Tigliane type macrocyclic diterpenoids with special structures and diverse bioactivities are mainly extracted from plants of Euphorbiaceae and Thymelaeaceae. According to the different functional groups, they can be classified into types of phorbol esters, C-4 deoxyphorbol esters, C-12 deoxyphorbol esters, C-16 or C-17 substituted phorbol esters and others. Most of them present promising antiviral activities and cytotoxic activities and are expected to be developed as candidates for anti-AIDS, anti-tuberculosis, and anti-tumor clinical trials, demonstrating great potential for the application in healthcare. This paper reviews 115 novel tigliane-type diterpenoids discovered since 2013 and summarize their chemical structures and bioactivities, aiming to lay a foundation for further development and utilization of these compounds and provide new ideas for the development of clinical drugs.
Phorbols ; Molecular Structure ; Diterpenes/chemistry* ; Antiviral Agents ; Phorbol Esters

OBJECTIVETo analyze the content of tanshinone IIA in Radix Salviae Miltiorrhizae from different habitats are regularly altered and find out the deviation between the studies.

METHODThe data of the content of tanshinone IIA in samples of Radix Salviae Miltiorrhizae from different areas and related information since 1997 was collected and statistically analyzed.

RESULT AND CONCLUSIONThe content of tanshinone IIA in wild Salvia was generally higher than that in the cultivated Salvia, and the content in nearly half cultivated Salvia was less than 0.2%. There existed a big difference between the used statistical model, and the data related the content in samples from Sichuan was the most divisive. The coefficient of variation of wild Salvia was below the cultivated Salvia, and the cultivated Salvia from different areas showed different coefficients of variation. The content of tanshinone IIA was lower when samples were extracted using the heating reflux method.

Diterpenes, Abietane ; Phenanthrenes ; analysis ; Salvia miltiorrhiza ; chemistry

OBJECTIVETo compare the influence on the dissolution of tanshinone IIA (TS IIA) solid dispersions in complex carriers and single, which used in preparation of TS IIA solid dispersions, and further enhance the dissolution of TS IIA.

METHODThe TS IIA solid dispersions were prepared by solvent technique with polyvinylpyrrolidone K30 (PVPK30), poloxamer188 (F68) and combination of PVPK30 and F68 as carriers, respectively. The physical characteristics of TS IIA solid dispersions was studied using differential scanning calorimetry (DSC). Dissolution rates were studied using small cup method (CHP XC III). The solubility of TS IIA with the solid dispersions and pure drug form were determined by HPLC method.

RESULTThe DSC analysis suggested that TS IIA was dispersed as an amorphous form in the combination of PVPK30 and F68. Dissolution profile of the prepared solid dispersions could be described by Weibull equation (R>0.99). For tested three carries, Td value (calculated time to 63.2% of total drug release according to Weibull equation) were (90.40 +/- 2.82) min, (204.5 +/- 8.20) min and (25.83 +/- 0.13) min, respectively. The PVPK30/F68-TS IIA solid dispersion resulted in a significant increase of TS IIA solubility compared with prepared PVPK30-TS IIA and F68-TS IIA solid dispersions (P<0.01).

CONCLUSIONAs compared to single use of PVPK30 or F68, the combination of PVPK30 and F68 improve the dissolution rate and solubility of TS IIA significantly in the prepared solid dispersions (P<0.01). The application of complex carriers in solid dispersion technology should be paid more attention to improvement of poorly soluble drugs dissolution in the future.

Diterpenes, Abietane ; Phenanthrenes ; chemistry ; Solubility ; Temperature

The technique of liquisolid compress is a new technique developed in 1990s, which was considered to be the most promising technique to improve the dissolution of water-insoluble drugs. In this article, tanshinone II(A) and the extracts of the ester-solubility fractions were chosen as the model drugs to evaluate the effects of the liquisolid technique for enhancement of dissolution properties of tanshinone II(A). Several liquisolid tablets (LS) formulations containing different dosage of drugs and various liquid vehicle were pre-pared and for all the formulations, microcrystalline cellulose and silica were chosen as the carrier and coating materials to evaluate their flow properties, such as angle of repose, Carr's compressibility index and Hausner's ratio. The interaction between drug and excipients in prepared LS compacts were studied by differential scanning calorimetry(DSC) and X-ray powder diffraction (XRPD). The dissolution curves of tanshinone II(A) from liquisolid compacts were investigated to determine the technique's effect in improving the dissolution of tanshinone II(A) and its impacting factors. According to the results, the dissolution increased with the rise in the dissolution of the liquid-phase solvent. The R-value and drug dosage can significantly affect the drug release, but with less impact on active fractions. This indicated that liquisolid technique is a promising alternative for improvement of dissolution property of water-soluble drugs, and can make a synergistic effect with other ester-soluble constituents and bettern improve the release of tanshinone II(A). Therefore, the technique of liquisolid compress will have a better development prospect in traditional Chinese medicines.
Calorimetry, Differential Scanning ; Diterpenes, Abietane ; chemistry ; Solubility ; X-Ray Diffraction

OBJECTIVETo study chemical constituents from pine cone of Pinus annandii.

