The NLRP3 inflammasome is a critical component of innate immunity that senses diverse pathogen-and host-derived molecules. However, its aberrant activation has been associated with the pathogenesis of multiple diseases, including cancer. In this study, we designed and synthesized a series of aryl sulfonamide derivatives (ASDs) to inhibit the NLRP3 inflammasome. Among these, compounds 6c, 7n, and 10 specifically inhibited NLRP3 activation at nanomolar concentrations without affecting the activation of the NLRC4 and AIM2 inflammasomes. Furthermore, we demonstrated that these compounds reduce interleukin-1β (IL-1β) production in vivo and attenuate melanoma tumor growth. Moreover, metabolic stability in liver microsomes of 6c, 7n, and 10 was studied along with plasma exposure in mice of the most interesting compound 6c. Therefore, we generated potent NLRP3 inflammasome inhibitors, which can be considered in future medicinal chemistry and pharmacological studies aimed at developing a new therapeutic approach for NLRP3 inflammasome-driven cancer.

Sulfonylureas are employed in a variety of applications including use as drugs to treat type II diabetes and as plant growth regulators or herbicides. Traditionally, the synthesis of sulfonylureas has been accomplished either by the treatment of sulfamides with isocyanates in the presence of a base or through sulfonamides conversion into N-sulfonyl isocyanates or N-sulfonyl carbamate derivatives which provide the corresponding sulfonylureas upon treatment with amines. Both approaches are severely limited by the weak nucleophilicity of sulfamides and by the difficulty in synthesizing and handling isocyanate species. Such a drawback could be mitigated by the emergence of protocols establishing the labile electrophilic functional groups in situ so that their coupling with nucleophilic partners takes place in one-pot. Recently, the development of environmentally friendly methods to prepare sulfonylurea containing compounds without using harmful reagents has attracted considerable attention. The aim of the minireview is to explore the different protocols emerged in the literature to generate sulfonylureas giving importance to the reaction mechanisms of crucial synthetic steps.

Plant-derived remedies rich in chalcone-based compounds have been known for centuries in the treatment of specific diseases, and nowadays, the fascinating chalcone framework is considered a useful and, above all, abundant natural chemotype. Velutone F, a new chalconoid from Millettia velutina, exhibits a potent effect as an NLRP3-inflammasome inhibitor; the search for new natural/non-natural lead compounds as NLRP3 inhibitors is a current topical subject in medicinal chemistry. The details of our work toward the synthesis of velutone F and the unknown non-natural regioisomers are herein reported. We used different synthetic strategies both for the construction of the distinctive benzofuran nucleus (BF) and for the key phenylpropenone system (PhP). Importantly, we have disclosed a facile entry to the velutone F via synthetic routes that can also be useful for preparing non-natural analogs, a prerequisite for extensive SAR studies on the new flavonoid class of NLRP3-inhibitors.

The synthesis of a small library of N-Boc or N-Fmoc protected (L)-phenylalanines carrying methyl groups at positions 2 and 6, and diverse functionalities at position 4 has been achieved. The approach, which took advantage of a Pd-catalyzed directed C-H dimethylation of picolinamide derivatives, allowed to alter the electronic/steric properties of the resulting amino acid derivatives by appending a variety of EWG, EDG, or bulky groups.