Natural disesquiterpenoids: an update.

Covering: July 2010 to August 2019. Previous review: Nat. Prod. Rep., 2011, 28, 594The review covers recent progress on the isolation, identification, bioactivity and biomimetic synthesis of natural dimeric sesquiterpenoids, along with a detailed discussion of the biogenesis of these metabolites. Structural revisions are included.

Streptomyces albogriseolus SY67903 Produces Eunicellin Diterpenoids Structurally Similar to Terpenes of the Gorgonian Muricella sibogae, the Bacterial Source.

Microeunicellols A (1) and B (2), two undescribed eunicellin diterpenoids, were isolated from the culture of a bacterial symbiont, Streptomyces albogriseolus SY67903. Their structures, including absolute configurations revealed by spectroscopic data and single-crystal X-ray diffraction analysis, are closely related with the diterpenoids from its host, a South China Sea gorgonian, Muricella sibogae. This is the first report of eunicellin diterpenoids, commonly coral-derived, from a bacterial symbiont of coral. The chemical metabolic relationship between the bacterium and its host is discussed. Biological evaluation revealed that compound 1 possessed cytotoxicities against several human cancer cell lines.

[Thermosensitive gel of polysaccharide from Ganoderma applanatum combined with paclitaxel for mice with 4T1 breast cancer].

Polysaccharide from Ganoderma applanatum has the activities of anti-tumor and enhancing immune function. There were no reports on antitumor effect of its intratumoral injection. In this study, the polysaccharide was extracted from G. applanatum by water extraction and alcohol precipitation, and purified by ceramic membrane after removing protein by Sevage method. The total polysaccharide content from G. applanatum(PGA)was about 63%. The combination of PGA and paclitaxel showed synergistic effect on cytotoxicity of 4 T1 cells at lower concentrations in vitro. In addition, the growth curve of 4 T1 cells showed that PGA could retard the growth of 4 T1 cells gradually. The PGA thermosensitive gel(PGA-TG)was prepared by using poloxamer 188 and 407. The gel temperature was 36 ℃, and the PGA-TG could effectively slow down the release rate of PGA in vitro. 4 T1 breast cancer-bearing mice were used as a model to evaluate the therapeutic effect of intratumoral injection of PGA combined with tail vein injection of nanoparticle albumin-bound paclitaxel(nab-PTX). In high and low dose PGA groups, each mice was given with 2.25, 1.125 mg PGA respectively, twice in total, and the dosage of paclitaxel was 15 mg·kg~(-1), once every 3 days, for a total of five times. The tumor inhibition rate was 29.65% in the high dose PGA-TG group, 58.58% in the nab-PTX group, 63.37% in low dose PGA-TG combined with nab-PTX group, and 68.10% in high dose PGA-TG combined with nab-PTX group respectively. The inhibitory effect in high dose PGA-TG group combined with nab-PTX on tumors was significantly higher than that in nab-PTX group(P<0.05). The results showed that paclitaxel therapy combined with intratumoral injection of PGA-TG could improve the therapeutic effect for 4 T1 mice and reduce the side effects of chemotherapy.

Synthesis and anti-tumor activity study of water-soluble PEG-celastrol coupling derivatives as self-assembled nanoparticles.

To improve the drug-ability of celastrol, a series of PEGylation celastrol (PEGC) were designed and synthesized by conjugation with different kinds of polyethylene glycols (PEGs) with celastrol. Most of PEGCs could easily dissolve in water. In particular, one of them (DC1000) could be dispersed in water to form nanoparticles by self-assembly. The cytotoxic evaluation of PEGCs revealed that some of PEGCs showed more potent cytotoxicity than celastrol, and the molecular weight of PEG parts in PEGCs had apparent influence on their cytotoxic activity. Anti-tumor evaluation in vivo showed DC1000 had higher tumor inhibition rate and better safety than celastrol by intravenous administration with equivalent molar weight. These results revealed PEGylation might be an efficient and economical method to improve the water solubility and safety of celastrol and similar natural products.

New Immunomodulating Polyhydroxypregnane Glycosides from the Roots of Cynanchum otophyllum C.K.Schneid.

Seven new polyhydroxypregnane glycosides, named cynotophyllosides P-V, together with three known analogs were isolated from the roots of Cynanchum otophyllum C.K.Schneid. Their structures were elucidated by a variety of spectroscopic techniques, as well as acid-catalyzed hydrolysis. All isolates were tested for their immunological activities in vitro against Con A- and LPS-induced proliferation of mice splenocytes. Immunoenhancing (for 1, 9) and immunosuppressive (for 2) activities were observed. Furthermore, cynotophylloside R (3) showed immunomodulatory as it enhanced the proliferation of splenocytes in low concentration and suppressed immune cells in concentration more than 1.0 µg/ml.

