Limonoids with 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitory Activities from Dysoxylum mollissimum

Thirteen new limonoids, dysoxylumosins A–M (<b>1</b>–<b>13</b>), along with six known analogues (<b>14</b>–<b>19</b>) were isolated from the twigs of Dysoxylum mollissimum. Their structures were established on the basis of spectroscopic data analysis. Compounds <b>1</b>–<b>6</b>, <b>8</b>, and <b>12</b> exhibited significant inhibitory activities against human and/or mouse 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Dysoxylumosin F (<b>6</b>), the most potent substance isolated, showed an IC₅₀ value of 9.6 ± 0.90 nM against human 11β-HSD1

Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes

Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound <b>2</b> with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound <b>15c</b>, with a molecular weight of 1401, a PSA value of 223 Ų, and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of <b>15c</b> were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist <b>2</b>

Ingol-Type Diterpenes from <i>Euphorbia antiquorum</i> with Mouse 11β<i>-</i>Hydroxysteroid Dehydrogenase Type 1 Inhibition Activity

Eighteen new ingol-type diterpenes, euphorantins A–R (<b>1</b>–<b>18</b>), along with four known analogues (<b>19</b>–<b>22</b>), were isolated from the aerial parts of <i>Euphorbia antiquorum</i>. Compounds <b>1</b>–<b>3</b> are the first examples of C-17-oxygenated ingol-type diterpenes, and compounds <b>16</b>–<b>18</b> represent a rare class of 2,3-di-epimers of ingols. Diterpenes <b>1</b>, <b>14</b>, and <b>22</b> exhibited inhibitory activities against mouse 11β<i>-</i>HSD1 with IC₅₀ values of 12.0, 6.4, and 0.41 μM, respectively

Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes

Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound <b>2</b> with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound <b>15c</b>, with a molecular weight of 1401, a PSA value of 223 Ų, and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of <b>15c</b> were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist <b>2</b>

Limonoids and Triterpenoids as 11β-HSD1 Inhibitors from Walsura robusta

Nine new cedrelone-type limonoid derivatives, walsunoids A–I (<b>1</b>–<b>9</b>), and 11 known compounds were isolated from the leaves of Walsura robusta. Walsunoid A (<b>1</b>) is a new degradation product of cedrelone-type limonoids, and walsunoid I (<b>9</b>) is a rare cedrelone-type limonoid amide. Their structures and absolute configurations were determined by spectroscopic data, single-crystal X-ray diffraction, and ECD data analyses. Five compounds showed moderate inhibitory activities against human and/or mouse 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) with IC₅₀ values ranging from 0.69 to 9.9 μM

11β-HSD1 Inhibitors from <i>Walsura cochinchinensis</i>

A search for inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) from <i>Walsura cochinchinensis</i> yielded 10 new limonoids, cochinchinoids A–J (<b>1</b>–<b>10</b>), and two new triterpenoids, 3-epimesendanin S (<b>11</b>) and cochinchinoid K (<b>12</b>). Their structures were assigned on the basis of spectroscopic data, with the absolute configurations of <b>1</b> and <b>12</b> being established by X-ray diffraction analysis. Of these compounds, cochinchinoid K (<b>12</b>) displayed inhibitory activity against mouse 11β-HSD1 with an IC₅₀ value of 0.82 μM

Design, Synthesis, and Antidiabetic Activity of 4‑Phenoxynicotinamide and 4‑Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists

4-Phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists are reported. Several 4-phenoxynicotinamide derivatives were found to activate human and mouse TGR5 (hTGR5 and mTGR5) with EC₅₀ values in the low nanomolar range. Compound <b>23g</b>, with an EC₅₀ value of 0.72 nM on hTGR5 and an EC₅₀ value of 6.2 nM on mTGR5, was selected for further in vivo efficacy studies. This compound exhibited a significant dose-dependent glucagon-like peptide-1 (GLP-1) secretion effect. A single oral dose of <b>23g</b> (50 mg/kg) significantly reduced blood glucose levels in <i>db/db</i> mice and caused a 49% reduction in the area under the blood glucose curve (AUC)_0–120 min following an oral glucose tolerance test (OGTT) in imprinting control region (ICR) mice. However, <b>23g</b> stimulated gallbladder filling, which might result in side effects to the gallbladder

Design and Synthesis of Novel Arctigenin Analogues for the Amelioration of Metabolic Disorders

Analogues of the natural product (−)-arctigenin, an activator of adenosine monophosphate activated protein kinase, were prepared in order to evaluate their effects on 2-deoxyglucose uptake in L6 myotubes and possible use in ameliorating metabolic disorders. Racemic arctigenin <b>2a</b> was found to display a similar uptake enhancement as does (−)-arctigenin. As a result, the SAR study was conducted utilizing racemic compounds. The structure–activity relationship study led to the discovery of key substitution patterns on the lactone motif that govern 2-deoxyglucose uptake activities. The results show that replacement of the <i>para</i>-hydroxyl group of the C-2 benzyl moiety of arctigenin by Cl has a pronounced effect on uptake activity. Specifically, analogue <b>2p</b>, which contains the <i>p</i>-Cl substituent, stimulates glucose uptake and fatty acid oxidation in L6 myotubes

Lithocarpic Acids A–N, 3,4-<i>seco</i>-Cycloartane Derivatives from the Cupules of <i>Lithocarpus polystachyus</i>

Fourteen new 3,4-<i>seco</i>-cycloartane-type triterpenes, lithocarpic acids A–N (<b>1</b>–<b>14</b>), together with one known compound, coccinetane E (<b>15</b>), were identified from the cupules of <i>Lithocarpus polystachyus</i>. The structures of <b>1</b>–<b>14</b> were determined by spectroscopic data analysis and chemical methods, and the absolute configurations of <b>1</b> and <b>4</b> were defined unequivocally by X-ray crystallography using Cu Kα radiation. Compounds <b>1</b>–<b>15</b> are the first examples of 3,4-<i>seco</i>-cycloartane derivatives isolated from the genus <i>Lithocarpus</i>. Among them, compounds <b>1</b> and <b>2</b>, <b>9</b> and <b>10</b>, and <b>11</b> and <b>12</b> were found to be three pairs of C-24 epimers, while compounds <b>7</b> and <b>8</b> represent the first examples of 3,4-<i>seco</i>-norcycloartane-type triterpenes. Compound <b>1</b>, as the major component of the plant extract, showed potent antibacterial activity against <i>Micrococcus luteus</i> and <i>Bacillus subtilis</i>, with MIC values of 3.1 and 6.3 μg/mL, respectively, as well as inhibitory activity against human and mouse 11β-hydroxysteroid dehydrogenase type 1, with IC₅₀ values of 1.9 and 0.24 μM, respectively

Conosilane A, an Unprecedented Sesquiterpene from the Cultures of Basidiomycete <i>Conocybe siliginea</i>

Conosilane A (<b>1</b>), a novel sesquiterpene with an unprecedented carbon skeleton, was isolated from the cultures of the basidiomycete <i>Conocybe siliginea</i>. Its structure was elucidated by extensive spectroscopic methods, and the absolute configuration was determined by single crystal X-ray diffraction analysis. Conosilane A was found to inhibit 11β-hydroxysteroid dehydrogenase significantly