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Biotransformation of betulonic acid (1) by Rhizopus arrhizus CGMCC 3.868 resulted in the production of 16 new (3, 5, 6, and 9-21) and five known compounds. Structures of the new compounds were established by analysis of spectroscopic data. Hydroxylation, acetylation, oxygenation, glycosylation, and addition reactions involved the C-20-C-29 double bond. Antineuroinflammatory activities of the obtained compounds in NO production were tested in lipopolysaccharides-induced BV-2 cells. Compared with the substrate betulonic acid, biotransformation products 3, 8, 9, 14, and 21 exhibited an improved inhibitory effect, with IC50 values of 10.26, 11.09, 5.38, 1.55, and 4.69 μM, lower than that of the positive control, NG-monomethyl-l-arginine.

In this study, the biotransformation of ursolic acid by Circinella muscae CGMCC 3.2695 was investigated. Scaled-up biotransformation reactions yielded ten metabolites. Their structures were established based on extensive NMR and HR-ESI-MS data analyses, and four of them are new compounds. C. muscae could selectively catalyze hydroxylation, lactonisation, carbonylation and carboxyl reduction reactions. Furthermore, all the identified metabolites were evaluated for their anti-neuroinflammatory activities in LPS-induced BV-2 cells. Most metabolites displayed pronounced inhibitory effect on nitric oxide (NO) production. The results suggested that biotransformed derivatives of ursolic acid might be served as potential neuroinflammatory inhibitors.

The members of the arylamine N-acetyltransferase (NAT) family of enzymes are important for their many roles in xenobiotic detoxification in bacteria and humans. However, very little is known about their roles outside of detoxification or their specificities for acyl donors larger than acetyl-CoA. Herein, we report the detailed study of PtmC, an unusual NAT homologue encoded in the biosynthetic gene cluster for thioplatensimycin, thioplatencin, and a newly reported scaffold, thioplatensilin, thioacid-containing diterpenoids and highly potent inhibitors of bacterial and mammalian fatty acid synthases. As the final enzyme of the pathway, PtmC is responsible for the selection of a thioacid arylamine over its cognate carboxylic acid and coupling to at least three large, 17-carbon ketolide-CoA substrates. Therefore, this study uses a combined approach of enzymology and molecular modeling to reveal how PtmC has evolved from the canonical NAT scaffold into a key part of a natural combinatorial biosynthetic pathway. Additionally, genome mining has revealed the presence of other related NATs located within natural product biosynthetic gene clusters. Thus, findings from this study are expected to expand our knowledge of how enzymes evolve for expanded substrate diversity and enable additional predictions about the activities of NATs involved in natural product biosynthesis and xenobiotic detoxification.

Carbohydrate-based drug discovery has gained more and more attention during the last few decades. Resin glycoside is a kind of novel and complex glycolipids mainly distributed in plants of the family Convolvulaceae. Over the last decade, a number of natural resin glycosides and derivatives have been isolated and identified, and exhibited a broad spectrum of biological activities, such as cytotoxic, multidrug-resistant reversal on both microbial pathogens and mammalian cancer cells, antivirus, anticonvulsant, antidepressant, sedative, vasorelaxant, laxative, and α-glucosidase inhibitory effects, indicating their potential as lead compounds for drug discovery. A systematic review of the literature studies was carried out to summarize the chemistry and biological activity of resin glycosides from Convolvulaceae species, based on various data sources such as PubMed, Web of Science, Scopus, and Google scholar. The keyword "Convolvulaceae" was paired with "resin glycoside," "glycosidic acid," "glycolipid," or "oligosaccharide," and the references published between 2009 and June 2021 were covered. In this article, we comprehensively reviewed the structures of 288 natural resin glycoside and derivatives newly reported in the last decade. Moreover, we summarized the biological activities and mechanisms of action of the resin glycosides with pharmaceutical potential. Taken together, great progress has been made on the chemistry and biological activity of resin glycosides from Convolvulaceae species, however, more exploratory research is still needed, especially on the mechanism of action of the biological activities.

Biotransformation of betulonic acid (

A new resin glycoside named evolvulin III (1) was isolated from the whole plants of Evolvulus alsinoides. Compound 1 was identified as a pentasaccharide macrolactone with a distinctive 3S,11R,14R-trihydroxyhexadecanoic acid acting as the aglycone. Interestingly, evolvulin III (1) is interconvertible with a known resin glycoside, namely, evolvulin II (2), by intramolecular transesterification. The structure of compound 1 was determined by spectroscopic data and the chemical analysis of the equilibrium mixture of 1 and 2.

