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The activation of TGR5 bestows on bile acids the ability to modulate nongenomic signaling pathways, which are responsible of physiological actions including immunosuppressive and anti-inflammatory properties as well as the regulation of glucose metabolism and energy homeostasis. TGR5 agonists have therefore emerged in drug discovery and preclinical appraisals as promising compounds for the treatment of liver diseases and metabolic syndrome. In this study, we have been devising site-selected chemical modifications of the bile acid scaffold to provide novel chemical tools able to modulate the functions of TGR5 in different tissues. Biological results of the tested collection of semisynthetic cholic acid derivatives were used to extend the structure-activity relationships of TGR5 agonists and to clarify the molecular basis and functional role of TGR5 hot-spots in the receptor activation and selectivity. Some unexpected properties deriving from the molecular structure of bile acids have been unveiled as relevant to the receptor activation and may hence be used to design novel, selective and potent TGR5 agonists. [Display omitted] • The synthesis of a collection of novel semisynthetic cholic acid derivatives is reported. • The C 7 β-butyl-CA (8) and the C 23 -difluoro-CA (19) were identified as selective low micromolar TGR5 agonists. • Biological data and computational modelling evidenced for the first time the negative impact of the 6α-ethyl group in the TGR5 activity of bile acids. • Unprecedented insights into the functional role of TGR5 hot-spots are reported and may be explored to design potent and selective TGR5 agonists. [ABSTRACT FROM AUTHOR]

A series of secondary and tertiary aryl sulfonamides were synthesized under flow conditions and evaluated for their ability to selectively inhibit tumor-associated carbonic anhydrase isoforms IX and XII. The tested compounds revealed to be highly potent CA IX inhibitors in nanomolar range, and to inhibit CA XII activity with different ranks of potencies. Remarkably, 4-methyl- N -phenyl-benzenesulfonamide was a selective nanomolar CA IX inhibitor with an IC 50 of 90 nM. [ABSTRACT FROM AUTHOR]

Abstract: A new stereoselective synthesis of E-guggulsterone is described starting from androsten-3,17-dione. Protection of the ring A enonic system, followed by regioselective Wittig reaction and C-16 oxidation, affords E-guggulsterone in good yields and high stereoselectivity, making this approach easily accessible and scalable. Moreover, an original normal-phase HPLC method enabling the fast quantitation of the guggulsterone isomeric purity, combined with the suitability for sampling procedures, is detailed. The relying upon the cellulose-based Chiralpak IB column and the chloroform as the “non-standard” component of the eluent mixture, allows to get profitably high chromatographic performances. [Copyright &y& Elsevier]

Abstract: A new divergent synthesis of DAF-12 ligands, namely Δ4- and Δ7-dafachronic acid, is described starting from the natural bile acid hyodeoxycholic acid. Homologation of the side chain followed by stereoselective reduction of the Δ24 olefinic linkage, 6α-dehydroxylation and C3-oxidation affords dafachronic acids in good yields and high diastereoselectivity making this approach easily accessible and scalable. [Copyright &y& Elsevier]

A series of β-amino acids with lipophilic diaromatic side chain was synthesized and characterized pharmacologically on mouse γ-amino butyric acid (GABA) transporter subtypes mGAT1-4 in order to investigate structure activity relationships (SAR) for mGAT2 (corresponding to hBGT-1). Variation in the lipophilic diaromatic side chain was probed to understand the role of the side chain for activity. This yielded several selective compounds of which the best (1 R ,2 S )- 5a was more than 10 fold selective towards other subtypes, although potency was moderate. A docking study was performed to investigate possible binding modes of the compounds in mGAT2 suggesting a binding mode similar to that proposed for Tiagabine in hGAT1. Specific interactions between the transporter and the amino acid part of the ligands may account for a reverted preference towards mGAT2 over mGAT1. [ABSTRACT FROM AUTHOR]

Abstract: A virtual screening procedure was applied to the discovery of structurally diverse non-steroidal Farnesoid X Receptor (FXR) agonists. From 117 compounds selected by virtual screening, a total of 47 compounds were found to be FXR agonists, with 34 of them showing activity below a concentration of 20μM. 1H-Pyrazole[3,4-e][1,4]thiazepin-7-one-based hit compound 7 was chosen for hit-to-lead optimization. A large number of 1H-pyrazole[3,4-e][1,4]thiazepin-7-one derivatives was designed, synthesized, and evaluated by a cell-based luciferase transactivation assay for their agonistic activity against FXR. Most of them exhibited low micromolar range of potency and very high efficacy. [Copyright &y& Elsevier]