METHODThe constituents were isolated by chromatographic method and the structures were identified on the basis of spectral analysis.

RESULTSeven compounds were identified as sandaracopimaric acid (I), isodextropimaric acid (II), 12-hydroxyabietic acid (III), dehydroabietic acid (IV), 15-hydroxydehydroabietic acid (V), beta-sitosterol (VI) and daucosterol (VII).

CONCLUSIONCompounds I-IV were isolated from this plant for the first time.

Diterpenes ; chemistry ; isolation & purification ; Diterpenes, Abietane ; chemistry ; isolation & purification ; Fruit ; chemistry ; Pinus ; chemistry ; Plants, Medicinal ; chemistry ; Sitosterols ; chemistry ; isolation & purification

Acetates ; metabolism ; Animals ; Antineoplastic Agents, Phytogenic ; metabolism ; pharmacokinetics ; Biotransformation ; Diterpenes ; metabolism ; Paclitaxel ; metabolism ; Taxoids ; metabolism ; pharmacokinetics

Thioredoxin reductase (TrxR) is one class of the most important antioxidant selenoproteins and is involved in regulating tumor genesis and progression. It has been reported that naphthoquinones can target and inhibit TrxR1 activity therefore produce reactive oxygen species (ROS) mediated by TrxR1, resulting into cellular redox imbalance and making the naphthoquinone compounds to become potential antitumor chemotherapy drugs. The purpose of this work is to explore the interaction between TrxR1 and menadione using biochemical and mass-spectrometric (MS) analyses, to further reveal the detailed mechanisms of TrxR1-mediated naphthoquinone reduction and inhibition of TrxR1 by naphthoquinone compounds. Using the site-directed mutagenesis and recombinantly expressed TrxR1 variants, we measured the steady-state kinetic parameters of menadione reduction mediated by TrxR1 and its variants, performed the inhibition analysis of menadione on TrxR1 activity, and eventually identified the interaction between menadione and TrxR1 through MS analysis. We found that Sec-to-Cys mutation at residue of 498 significantly enhanced the efficiency of TrxR1-mediated menadione reduction, though the Sec⁴⁹⁸ is capable to catalyze the menadione reduction, indicating that TrxR1-mediated menadione reduction is dominantly in a Se-independent manner. Mutation experiments showed that Cys⁴⁹⁸ is mainly responsible for menadione catalysis in comparison to Cys⁴⁹⁷, while the N-terminal Cys⁶⁴ is slightly stronger than Cys⁵⁹ regarding the menadione reduction. LC-MS results detected that TrxR1 was arylated with one molecule of menadione, suggesting that menadione irreversibly modified the hyper-reactive Sec residue at the C-terminus of selenoprotein TrxR1. This study revealed that TrxR1 catalyzes the reduction of menadione in a Se-independent manner meanwhile its activity is irreversibly inhibited by menadione. Hereby it will be useful for the research and development of naphthoquinone anticancer drugs targeting TrxR1.
Catalysis ; Drug Development ; Oxidation-Reduction ; Thioredoxin Reductase 1/metabolism* ; Vitamin K 3/metabolism*

BACKGROUND/AIMS: Ecabet sodium is known for its bactericidal effect against H. pylori. It was reported that a supplement of ecabet sodium to conventional triple therapy showed good results in Asia. The Aim of this study was to ascertain the efficacy of additional ecabet sodium on conventional triple therapy for eradication of H. pylori. METHODS: We reviewed the cases of 111 patients (Group A) with H. pylori infection who received ecabet sodium with triple therapy (20 mg of rabeprazole, 1 g of amoxicillin, 500 mg of clarithromycin and 1 g of ecabet sodium, twice daily for 7 days). Another 186 patients (Group B) received PPI-based triple therapy (same as the above, except without the ecabet sodium). Eradication was evaluated 4 weeks later after completion of treatment by 13C-UBT. RESULTS: Eradication rates were 74.8% (83/111) in group A and 70.4% (131/186) in group B by intention-to-treat analysis (p=0.420), and 75.2% (82/109) in group A and 70.7% (128/181) in group B by per protocol analysis (p=0.405). CONCLUSIONS: The addition of ecabet sodium to conventional triple therapy did not increase the eradication rate of H. pylori in this study. These findings imply that ecabet sodium as an additional agent cannot overcome antibiotic resistance, which is the most important cause of failure of triple therapy.
2-Pyridinylmethylsulfinylbenzimidazoles ; Amoxicillin ; Asia ; Clarithromycin ; Diterpenes, Abietane ; Drug Resistance, Microbial ; Helicobacter ; Helicobacter pylori ; Humans ; Korea ; Sodium