A new tetranorditerpenoid (1), two new labdane diterpenoids (2, 3), and nine known analogues (4-12) were isolated from the rhizomes of Amomum villosum var. xanthioides. Compound 1 is an unprecedented rearranged tetranorlabdane diterpenoid, featuring a 6/6/5 fused tricarbocyclic skeleton with an α,β-unsaturated cyclopentenone unit, while 2 is a structurally rare labdane diterpenoid carrying a five-membered cyclic anhydride moiety. Their structures and absolute configurations were established on the basis of spectroscopic data and the experimental and calculated ECD data. Compound 4 showed inhibitory activity against nitric oxide production, with an IC50 value of 2.4 μM, and also inhibited α-glucosidase activity (IC50 = 10.0 μM).

Alkaline hydrolysis of the resin glycoside fraction of the whole plants of Convolvulus arvensis gave two new glycosidic acids, named arvensic acids K and L (1 and 2). Their structures were characterized on the basis of spectroscopic data as well as chemical evidence. They possessed a same pentasaccharide chain, composed of one D-fucose, three D-glucose and one L-rhamnose units. The aglycone of compound 1 was identified to be rarely existing 11S-hydroxyheptadecanoic acid, while compound 2 possessed 11S-hydroxyhexadecanoic acid as the aglycone. Their cytotoxic and anti-migration activities were also evaluated.

In this study, the microbial transformation of cycloastragenol (CA) by the fungi Mucor subtilissimus AS 3.2456 and Aspergillus oryzae AS 3.407 yielded 19 metabolites. Their structures were established based on extensive NMR and HR-MS data analyses, and six of them are new compounds. The two fungal strains exhibited distinct biocatalytic features. M. subtilissimus could catalyse hydroxylation and carbonylation reactions meanwhile the fragile 9,19-cyclopropane ring remained intact. A. oryzae preferred to catalyse hydroxylation, acetylation and ring expansion reactions. These highly specific reactions are difficult to achieve by chemical synthesis, particularly under mild conditions. Furthermore, we found that most of the metabolites could significantly extend the lifespan of Caenorhabditis elegans at 50 µM. These biotransformed derivatives of CA could be potential anti-aging agents.

Evolvulins I and II (1 and 2), representing a new class of resin glycosides with an unprecedented trihydroxy aglycone unit, 3S,11R,14R-trihydroxyhexadecanoic acid (4), were isolated from the whole plants of Evolvulus alsinoides. Their structures were thoroughly characterized by extensive spectroscopic analyses as well as chemical evidence. Compound 1 exhibited the most potent cytotoxic activity against MCF-7 cells, with an IC50 value of 3.12 μM.

Six new glycosidic acids, arvensic acids E-J (1-6), were obtained from a glycosidic acid fraction afforded by alkaline hydrolysis of the crude resin glycosides from Convolvulus arvensis whole plants. Their structures were established from the spectroscopic data obtained and by chemical evidence. They were defined as heptasaccharides or hexasaccharides, comprising d-fucose, d-glucose, and l-rhamnose units. Compounds 1, 3, and 5 were assigned the 11 S-hydroxyheptadecanoic acid as the aglycone, while compounds 2, 4, and 6 were found to possess 11 S-hydroxyhexadecanoic acid as the aglycone. Compounds 1, 3, and 5 are the first representatives of resin glycosides with 11 S-hydroxyheptadecanoic acid as the aglycone.

As a continue investigation of the bioactive secondary metabolites from marine derived fungi, two new anthraquinone dimers (1, 2), along with three known anthraquinones (3-5) and two known xanthones (6, 7) were isolated from the marine-derived fungus Aspergillus versicolor. Their structures, including the absolute configurations, were elucidated by NMR, HRMS, and comparison with reported ones. Among them, compounds 1 and 2 were identified as anthraquinone dimers which dimerized by a rare C-O-C ether linkage, and both of them showed selective antibacterial activity against Gram-positive Staphylococcus aureus; whilst compound 6 exhibited moderate cytotoxicity against human cancer cell lines.