Biotransformation of Huperzine B by a Fungal Endophyte of Huperzia serrata.

The biotransformation of huperzine B (hupB), one of the characteristic bioactive constituents of the medicinal plant Huperzia serrata, by a fungal endophyte of the host plant was studied. One new compound, 8α,15α-epoxyhuperzine B (1), along with two known oxygenated hupB analogs, 16-hydroxyhuperzine B (2) and carinatumin B (3), was isolated and identified. The structures of all the isolates were deduced by spectroscopic methods including NMR, MS, IR, and UV spectra. The known compounds 2 and 3 were obtained from a microbial source for the first time. To the best of our knowledge, it is the first report on the microbial transformation of hupB and would facilitate further structural modification of hupB by chemo-enzymatic method. In the LPS-induced neuro-inflammation injury assay, 8α,15α-epoxyhuperzine B (1) exhibited moderate neuroprotective activity by increasing the viability of U251 cell lines with an EC50 of 40.1 nm.

Studies on the Chemical Diversities of Secondary Metabolites Produced by Neosartorya fischeri via the OSMAC Method.

The One Strain Many Compounds (OSMAC) method was applied to explore the chemical diversities of secondary metabolites produced by Neosartorya fischeri NRRL 181. Four pyripyropenes 1⁻4, eight steroids 5⁻11, and four prenylated indole alkaloids 12⁻15, were obtained from the fungus cultured in petri dishes containing potato dextrose agar (PDA). 1,7,11-trideacetylpyripyropene A (1) and 1,11-dideacetyl pyripyropene A (2) were obtained and spectroscopically characterized (1D, 2D NMR, and HR-ESI-MS) from a natural source for the first time. It offered a sustainable source of these two compounds, which were usually used as starting materials in preparing pyripyropene derivatives. In addition, as compared with all the other naturally occurring pyripyropenes, 1 and 2 possessed unique acetylation patterns that did not follow the established late-step biosynthetic rules of pyripyropenes. The natural occurrence of 1 and 2 in the fungus implied that the timing and order of hydroxylation and acetylation in the late-step biosynthetic pathway of pyripyropenes remained to be revealed. The isolation and identification of 1⁻15 indicated that the OSMAC method could remarkably alter the metabolic profile and enrich the chemical diversities of fungal metabolites. Compounds 1⁻4 exhibited no obvious cytotoxicity against the triple-negative breast cancer cell line MDA-MB-231 as compared with taxol.

Synthesis of 3- and 29-substituted celastrol derivatives and structure-activity relationship studies of their cytotoxic activities.

A series of 3-carbamate and 29-ester celastrol derivatives (compounds 1-26) were designed and synthesized. These analogues were evaluated for their cytotoxic activities against several cancer cell lines. Cytotoxicity data revealed that the properties of substituents and substitution position had important influence on cytotoxic activity. Modification of C-3 hydroxyl with size-limited groups did not reduce the activity obviously. The introduction of polarity group like piperazine could improve the solubility. Compound 23 was chosen to further evaluate anti-tumor efficacy in vivo. It showed higher inhibition rate and better safety than celastrol during in vivo experiment by intragastric administration. The preliminary antitumor studies of compound 23in vivo showed that it might be promising for the development of new antitumor agents.

New Eudesmane Sesquiterpenoids from Salvia plebeia R. Br.

Three new sesquiterpenoids, salplebeones A - C (1 - 3), were isolated from the ethanol-soluble extract of the aerial part of Salvia plebeia R. Br. Their structures were established by detailed analysis of NMR and MS spectra. Salplebeone A was an eudesmane lactone, while salplebeones B and C were rare eudesmane sesquiterpenoids, containing 12,8-lactam groups. Antiproliferative activities of salplebeones A - C to myeloid leukemia cell lines were evaluated.

Bergamotane Sesquiterpenes with Alpha-Glucosidase Inhibitory Activity from the Plant Pathogenic Fungus Penicillium expansum.

Two new bergamotane sesquiterpene lactones, named expansolides C and D (1 and 2), together with two known compounds expansolides A and B (3 and 4), were isolated from the plant pathogenic fungus Penicillium expansum ACCC37275. The structures of the new compounds were established by detailed analyses of the spectroscopic data, especially 1D-, 2D-NMR, and HR-ESI-MS. In an in vitro bioassay, the epimeric mixture of expansolides C and D (1 and 2) (in a ratio of 2:1 at the temprature of the bioassay) exhibited more potent α-glucosidase inhibitory activity (IC50 =0.50 ± 0.02 mm) as compared with the positive control acarbose (IC50 = 1.90 ± 0.05 mm). To the best of our knowledge, it was the first report on the α-glucosidase inhibitory activity of bergamotane sesquiterpenes.