Fingerprints of lipophilic components in the roots of Salvia miltiorrhiza and S.yunnanensis were analyzed by UPLC-DADand UPLC coupled with mass spectroscopy to evaluate the differences and similarities of the lipophilic components in the two kinds of herbs.The UPLC analysis of 18 batches of S.miltiorrhiza and 16 batches of S.yunnanensis was performed on a 25℃Thermo Accucore C_(18)column(2.1 mm×100 mm,2.6μm)by Shimadzu LC-20AD;mobile phase was 0.026%phosphoric acid(A)-acetonitrile(B)with gradient elution;flow rate was 0.4 m L·min~(-1);detection wavelength was set at 270 nm;injection volume was 2μL.The molecular structures of the lipophilic components were analyzed on a 25℃Thermo Accucore C_(18)column(2.1 mm×100 mm,2.6μm)by Thermo U3000 UPLC Q Exactive Orbitrap LC-MS/MS with a mobile phaseconsisting of 0.1%formic acid water(A)and 0.1%formic acidacetonitrile(B).The mass spectrometry was acquired in positive modes using ESI.There are 10 common peaks in the lipophilic components of S.miltiorrhiza.The similarity between the 16 batches of S.miltiorrhiza and their own reference spectra was greater than 0.942,and the average similarity was 0.973.There are 12 common peaks in the lipophilic components of S.yunnanensis.The similarity between the 18 batches of S.yunnanensis and their own reference spectra was greater than 0.937,and the average similarity was 0.976.The similarity between the reference chromatograms of S.miltiorrhiza and S.yunnanensis was only 0.900.There are three lipophilic components in S.yunnanensis,which are not found in S.miltiorrhiza,and one of which isα-lapachone.There is a lipophilic component in S.miltiorrhiza not found in S.yunnanensis,which may be miltirone.The two herbs contain 8 common lipophilic components including dihydrotanshinoneⅠ,cryptotanshinone,tanshinoneⅠ,tanshinoneⅡ_A,nortanshinone in which the content of tanshinoneⅡ_A,dihydrotanshinoneⅠand cryptotanshinone of S.yunnanensisis significantly lower than that of S.miltiorrhiza(P<0.01),and the contents of tanshinoneⅠand nortanshinone are significantly lower than that of S.miltiorrhiza too(P<0.05).There are significant differences in the types and contents of lipophilic components between the roots of S.miltiorrhiza and S.yunnanensis,and the similarity between the fingerprints of interspecies is much lower than that between the same species.Therefore,the roots of S.miltiorrhiza and S.yunnanensis are two kinds of herbs which are quite different in chemical compounds and compositions.
Chromatography, Liquid ; Diterpenes, Abietane ; Molecular Structure ; Plant Roots ; Salvia miltiorrhiza ; Tandem Mass Spectrometry

An efficient method of ultra-high performance liquid chromatography coupled with linear ion trap-Orbitrap (UHPLC-LTQ-Orbitrap) mass spectrometer was established to elucidate the metabolites of tanshinone Ⅰ and tanshinone ⅡA in rats. Urine and plasma samples were collected after oral gavage. After processing biological sample by solid phase extraction, Waters ACQUITY HPLC BEH C₁₈ column (2.1 mm×100 mm, 1.7 μm) was used with 0.1% formic acid (A) - acetonitrile (B) solution as the mobile phase for gradient elution. The plasma, urine and the blank samples were then analyzed by ESI-LTQ-Orbitrap equipped with an ESI ion source under positive ion mode. On the basis of the accurate mass measurements, multiple mass spectra and comparison of data with published literature, a total of 26 metabolites were tentatively identified and characterized in the rat samples. Among them, 7 metabolites were derived from tanshinone Ⅰ through metabolic pathways of glucuronide conjugation, hydroxylation, reduction reaction, demethylation reaction, methylation, sulfate conjugation and their composite reactions. Nineteen metabolites were derived from tanshinone ⅡA through metabolic pathways of hydroxylation, reduction reaction, methylation, sulfate conjugation, glucuronidation, glucosylation and their complicated reactions. The results showed that the metabolism of tanshinone Ⅰ and tanshinone ⅡA in rats could be comprehensively clarified by using UHPLC-LTQ-Orbitrap mass spectrometer, providing material basis for the further research in terms of pharmacodynamics, toxicology, and secondary development of Chinese medicine.
Animals ; Chromatography, High Pressure Liquid ; Diterpenes, Abietane ; blood ; metabolism ; urine ; Rats