The arylamine N-acetyltransferase (NAT) family of enzymes are important for their many roles in xenobiotic detoxification in bacteria and humans. However, very little is known about their roles outside of detoxification or their specificities for acyl donors larger than acetyl-CoA. Herein, we report the detailed study of PtmC, an unusual NAT homologue encoded in the biosynthetic gene cluster for thioplatensimycin, thioplatencin, and a newly reported scaffold, thioplatensilin, thioacid-containing diterpenoids and highly potent inhibitors of bacterial and mammalian fatty acid synthases. As the final enzyme of the pathway, PtmC is responsible for the selection of a thioacid arylamine over its cognate carboxylic acid and coupling to at least three large, 17-carbon ketolide-CoA substrates. Therefore, this study uses a combined approach of enzymology and molecular modeling to reveal how PtmC has evolved from the canonical NAT scaffold into a key part of a natural combinatorial biosynthetic pathway. Additionally, genome mining has revealed the presence of other related NATs located within natural product biosynthetic gene clusters. Thus, findings from this study are expected to expand our knowledge of how enzymes evolve for expanded substrate diversity and enable additional predictions about the activities of NATs involved in natural product biosynthesis and xenobiotic detoxification.

Biotransformation of betulinic acid was carried out with Circinella muscae CGMCC 3.2695 and Cunninghamella echinulata CGMCC 3.970, yielded six previously undescribed hydroxylated metabolites and four known compounds. C. muscae could catalyze the regioselecitve hydroxylation and carbonylation at C-3, C-7, C-15 and C-21 to yield seven products. C. echinulata could catalyze the C-1, C-7 and C-26 regioselecitve hydroxylation and acetylation to yield five metabolites. The structures of the metabolites were established based on extensive NMR and HR-ESI-MS data analyses. Furthermore, most of the metabolites exhibited pronounced inhibitory activities on lipopolysaccharides-induced NO production in RAW264.7 cells.

Two new glycosidic acids, evolvulic acids B and C (

Two new glycosidic acids, evolvulic acids B and C (1 and 2), along with a known one, evolvulic acid A (3), were isolated from the glycosidic acid fraction afforded by alkaline hydrolysis of crude resin glycosides from Evolvulus alsinoides whole plants. Their structures were characterized by the spectroscopic data and chemical evidences. Compounds 1 and 2 are both defined as tetrasaccharides, composed of D-fucose, D-glucose, L-rhamnose or D-galactose units. Their aglycones are identified to be a distinctive 3S,11R,14R-trihydroxyhexadecanoic acid, which is only discovered from E. alsinoides up to now. The cytotoxic and anti-migration activities of compounds 1–3 were also tested.

In this study, a resin glycoside fraction with cytotoxic activity was isolated from the alcoholic extract of C. arvensis whole plants. To describe the chemical feature of the resin glycosides, the fraction was alkaline hydrolyzed and four novel glycosidic acids, named arvensic acids A-D (1-4), were isolated. Their structures were thoroughly elucidated on the basis of spectroscopic data and chemical evidences. They all possess a same heptasacharride core, consisting of one D-fucose, two L-rhamnose and four d-glucose units. The difference among these glycosidic acids was placed on the aglycone, which is 12S-hydroxypentadecanoic acid for 1, 12S-hydroxyhexadecanoic acid for 2, 3S,12S-dihydroxypentadecanoic acid for 3, and 3S,12S- dihydroxyhexadecanoic acid for 4. These aglycones are rarely found in the structures of resin glycosides and are firstly identified in the genus Convolvulus.

A new tetranorditerpenoid (

Alkaline hydrolysis of the resin glycoside fraction of the whole plants of

Biotransformation of lupane-type triterpenoid betulin was carried out with Mucor subtilissimus CGMCC 3.2456. Yielded nine previously undescribed hydroxylated compounds. M. subtilissimus biotransformation provided C-7, C-11, C-15 and C-24 hydroxylated compounds along with C-7 oxidized and C-28 acetylated derivatives. The structures of the metabolites were established based on extensive NMR and HR-ESI-MS data analyses. Furthermore, we found that most of the metabolites exhibited pronounced inhibitory activities on lipopolysaccharides-induced NO production in RAW264.7 cells.

Water spinach (I. aquatica) is one of the common green leafy vegetables used in Asia. In a continuing chemical investigation on the cytotoxic resin glycosides from water spinach, eight new resin glycosides, Aquaterins XII–XIX (1–8), were isolated, among which 1, 2 and 4 exhibited potent cytotoxic activities. To further characterise the anticancer potential of the resin glycosides from water spinach, Aquaterin II obtained previously was investigated on HepG2 cells. The results showed that Aquaterin II induced G0/G1 arrest regulated by related proteins CDK4/6, cyclin D/E and p21, and caused mitochondria-mediated apoptosis featured by MMP decrease, ROS accumulation, caspase cascade activation and Bax/Bcl-2 alteration. Additionally, the suppression on PI3K/Akt signalling pathway was observed, suggesting that it participated in the Aquaterin II-induced cell growth inhibition. Our results are the first to demonstrate the antiproliferative mechanism of resin glycosides. This investigation also advanced the potential application of water spinach as a functional food.

