A novel DPP-4 inhibitor Gramcyclin A attenuates cognitive deficits in APP/PS1/tau triple transgenic mice via enhancing brain GLP-1-dependent glucose uptake.

Enhancing glucagon-like peptide 1 (GLP-1) signaling with a dipeptidyl peptidase IV (DPP-4) inhibitor might exert protective effects on Alzheimer's disease (AD). We found that intragastric administration of Gramcyclin A (10, 20 and 40 mg/kg), a novel DPP-4 inhibitor, for 3 months significantly reversed cognitive decline in APP/PS1/tau triple transgenic mice in a dose-dependent manner. Gramcyclin A treatment markedly reduced Aß plaques as well as the insoluble and soluble forms of Aß40 and Aß42 in the hippocampus of APP/PS1/tau mice. Treatment with Gramcyclin A remarkedly decreased the level of microglia and suppressed neuroinflammation in the hippocampus of APP/PS1/tau mice. Moreover, Gramcyclin A treatment could increase brain glucose uptake in APP/PS1/tau mice, as detected by 18-fluoro-2-deoxyglucose (18 F-FDG) micro-positron emission tomography (micro-PET) imaging. Furthermore, Gramcyclin A significantly increased expression of glucagon-like peptide-1 (GLP-1), GLP-1R, proliferator-activated receptor gamma coactivator (PGC)-1α and glucose transporter 4 (GLUT4), and inhibited insulin receptor (IRS)-1 phosphorylation and tau hyperphosphorylation in the hippocampus of APP/PS1/tau mice. Collectively, Gramcyclin A conferred protective effects against AD via enhancing brain GLP-1-dependent glucose uptake. The DPP-4 inhibitor Gramcyclin A might be a potential therapeutic drug for AD.

Five New Polyoxypregnane Glycosides from the Vines of Aspidopterysobcordata and Their Antinephrolithiasis Activity.

From the dried vines of Aspidopterys obcordata Hemsl, five new polyoxypregnane glycosides, named obcordatas J-N (1-5), were obtained. Their structures were fully elucidated and characterized by HRESIMS and extensive spectroscopic data. In addition, all of the new compounds were screened for their antinephrolithiasis activity in vitro. The results showed that compounds 1-3 have prominent protective effects on calcium oxalate crystal-induced human kidney 2 (HK-2) cells, with EC50 values ranging from 6.72 to 14.00 µM, which is consistent with the application value of A. obcordata in folk medicine for kidney stones.

The Biosynthesis Related Enzyme, Structure Diversity and Bioactivity Abundance of Indole-Diterpenes: A Review.

Indole diterpenes are a large class of secondary metabolites produced by fungi, possessing a cyclic diterpenoid backbone and an indole moiety. Novel structures and important biological activity have made indole diterpenes one of the focuses of synthetic chemists. Although the discovery, identification, structural diversity, biological activity and especially structure-activity relationship of indole diterpenes have been reported in some papers in recent years, they are absent of a systematic and comprehensive analysis, and there is no elucidation of enzymes related to this kind of natural product. Therefore, it is necessary to summarize the relevant reports to provide new perspectives for the following research. In this review, for the first time, the function of related synthases and the structure-activity relationship of indole diterpenes are expounded, and the recent research advances of them are emphasized.

Natural Nitrogenous Sesquiterpenoids and Their Bioactivity: A Review.

Nitrogenous sesquiterpenoids fromnatural sourcesare rare, so unsurprisingly neither the potentially valuable bioactivity nor thebroad structural diversity of nitrogenous sesquiterpenoids has been reviewed before. This report covers the progressduring the decade from 2010 to February 2020 on the isolation, identification, and bioactivity of 391 nitrogen-containing natural sesquiterpenes from terrestrial plant, marine organisms, and microorganisms. This complete and in-depth reviewshouldbe helpful for discovering and developing new drugs of medicinal valuerelated to natural nitrogenous sesquiterpenoids.

Two new daphnane diterpenes from the roots of Stelleropsis tianschanica.