Preparation and evaluation of metoprolol tartrate sustained-release pellets using hot melt extrusion combined with hot melt coating.

The objective of this study was to prepare and evaluate metoprolol tartrate sustained-release pellets. Cores were prepared by hot melt extrusion and coated pellets were prepared by hot melt coating. Cores were found to exist in a single-phase state and drug in amorphous form. Plasticizers had a significant effect on torque and drug content, while release modifiers and coating level significantly affected the drug-release behavior. The mechanisms of drug release from cores and coated pellets were Fickian diffusion and diffusion-erosion. The coated pellets exhibited sustained-release properties in vitro and in vivo.

Effects of astaxanthin on blood coagulation, fibrinolysis and platelet aggregation in hyperlipidemic rats.

CONTEXT: Astaxanthin (ASTX) is a xanthophyll carotenoid that reduces hemostasis in hyperlipidemic organisms. Its antihemostatic mechanisms remain unclear. OBJECTIVE: The effects of ASTX on coagulation, the fibrinolytic system and platelet aggregation were investigated in hyperlipidemic rats. MATERIALS AND METHODS: Different doses of ASTX (5, 10 and 30 mg/kg/day, p.o.) were administered for four weeks to high-fat diet-induced hyperlipidemic rats. Serum lipid and lipoprotein levels were measured with an automatic biochemical analyzer. The prothrombin time (PT), activated partial thromboplastin time (APTT) and maximum platelet aggregation rate (MAR) were determined by a coagulation analyzer. The activities of the tissue-type plasminogen activator (t-PA), type-1 plasminogen activator inhibitor (PAI-1) and endothelial nitric oxide synthase (eNOS), as well as the levels of thromboxane B(2) [TXB(2)], 6-keto prostaglandin F(1α) [6-keto-PGF(1α)] and platelet granule membrane protein (GMP-140), were measured with enzyme-linked immunosorbent assay kits. Gene and protein expression levels were analyzed by reverse transcriptase polymerase chain reaction and Western blot, respectively. RESULTS: ASTX (30 mg/kg) treatment in hyperlipidemic rats reduced serum TG (0.58 ± 0.14 versus 1.12 ± 0.24 mmol/L), serum TC (1.77 ± 0.22 versus 2.24 ± 0.21 mmol/L), serum LDL-C (1.13 ± 0.32 versus 2.04 ± 0.48 mmol/L), serum MDA (69%), plasma MAR (55%), serum TXB2/6-keto-PGF1α (34%) and serum GMP-140 levels (25%), plasma PAI-1 activity (48%) and downregulated the mRNA (33%) and protein (23%) expression of aorta eNOS, the mRNA (79%) and protein (72%) expression levels of aorta PAI-1. However, ASTX (30 mg/kg/d) treatment increased serum SOD activity (2.1 fold), serum GPx activity (1.8 fold), plasma PT (1.3 fold), plasma APTT (1.7 fold), serum NO (1.4-fold), serum 6-keto-PGF1α (1.3 fold). CONCLUSIONS: ASTX reduced blood coagulation and platelet aggregation and promoted fibrinolytic activity in hyperlipidemic rats. These activities were closely correlated with ASTX, maintaining the balance of t-PA/PAI-1, NO/ROS and TXA2/PGI2 in vivo.

Simulation and evaluation of tablet-coating burst based on finite element method.

The objective of this study was to simulate and evaluate the burst behavior of coated tablets. Three-dimensional finite element models of tablet-coating were established using software ANSYS. Swelling pressure of cores was measured by a self-made device and applied at the internal surface of the models. Mechanical properties of the polymer film were determined using a texture analyzer and applied as material properties of the models. The resulted finite element models were validated by experimental data. The validated models were used to assess the factors those influenced burst behavior and predict the coating burst behavior. The simulation results of coating burst and failure location were strongly matched with the experimental data. It was found that internal swelling pressure, inside corner radius and corner thickness were three main factors controlling the stress distribution and burst behavior. Based on the linear relationship between the internal pressure and the maximum principle stress on coating, burst pressure of coatings was calculated and used to predict the burst behavior. This study demonstrated that burst behavior of coated tablets could be simulated and evaluated by finite element method.

[Preparation and in vitro dissolution of magnolol solid dispersion].