Central nervous system (CNS) disorders play a major impact on individual lives and place a severe strain on health care resources. Convolvulaceae is a family comprising approximately 1,600-1,700 species grouped in 55-60 genera, and many species are reported to have an effect on CNS functions. A systematic review of the literature studies was carried out to summarize available evidences on Convolvulaceae plants with CNS efficacies. This review is based on various data sources such as Google Scholar, Web of Science, Scopus, PubMed, and Wanfang Data. A total of 200 related articles were included in this review. According to the research result, 54 Convolvulaceae species are suggested to display CNS efficacies historically, and 46 species have been evaluated for their CNS efficacies. In addition, 67 compounds from 16 Convolvulaceae species are recognized to possess CNS efficacies. Despite great progress made through pharmacology and phytochemistry studies on CNS active Convolvulaceae species, more exploratory research is needed to gain a better understanding of the CNS efficacies of this plant family.

by Jian-Guang Luo, Hong Yin, Bo-Yi Fan, and Ling-Yi Kong*State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry,China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China(phone/fax: þ86-25-83271405; e-mail: cpu_lykong@126.com)A rare labdane diterpene g-lactam, 1, and two new labdane diterpenoids, 2 and 3, along with twoknown diterpenes, 4 and 5, were isolated from the roots of Amomum maximum. Their structures wereestablished on the basis of spectroscopic data. All of the isolates were evaluated for their cytotoxicactivities, and compound 3 was found to exhibit an inhibitory activity against MG-63 cell lines with anIC

Two new resin glycosides, cuses 3 (1) and 4 (2), were initially obtained from the seeds of Cuscuta chinensis. Both of them contained a reducing glucose unit, and thus existed as a pair of isomers. In order to solve the existing problem of tautomerism, the remanent resin glycoside fraction was converted into aminoalditol derivatives with p-anisidine, and then another eight new resin glycosides cuses 5–12 (3–10) were further isolated. Cuses 7–12 (6–10) were considered to be generated via glycosidation of two acylated oligosaccharides, and thus characterized as ether-type resin glycoside dimers. Their structures including absolute stereochemistry were elucidated by a combination of spectroscopic and chemical methods. Compounds 3–10 exhibited cytotoxic activity toward MCF-7, SMMC-7721, and MG-63 cell lines with IC50 values ranging from 8.72 to 59.35 μg/mL.

Ten honokiol oligomers (1-10), including four novel trimers (1-4) and four novel dimers (5-8), were obtained by means of biotransformation of honokiol catalyzed by Momordica charantia peroxidase (MCP) for the first time. Their structures were established on the basis of spectroscopic methods. The biological results demonstrated that most of the oligomers were capable of inhibiting α-glucosidase with significant abilities, which were one to two orders of magnitude more potent than the substrate, honokiol. In particular, compound 2, the honokiol trimer, displayed the greatest inhibitory activity against α-glucosidase with an IC50 value of 1.38μM. Kinetic and CD studies indicated that 2 inhibited α-glucosidase in a reversible, mixed-type manner and caused conformational changes in the secondary structure of the enzyme protein. These findings suggested that 2 might be exploited as a promising drug candidate for the treatment of diabetes.

Nine biflavonoids (1–9) were isolated from ethanolic extract of Selaginella uncinata (Desv.) Spring. Their structures were determined by spectra analysis. Compounds 1–9 were classified into four types according to the connection styles of the two flavonoid parts. Among them, 1 was elucidated as a new compound, while 4 was one with a new configuration. All isolates exhibited inhibitory activities against protein tyrosine phosphatase 1B (PTP1B) in an enzyme assay with IC50 values ranging from 4.6 to 16.1 μM, and the relationship between the structures and activities was discussed. Docking simulations of these compounds demonstrated they had tight binding capacities towards the allosteric site of PTP1B. Additionally, the glucose uptake activities of 1–9 were evaluated in insulin-resistant HepG2 cells, while the effect of 1 on the activation of IRS-1/PI3K/Akt pathway was revealed by Western Blot analysis.