Two new daphnane diterpenes named tianchaterpenes A and B were isolated from the roots of Stelleropsis tianschanica. Their structures were elucidated on the basis of chemical and spectral analysis, including 1D, 2D NMR analyses and HRESIMS. Compounds 1 and 2 were evaluated for their cytotoxic activities against HeLa and HCT-8 cell lines. The results showed that all compounds displayed weak cytotoxicities to the HeLa cells and were inactive to the HCT-8 cells.

Quantitative Evaluation of Twelve Major Components of Sulfur-Fumigated Astragali Radix with Different Durations by UPLC-MS.

In this study, an improved UPLC-MS (Ultra-high performance liquid chromatography-tandem mass spectrometry) method for simultaneously quantifying twelve major components belonging to two chemical types was developed and validated, and was applied to quantitatively compare the quality of sulfur-fumigated Astragali Radix of different durations and of the fresh reference sample. The results showed that the contents of triterpenes astragaloside III and astragaloside IV decreased moderately, while the flavonoids calycosin, formononetin, and 7,2'-dihydroxy-3',4'-dimethoxyisoflavane decreased significantly. The corresponding flavonoid glycosides increased accordingly, which indicated the occurrence of chemical transformation of flavonoids and glycosides in the process of sulfur-fumigation. These transformations were further confirmed by the synthesis of flavonoid glycosides under simulated sulfur-fumigation circumstances. Furthermore, the sulfur-fumigated duration varied in proportion with the contents of compounds 7, 11, and 12. These results suggest that the established method was precise, accurate and sensitive enough for the global quality evaluation of sulfur-fumigated Astragali Radix. Further, sulfur-fumigation not only changes the proportions of bioactive components, but also causes chemical transformation in Astragali Radix.

Pyrrole Alkaloids from the Edible Mushroom Phlebopus portentosus with Their Bioactive Activities.

Seven pyrrole alkaloids, three of which are novel (phlebopines A⁻C (1⁻3)), were isolated from the fruiting bodies of the edible mushroom Phlebopus portentosus. Their structures were determined on the basis of spectroscopic data. All the isolated compounds were tested for their neuroprotective properties and acetylcholine esterase (AChE) inhibition activities. Compound 7 displayed remarkable neuroprotective effects against hydrogen peroxide (H2O2)-induced neuronal-cell damage in human neuroblastoma SH-SY5Y cells.

[A new naphthalene derivative from bulbs of Eleutherine americana].

A new naphthalene derivative and three known compounds were isolated from the petroleum ether extract of the bulbs of Eleutherine americana by using various chromatographic techniques, such as column chromatography over silica gel and semi-preparative HPLC. Their structures were elucidated by spectroscopic date (MS, UV, IR, NMR), which were identified as eleutherol B (1), 4,8-dihydroxy-3-methoxy-1-methylanthraquinone-2-carboxylic acid methyl ester (2), 8-hydroxy-3,4-dimethoxy-1-methylanthraquinone-2-carboxylic acid methyl ester (3), and isoeleutherine (4). Compound 1 is a new compound. The diastolic blood vessels activity of compound 1 and 2 were potent, reaching 82.5% and 85.3% at the concentration of 10 µmol·L⁻¹, which were basically the same as that of the positive drug tanshinone ⅡA.

Two new sesquiterpenes from the aerial parts of Schizonepeta tenuifolia.

Two new sesquiterpenes named petafolias A-B were isolated from the aerial parts of Schizonepeta tenuifolia. Their structures were elucidated by various spectroscopic techniques (UV, IR, MS, CD, 1D, and 2D NMR).

Cassane-type diterpenes from Caesalpinia minax induce apoptosis in pituitary adenoma: structure-activity relationship, ER stress and Wnt/ß-catenin pathways.