In this study, solid dispersion system of magnolol in croscarmellose sodium was prepared by using the solvent evaporation method, in order to increase the drug dissolution. And its dissolution behavior, stability and physical characteristics were studied. The solid dispersion was prepared with magnolol and croscarmellose sodium, with the proportion of 1∶5, the in vitro dissolution of magnolol solid dispersion was up to 80.66% at 120 min, which was 6.9 times of magnolol. The results of DSC (differential scanning calorimetry), IR (infra-red) spectrum and SEM (scanning electron microscopy) showed that magnolol existed in solid dispersion in an amorphous form. After an accelerated stability test for six months, the drug dissolution and content in magnolol solid dispersion showed no significant change. So the solid dispersion prepared with croscarmellose sodium as the carrier can remarkably improve the stability and dissolution of magnolol.

α-Glucosidase Inhibitors from the Fungus Aspergillus terreus 3.05358.

One new diketopiperazine alkaloid amauromine B (1), along with three known meroterpenoids, austalide B (2), austalides N and O (3 and 4), and two known steroids (5 and 6), was isolated and identified from the culture broth of the fungus Aspergillus terreus 3.05358. Their structures were elucidated by extensive spectroscopic techniques, including 2D-NMR and MS analysis, the absolute configuration of 1 was unambiguously established by single crystal X-ray diffraction analysis. All the isolates were evaluated for their inhibitory effects on α-glucosidase. Amauromine B (1) and austalide N (3) exhibited more potent α-glucosidase inhibitory activities than the positive control acarbose.

Lupane- and Friedelane-Type Triterpenoids from Celastrus stylosus.

Two new triterpenoids, 30-hydroxylup-20(29)-ene 3ß-caffeate (1) and 24-nor-friedelan-6α,10-dihydroxy-1,2-dioxo-4,7-dien-29-oic acid (2), together with eight known compounds 3-10, were isolated from the roots of Celastrus stylosus. The structures of these compounds were elucidated on the basis of spectroscopic analyses. To the best of our knowledge, this represents the first study on the chemical constituents of C. stylosus. The antiproliferative activities of the triterpenoids against six human cancer cell lines (PANC-1, A549, PC-3, HepG2, SGC-7901, and HCCLM3) were evaluated. Compounds 3, 4, and 10 exhibited comparable activities against PC-3 and HCCLM3 cell lines as the positive control taxol.

Biotransformation of huperzine A by a fungal endophyte of Huperzia serrata furnished sesquiterpenoid-alkaloid hybrids.

Biotransformation of huperzine A (hupA) by a fungal endophyte, Ceriporia lacerate HS-ZJUT-C13A, afforded compounds 1-5 and three tremulane sesquiterpenoids, 6-8. Huptremules A-D (1-4) feature unusual sesquiterpenoid-alkaloid hybrid structures that integrate the characteristics of fungal metabolites (tremulane sesquiterpenoids) and the exogenous substrate (hupA). These results support the use of fungal endophytes as biocatalysts for the biotransformation of natural products, particularly those originating from the host plant.

Natural friedelanes.

This review covers the occurrence and biological activities of all natural friedelane triterpenoids found between 1977 and March 2011. The biogeneses of dimeric friedelanes and several rearranged friedelanes are discussed. The pharmacological properties of representative compounds, including celastrol and correolide, have also been compiled, on the basis of 344 references.

Diterpenoids and a diarylheptanoid from Hedychium coronarium with significant anti-angiogenic and cytotoxic activities.

Two new labdane diterpenoids, namely hedycoronals A and B (1 and 2, resp.), were isolated from the rhizomes of Hedychium coronarium, together with eight known diterpenoids, 4-11, and a known diarylheptanoid, 3. The structures of 1 and 2 were established by detailed interpretation of their 1D- and 2D-NMR spectra and HR-ESI-MS data. Inhibitory activities against human umbilical vein endothelial cells (HUMECs) proliferation and cytotoxic activities against four cancer cell lines were assessed for all the isolates. Most of these metabolites showed moderate or potent cytotoxic activities against four cancer cell lines. Moreover, compounds 3 and 8 exhibited promising inhibitory activities against HUMECs with the IC(50) values of 6.4 to 3.3 µM.

Two new metabolites from a soil fungus Curvularia affinis strain HS-FG-196.

Two new metabolites, pyrenocine J (1) and pyrenochaetic acid D (2), together with two known metabolites, pyrenocine A (3) and pyrenochaetic acid A (4), were isolated from a soil fungus, Curvularia affinis strain HS-FG-196. Their structures were established by extensive spectroscopic analysis. Compound 1 showed cytotoxic activity against the human hepatic cancer cell line HepG2 with an IC(50) value of 28.5 µg/ml.