, was also synthesized as a part of this effort and initial in vivo results showed a drastically improved plasma concentration and better drug-like properties.

Synthesis, optimization, and evaluation of dialkylated curcumin analogs as inhibitors of the JAK2/STAT3 pathway

246th National Meeting (2013)

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