Yue-Wei Guo

Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades

This article provides an overview of approximately 300 secondary metabolites with inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), which were isolated from various natural sources or derived from synthetic process in the last decades. The structure-activity relationship and the selectivity of some compounds against other protein phosphatases were also discussed. Potential pharmaceutical applications of several PTP1B inhibitors were presented.

Structure, bioactivities, biosynthetic relationships and chemical synthesis of the spirodioxynaphthalenes

Covering: 1989 to September 2010 The spirodioxynaphthalenes are a group of fungal secondary metabolites, consisting of a 1,8-dihydroxynaphthalene-derived spiroketal unit linked to a second oxidized naphthalene moiety, that show a great variety of biological activities. This review summarizes the research on the isolation, structure elucidation, biological activities, biosynthesis, and chemical synthesis of the spirodioxynaphthalenes published over the last 20 years. More than 100 fungal and plant metabolites are described, and over 100 references cited.

Disulfide- and Multisulfide-Containing Metabolites from Marine Organisms

Disulfideand Multisulfide-Containing Metabolites from Marine Organisms Cheng-Shi Jiang, Werner E. G. M€uller, Heinz C. Schr€oder, and Yue-Wei Guo* State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang High-Tech Park, Shanghai 201203, People’s Republic of China Institute for Physiological Chemistry, Medical Center of the Johannes Gutenberg-University, Duesbergweg 6, D-55128 Mainz, Germany

Structure and cytotoxicity of phidianidines A and B: first finding of 1,2,4-oxadiazole system in a marine natural product.

Two indole alkaloids, phidianidines A (1) and B (2), exhibiting an uncommon 1,2,4-oxadiazole ring linked to the indole system, have been isolated from the marine opisthobranch mollusk Phidiana militaris. The structures of the two metabolites have been elucidated by spectroscopic techniques. Phidianidines exhibit high cytotoxicity against tumor and nontumor mammalian cell lines in in vitro assays.

Secondary Metabolites from the South China Sea Invertebrates: Chemistry and Biological Activity

The increasing demand for new lead compounds in the pharmaceutical and agrochemical industries has driven scientists to search for new sources of bioactive natural products. Marine invertebrates are a rich source of novel, bioactive secondary metabolites and they have attracted a great deal of attention from scientists in the fields of chemistry, pharmacology, ecology, and molecular biology. During the past 25 years, many complex and structurally unique secondary metabolites have been isolated from the invertebrates inhabiting the South China Sea. These metabolites are responsible for various bioactivities such as anti-tumor, anti-inflammation and antioxidant activities, and/or they act on the cardiovascular system. This review will focus on the marine natural product chemistry of invertebrates from the South China Sea, aiming to give the reader a brief view of the compounds isolated from these invertebrates, as well as their biological activities. The article covers the literature published during the period from the beginning of 1980 to the end of 2005, with 340 citations and 811 compounds from invertebrates from the South China Sea, including sponges, coelenterates, molluscs and echinoderms.

Structural and Stereochemical Studies of alpha-Methylene-gamma-lactone-Bearing Cembrane Diterpenoids from a South China Sea Soft Coral Lobophytum crassum

Four new alpha-methylene-gamma-lactone-bearing cembranoids, 20-acetylsinularolide B (6), presinularolide B (7), 3-dehydroxylpresinularolide B (8), and 3-dehydroxyl-20-acetylpresinularolide B (9), together with five known analogues, sinularolides B-E (1- 4) and 20-acetylsinularolide C (5), were isolated from a South China Sea soft coral Lobophytum crassum. Their structures and relative stereochemistry were established by a combination of detailed spectroscopic data analysis and chemical correlations. The structures of 1- 9 were further confirmed by an X-ray diffraction study on a single crystal of sinularolide B (1). The absolute configurations of sinularolide B (1) and presinularolide B (7) were determined by a novel solid-state CD/TDDFT approach and by a modified Moshers method, respectively. This study also revealed that the coupling constant between the lactonic methine protons ((3) J 1,2) varies considerably with different functional groups on the cembrane ring and that the determination of the stereochemistry of lactone ring fusion based on this coupling constant is risky. In a bioassay, sinularolides B and C (1 and 2) and new cembranoids 7 and 8 showed in vitro cytotoxicity against the tumor cell lines A-549 and P-388.

