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 Highly Polar β‑Homophenylalanine Derivatives as Nonsystemic Intestine-Targeted Dipeptidyl Peptidase IV Inhibitors

Although intensively expressed within intestine, the precise roles of intestinal dipeptidyl peptidase IV (DPPIV) in numerous pathologies remain incompletely understood. Here, we first reported a nonsystemic intestine-targeted (NSIT) DPPIV inhibitor with β-homophenylalanine scaffold, compound 7, which selectively inhibited the intestinal rather than plasmatic DPPIV at an oral dosage as high as 30 mg/kg. We expect that compound 7 could serve as a qualified tissue-selective tool to determine undetected physiological or pathological roles of intestinal DPPIV

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

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

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>

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

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

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

Chemical Constituents and Their Bioactivities of “Tongling White Ginger” (<i>Zingiber officinale</i>)

Gingerols and their corresponding dehydration products shogaols were considered as the active principles of ginger, the rhizome of the plant Zingiber officinale, for its antioxidant, anti-inflammatory, and antitumor activities. Ginger (Z. officinale) has been cultivated for thousands of years as a spice and for medicinal purposes in China. Tongling (Anhui province, China) has traditionally been regarded as an ideal cultivation place. “Tongling White Ginger” enjoys a reputation for being one of the top gingers in China for its thin white peel, tender flesh, rich juice, and flavor. In this study, we have isolated and identified two novel gingerdione dimers, bisgingerdiones A (1) and B (2); two new gingerol derivatives, (5R)-5-acetoxy-1,7-bis(4-hydroxy-3-methoxyphenyl)heptan-3-one (3) and methyl (Z)-neral acetal-[6]-gingerdiol (4); and 38 known compounds (5–42) from rhizomes of Zingiber officinale collected from Tongling, China. Their structures were elucidated by means of spectroscopic methods. Compounds 1–4 showed weak cytotoxic and anti-HIV-1 activities. Compounds 6, 8, and 26 showed inhibitory activities against human and mouse 11β-HSD1 (11β-hydroxysteroid dehydrogenases) with IC50 values between 1.09 and 1.30 μM