Building a Sulfonamide Library by Eco-Friendly Flow Synthesis

A rapid and eco-friendly synthesis of a sulfonamide library under flow conditions is described. The study illustrates an efficient, safe, and easily scalable preparation of sulfonamides by use of a meso-reactor apparatus, thus demonstrating the impact of flow technologies within drug discovery. Waste minimization, employment of green media, and nontoxic reactants are achieved by the optimization of the flow setup and experimental protocol designed to sequentially synthesize primary, secondary, and tertiary sulfonamides. Isolation of the products involves only extraction and precipitation affording pure compounds in good to high yields without further purification for biological evaluation

Discovery of 3α,7α,11β-Trihydroxy-6α-ethyl-5β-cholan-24-oic Acid (TC-100), a Novel Bile Acid as Potent and Highly Selective FXR Agonist for Enterohepatic Disorders

As a continuation of previous efforts in mapping functional hot spots on the bile acid scaffold, we here demonstrate that the introduction of a hydroxy group at the C11β position affords high selectivity for FXR. In particular, the synthesis and FXR/TGR5 activity of novel bile acids bearing different hydroxylation patterns at the C ring are reported and discussed from a structure–activity standpoint. The results obtained led us to discover the first bile acid derivative endowed with high potency and selectivity at the FXR receptor, 3α,7α,11β-trihydroxy-6α-ethyl-5β-cholan-24-oic acid (TC-100, <b>7</b>) which also shows a remarkable physicochemical and pharmacological profile. Compound <b>7</b> combines the excellent physicochemical properties of hydrophilic bile acids such as ursodeoxycholic acid, with the distinct ability to specifically bind and regulate FXR activity in vivo, thus providing a bona fide novel therapeutic agent to treat enterohepatic disorders such as cholestasis, NASH, and inflammatory bowel disease