Small molecules from natural sources, targeting signaling pathways in diabetes.

Diabetes mellitus (DM) is a metabolic disease caused by genetic or environmental factors. It has rendered a severe menace to the middle-aged and elderly, while there is still lack of efficient drugs against this disease. The pathogenic mechanism for DM is complex, and the complicated networks related to this disease involve distinct signaling pathways. Currently, discovery of potential modulators targeting these pathways has become a potent approach for anti-diabetic drug lead compound development. Compared with synthetic compounds, natural products provide inherent larger-scale structural diversity and have been the major resource of bioactive agents for new drug discovery. To date, more and more active components from plants or marine organisms have been reported to regulate diabetic pathophysiological signaling pathways and exhibit anti-diabetic activity. This review will summarize the regulation of natural small molecules on some key signaling pathways involved in DM. These pathways include insulin signaling pathway, carbohydrate metabolism pathway, the pathways involving insulin secretion and PPAR regulation, endoplasmic reticulum (ER) stress and inflammation related pathways and chromatin modification pathways.

Rare casbane diterpenoids from the Hainan soft coral Sinularia depressa.

A series of nine casbane diterpenes, compounds 5-13, exhibiting either cis or trans ring junctions were isolated from the Hainan soft coral Sinularia depressa. The structures of this group of compounds, the basic member of which was named depressin (5), were established by detailed spectroscopic analysis. In addition, the absolute configuration of the main metabolite, 10-hydroxydepressin (7), and of its epimer, 1-epi-10-hydroxydepressin (8), was determined by a combination of conformational analysis and the modified Moshers method. A stereochemical relationship between all isolated molecules was investigated by analyzing their circular dichroism profiles. Antiproliferative and antibacterial activities of the depressins were also evaluated.

A novel sesquiterpene quinone from Hainan sponge Dysidea villosa

A new sesquiterpene quinone, 21-dehydroxybolinaquinone (5), together with two known related analogues, bolinaquinone (6) and dysidine (7), had been isolated from the Hainan sponge Dysidea villosa. The structure of the new compound 5 was elucidated on the basis of detailed analysis of spectroscopic data and by comparison with related model compounds. Compounds 5-7 were evaluated for the inhibitory activity against hPTP1B, a potential drug target for treatment of type-II diabetes and obesity, and cytotoxic activity against Hela cell line. The results showed that dysidine (7) had the strongest hPTP1B inhibitory activity with an IC(50) value of 6.70microM and 6 had significant cytotoxic activity against Hela cell line with an IC(50) value of 5.45microM. New compound 5 showed moderate PTP1B inhibitory activity and cytotoxicity with IC(50) values of 39.50 and 19.45microM, respectively.

Hyrtiosal, a PTP1B Inhibitor from the Marine Sponge Hyrtios erectus, Shows Extensive Cellular Effects on PI3K/AKT Activation, Glucose Transport, and TGFβ/Smad2 Signaling

Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling, and PTP1B inhibitors have been seen as promising therapeutic agents against obesity and type 2 diabetes. Here we report that the marine natural product hyrtiosal, from the marine sponge Hyrtios erectus, has been discovered to act as a PTP1B inhibitor and to show extensive cellular effects on PI3K/AKT activation, glucose transport, and TGFβ/Smad2 signaling. This inhibitor wad able to inhibit PTP1B activity in dose‐dependent fashion, with an IC50 value of 42 μM in a noncompetitive inhibition mode. Further study with an IN Cell Analyzer 1000 cellular fluorescence imaging instrument showed that hyrtiosal displayed potent activity in abolishing the retardation of AKT membrane translocation caused by PTP1B overexpression in CHO cells. Moreover, it was found that this newly identified PTP1B inhibitor could dramatically enhance the membrane translocation of the key glucose transporter Glut4 in PTP1B‐overexpressed CHO cells. Additionally, in view of our recent finding that PTP1B was able to modulate insulin‐mediated inhibition of Smad2 activation, hyrtiosal was also tested for its capabilities in the regulation of Smad2 activity through the PI3K/AKT pathway. The results showed that hyrtiosal could effectively facilitate insulin inhibition of Smad2 activation. Our current study is expected to supply new clues for the discovery of PTP1B inhibitors from marine natural products, while the newly identified PTP1B inhibitor hyrtiosal might serve as a potential lead compound for further research.