Plant-derived natural products have been the highly significant sources of novel antitumor agents. The cassane-type diterpenes of genus Caesalpinia have been reported to bear antiproliferative activities toward different types of cancer cells. In this study, we evaluated the antineoplasmic activities of 16 natural origin cassane-type diterpenes isolated from the CHCl3 extract of the seeds of C. minax in pituitary adenomas cells and identified caesalpin G (CAG) showed the strongest cytotoxicity. Moreover, we further investigated the structure-activity relationship and molecular mechanism of these derivatives systematically. The results confirmed the unsaturated lactone-type ring, hydroxyl at C-7, and alkenyl at C-11 or C-14 functionality as critical for anticancer activity in this family of natural products. In addition, the mechanism experiments also demonstrated unfolded protein response and ER stress and Wnt/ß-catenin pathway were involved in the CAG-induced apoptosis.

Oleanane triterpene saponins with cardioprotective activity from Clinopodium polycephalum.

Two new triterpene saponins, clinopodiside VI (1) and saikosaponin c (2), along with six known saikosaponins (3-8), were isolated from the plant of Clinopodium polycephalum. Compounds 1-3 showed moderate inhibition against H9c2 cell damage induced by H2O2.

New Cassane Diterpenoids from Caesalpinia sappan and their Antiplasmodial Activity.

One new cassane diterpene possessing an unusual N bridge between C-19 and C-20 named caesalsappanin R (1), as well as another new diterpene caesalsappanin S (2), were isolated from the seeds of Caesalpinia sappanwith methanol extract. Their structures were determined by spectroscopic analysis and examined alongside existing data from prior studies. Their biological activities were profiled by their antiplasmodial activity.

[Studies on chemical constituents of Clinopodium chinense].

Twenty-eight compounds were isolated and purified from Clinopodium chinense by Sephedax LH-20, ODS, MCI and preparative HPLC. Their structures were identified as apigenin (1), apigenin-7-O-ß-D-glucopyranoside (2), apigenin-7-O-ß-D-glucuronopyranoside (3), thellungianol (4), apigenin-7-O-ß-D-rutinoside (5), luteolin (6), luteolin-4'-O-ß-D-glucopyranoside (7), apigenin-7-O-ß-D-pyranglycuronate butyl ester (8), luteolin-7-O-ß-D-rutinoside (9), luteolin-7-O-ß-D-noehesperidoside (10), acacetin (11), acacetin-7-O-ß-D-glucuronopyranoside (12), buddleoside (13), naringenin (14), pruning (15), nairutin (16), isosakuranetin (17), isosakuranin (18), didymin (19), hesperidin (20), kaempferol (21), quercetin (22), kaempferol-3-O-α-L-rahmnoside (23), p-hydroxycinnamic acid (24), caffeic acid (25), cis-3-[2-[1-(3,4-dihydroxy-phenyl)-1 -hydroxymethyl]-1,3-ben-zodioxol-5-yl]-(E)-2-propenoic acid (26), mesaconic acid (27), gentisic acid 5-O-ß-D-(6'-salicylyl)-glucopyranoside (28). Among them, compounds 7, 9-10, 12, 23, 26-28 were isolated from the Clinopodium for the first time. The protective effects of compounds 1-6, 8-17 and 19 against H2O2-induced H9c2 cardiomyocyte injury were tested, compounds 15 exhibited significantly protective effects. Compared with the cell viability of (62.12±6.18)% in the model, pruning exhibited viabilities of (84.25±7.36)% at 25.0 mg•L⁻¹, respectively, using quercetin as a positive control [cell viability of (84.55±8.26)%, 20 mg•L⁻¹].

The new steroidal glycosides from the aerial parts of Lepidogrammitis drymoglossoides.

Two new steroidal glycosides ponasteroside C (1) and ponasteroside D (2) were isolated from the aerial parts of Lepidogrammitis drymoglossoides. Their structures were elucidated by various spectroscopic techniques (IR, HRESIMS, 1D and 2D NMR). All compounds were evaluated for their cytotoxicity against HeLa and HCT-8 cell lines, and compounds 1 and 2 showed mild activity against all the test cell lines.

Diarylpentanol constituents from the aerial part of Stelleropsis tianschanica.

Five diarylpentanol derivatives including two new compounds stellerasme A (1), stellerasme B (2) were isolated from the aerial parts of Stelleropsis tianschanica. Their structures were elucidated by various spectroscopic techniques (UV, IR, MS, CD, 1D and 2D NMR). All compounds were evaluated for their cytotoxicity activity against HeLa and KB cell lines, and compound 1 showed selective activities against HeLa cell line with an IC50 value of 7.4 µM.