Metabolomics can be used to identify potential markers and discover new targets for future therapeutic interventions. Here, we developed a novel application of the metabonomics method based on gas chromatography-mass spectrometry (GC/MS) analysis and principal component analysis (PCA) for rapidly exploring the anticancer mechanism of physapubenolide (PB), a cytotoxic withanolide isolated from Physalis species. PB inhibited the proliferation of hepatocellular carcinoma cells in vitro and in vivo, accompanied by apoptosis-related biochemical events, including the cleavage of caspase-3/7/9 and PARP. Metabolic profiling analysis revealed that PB disturbed the metabolic pattern and significantly decreased lactate production. This suggests that the suppression of glycolysis plays an important role in the anti-tumour effects induced by PB, which is further supported by the decreased expression of glycolysis-related genes and proteins. Furthermore, the increased level of p53 and decreased expression of p-Akt were observed and the attenuated glycolysis and enhanced apoptosis were reversed in the presence of Akt cDNA or p53 siRNA. These results confirm that PB exhibits anti-cancer activities through the Akt-p53 pathway. Our study not only reports for the first time the anti-tumour mechanism of PB, but also suggests that PB is a promising therapeutic agent for use in cancer treatments and that metabolomic approaches provide a new strategy to effectively explore the molecular mechanisms of promising anticancer compounds.

Oxidative stress plays a critical role in the pathogenesis of diabetic vascular complications. Trans-δ-viniferin (TVN), a polyphenolic compound, has recently attracted much attention as an antioxidant exhibiting a hypoglycemic potential. In the present study, we aimed at investigating the protective effect of TVN against high glucose-induced oxidative stress in human umbilical vein endothelial cells (HUVECs) and the potential mechanism involved. We found that TVN attenuated reactive oxygen species (ROS) production, increased catalase (CAT) activity and decreased malondialdehyde (MDA) levels to ameliorate cell survival induced by 35 mM glucose. Meanwhile, it inhibited high glucose-induced apoptosis by maintaining Ca(2+) and preserving mitochondrial membrane potential (MMP) levels. The immunoblot analysis indicated that TVN efficiently regulated the cleavage of caspase family, p53, Bax and Bcl-2, all mediated by SIRT1. Furthermore, the increased level of SIRT1 induced by TVN was inhibited by nicotinamide and siRNA-medicated SIRT1 silencing (si-SIRT1), thereby confirming the significant role of SIRT1 in these events. In conclusion, our results indicated that TVN efficiently reduced oxidative stress and maintained mitochondrial function related with activating SIRT1 in high glucose-treated HUVECs. It suggested that TVN is pharmacologically promising for treating diabetic cardiovascular complications.

by Jian-Guang Luo, Hong Yin, Bo-Yi Fan, and Ling-Yi Kong*State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry,China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China(phone/fax: þ86-25-83271405; e-mail: cpu_lykong@126.com)A rare labdane diterpene g-lactam, 1, and two new labdane diterpenoids, 2 and 3, along with twoknown diterpenes, 4 and 5, were isolated from the roots of Amomum maximum. Their structures wereestablished on the basis of spectroscopic data. All of the isolates were evaluated for their cytotoxicactivities, and compound 3 was found to exhibit an inhibitory activity against MG-63 cell lines with anIC

Six new indole glucosides (1-6) and fifteen known alkaloids (7-21) were isolated from the fruit of Camptotheca acuminata. The planar structures of 1-6 were determined on the basis of spectroscopic data analysis and their absolute configurations were established by CD. The isolated indole glucosides showed a clear biosynthetic pathway of camptothecin (7), which started from tryptamine and secologanin and was proposed by synthetic chemists previously. Particularly, compound 1 supplemented the process of the transformation from pumiloside (20) or 3-epi-pumiloside (21) to camptothecin (7). In addition, camptothecin 10-O-β-D-glucopyranoside (13) and norcamptothecin (17), synthesized in the early structural modification of 7, were first isolated from the natural resources. The new compounds 1-6 were screened for their in vitro cytotoxicity but they did not show any exciting result.

Eleven new resin glycosides, aquaterins I-XI (1-11), were isolated from the whole plants of Ipomoea aquatica. The structures of 1-11 were elucidated by a combination of spectroscopic and chemical methods. They were found to be partially acylated tetra- or pentasaccharides derived from simonic acid B and operculinic acids A and C. The site of the aglycone macrolactonization was placed at C-2 or C-3 of the second saccharide moiety, while the two acylating residues could be located at C-2 (or C-3) of the second rhamnose unit and at C-4 (or C-3) on the third rhamnose moiety. All compounds were evaluated for cytotoxicity against a small panel of human cancer cell lines. Compound 4 exhibited the most potent activity against HepG2 cells with an IC50 value of 2.4 μM. Cell cycle analysis revealed 4 to inhibit the proliferation of HepG2 cells via G0/G1 arrest and apoptosis induction. In addition, compounds 1-4, 7, 9, and 10 were found to elevate Ca(2+) in HepG2 cells, which might be involved in the regulation of the cytotoxic activities observed.