[Cassane diterpenes from the seeds of Caesalpinia decapetala].

Four casssane diterpenes were isolated from the ethanol extract of the seeds of Caesalpinia decapetala (Fabaceae), with a combination of various chromatographic approaches, including silica gel, Sephadex LH-20, reverse phase C18 and so on. On the basis of spectroscopic data analysis, they were identified as caesalpinin MQ (1), neocaesalpin N(2), caesalmin F (3) and α-caesalpin (4). Among them, compound 1 is a new diterpene, compounds 2-4 were isolated for the first time from the plant of C. decapetala.

Antimalarial and Antiproliferative Cassane Diterpenes of Caesalpinia sappan.

Bioassay-guided fractionation of a methanol extract of the seeds of Caesalpinia sappan led to the isolation of 12 new cassane-type diterpenes, caesalsappanins A-L (1-12). Their structures were elucidated on the basis of NMR and HRESIMS analysis, and the absolute configuration of compound 1 was determined by single-crystal X-ray crystallography. All isolated compounds were tested against a chloroquine-resistant Plasmodium falciparum strain for antiplasmodial activities and against a small panel of human cancer cell lines for antiproliferative activities. Compounds 7 and 8 displayed antimalarial activity against the chloroquine-resistant K1 strain of P. falciparum with IC50 values of 0.78 and 0.52 µM and selectivity indices of 17.6 and 16.4, respectively. Compound 10 showed antiproliferative activity against the KB cancer cell line with an IC50 value of 7.4 µM.

A new drimane sesquiterpenoid and a new triterpene lactone from fungus of Fomes officinalis.

A new sesquiterpenoid fomeffic acid (1) and a new triterpene lactone fomefficinin (2) were isolated from the fungus Fomes officinalis, together with another six known compounds fomitopsin C (3), dehydrosulfurenic acid (4), dehydroeburiconic acid (5), dehydroeburicoic acid (6), 3-keto-dehydrosulfurenic acid (7), and laricinolic acid (8). The structures and stereochemistry of 1 and 2 were determined by NMR and X-ray diffraction analyses. The sesquiterpenoid and five triterpenes were tested for cytotoxicity against HL-60, Bel-7402, and KB cancer lines in vitro, and they appeared to be modestly active.

[Cassae-type diterpenes from seeds of Caesalpinia minax].

Fifteen cassaen-type diterpenes were isolated from the 95% ethanolic extract of the seeds of C. minax through various chromatographic techniques. Their structures were identified on the basis of spectroscopic data as pulcherralpin (1), caesalpinin ML (2), chamaetexane C (3), chamaetexane D (4), 6ß, 18-diacetoxycassan-13, 15-diene (5), neocaesalpin K (6), neocaesalpin MP (7), neocaesalpin M (8), neocaesalpin Q (9), neocaesalpin P (10), neocaesalpin R (11), caesaldekarin D (12), caesaldekarin A (13), caesaldekarin b (14), 3ß,6α-diacetoxyvouacapane (15). Among them, compounds 14, 9-11 were isolated from this plant for the first time.

Aphanamixins A-F, acyclic diterpenoids from the stem bark of Aphanamixis polystachya.

Six new acyclic diterpenoids named Aphanamixins A-F (1-6), together with two known compounds of nemoralisin and nemoralisin C, were isolated from the stem bark of Aphanamixis polystachya (WALL) J. N. BARKER. Their structures were established through a comprehensive analysis of NMR spectroscopic data and high resolution mass spectrometric data. The absolute configurations of carbon stereocenters were determined by means of auxiliary chiral α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA) derivatives and circular dichroism (CD), respectively. All the new isolates were tested for their antiproliferative activity against HepG2, AGS, MCF-7, and A-549 cancer cell lines and they exhibited weak cytotoxicities (IC50>10 µM). Moreover, we highlighted that the six new diterpenoids characterized by acyclic skeleton was rarely seen in nature.