A New Benzylisoquinoline Alkaloid from Sabia parviflora

A new benzylisoquinoline alkaloid, 1, 2, 3, 4-tetrahydro-5-hydroxyl-8-methoxyl-2- methyl-4'-methoxyl-benzylisoquinoline, was isolated from the arial parts of Sabia parviflora. Its structure was established on the basis of spectral analysis.

A new benzylisoquinoline alkaloid from stems of Nelumbo nucifera

A new benzylisoquinoline alkaloid, named nelumstemine （1）, 1-（4＇-hydroxybenzoyl）-6,7-dimethoxy-3,4-dihydroisoquinoline, was isolated from the stems of Nelumbo nucifera Geartn. Its structure was established on the basis of spectral analysis.

The Genome of Medicinal Plant Macleaya cordata Provides New Insights into Benzylisoquinoline Alkaloids Metabolism

The overuse of antibiotics in animal agriculture and medicine has caused a series of potential threats to public health. Macleaya cordata is a medicinal plant species from the Papaveraceae family, providing a safe resource for the manufacture of antimicrobial feed additive for livestock. The active constituents from M. cordata are known to include benzylisoquinoline alkaloids （BIAs） such as sanguinarine （SAN） and chelerythrine （CHE）, but their metabolic pathways have yet to be studied in this non-model plant. The active biosynthesis of SAN and CHE in M. cordata was first examined and confirmed by feeding ^13C-labeled tyrosine. To gain further insights, we de novo sequenced the whole genome of M. cordata, the first to be sequenced from the Papaveraceae family. The M. cordata genome covering 378 Mb encodes 22,328 predicted protein-coding genes with 43.5% being transposable elements. As a member of basal eudicot, M. cordata genome lacks the paleohexaploidy event that occurred in almost all eudicots. From the genomics data, a complete set of 16 metabolic genes for SAN and CHE biosynthesis was retrieved, and 14 of their biochemical activities were validated. These genomics and metabolic data show the conserved BIA metabolic pathways in M. cordata and provide the knowledge foundation for future productions of SAN and CHE by crop improvement or microbial pathway reconstruction.

Enzymatic biosynthesis of benzylisoquinoline alkaloid glycosides via promiscuous glycosyltransferases from Carthamus tinctorius

Enzymatic glycosylation catalyzed by glycosyltransferases (GTs) has great potential in creating diverse novel and bioactive glycosides. Herein, three new GTs (UGT84 A33, UGT71 AE1 and UGT90 A14) from Carthamus tinctorius exhibited robust catalytic promiscuity to benzylisoquinoline alkaloids, and were used as enzymatic tools in glycosylation of bioactive benzylisoquinoline alkaloids. Seven novel benzylisoquinoline alkaloids O-glycosides were synthesized with high efficiency. These studies indicate the significant potential of promiscuous GTs in synthesis of benzylisoquinoline alkaloids glycosides for drug discovery.

Synthesis and evaluation of benzylisoquinoline derivatives for their inhibition on pancreatic lipase and preadipocyte proliferation

The present study was designed to synthesize and evaluate a series of benzylisoquinoline derivatives. These compounds were synthesized by Bischler-Napieralski cyclization to yield 1-benzyl-3,4-dihydroisoquinolines, and the products were obtained by reductions. All these compounds were identified by MS, 1H NMR and 13 C NMR. The inhibitory activities on pancreatic lipase and preadipocyte proliferation for the synthesized compounds and alkaloids from Nulembo nucifera were assessed in vitro. Most of the compounds showed inhibitory activities on both pancreatic lipase and preadipocyte proliferation. Particularly, compounds 7p-7u and 9d-9f exhibited significant inhibitory activity on pancreatic lipase while compounds 7c, 7d, 7f, 7g, 7i, and 7j potently inhibited the proliferation of 3T3-L1 preadipocytes. Our results provided a basis for future evaluation and development of these compounds as leads for therapeutics for human diseases.

Engineering Saccharomyces cerevisiae to produce plant benzylisoquinoline alkaloids

Benzylisoquinoline alkaloids(BIAs)are a diverse family of plant natural products with extensive pharmacological properties,but the yield of BIAs from plant is limited.The understanding of BIA biosynthetic mechanism in plant and the development of synthetic biology enable the possibility to produce BIAs through microbial fermentation,as an alternative to agriculture-based supply chains.In this review,we discussed the engineering strategies to synthesize BIAs in Saccharomyces cerevisiae(yeast)and improve BIA production level,including heterologous pathway reconstruction,enzyme engi neering,expression regulation,host engineering and fermentation engineering.We also highlight recent meta bolic engineering advances in the production of BIAs in yeast.

UPLC-QTOF-MS FOR METABOLITES IDENTIFICATION IN CACO-2 CELLS OF BENZYLISOQUINOLINE ALKALOIDS IN NELUMBINIS PLUMULA

The aim of the study was to identify main metabolites of benzylisoquinoline alkaloids from Nelumbinis Plumula after biotransformation by Caco-2 cells.Caco-2 cells were seeded to a 6-well plate and cultured for a period of time until 80%of each well was filled with cells.Then,cell medium was replaced and the norcoclaurine,liensinine,isoliensinine and neferine were respectively added to

Pharmacology of tetrandrine and its therapeutic use in digestive diseases

INTRODUCTIONTetrandrine (Tet) is a dibenzylisoquinoline alkaloid isolatedfrom Stephania tetrandra S. Moore, a Chinese herbalmedicine. In the past decade, lots of studies demonstrated that Tet has multiple bioactivities, It is promising to use Tet as an antifibrogenetic in liver or lung fibrosis with or without portal or pulmonary hypertension, as well as an immunomodulating and anticarcinoma drug.

The Effect of calmodulin antagonist berbaminederivative-EBB on hepatoma in vitro and in vivo

OBJECTIVE: To evaluate the anti-hepatoma effect of Calmodulin antagonist 0 - 4-ethoxyl-butyl-Berbamine (EBB), one of the berbamine derivatives. METHODS: Monotetrazolium (MTT) method was used to analyze the effect of EBB on the proliferation and growth inhibition effect. Of a hepatoma cell line in vitro. A mouse hepatoma model was induced by injection of hepatoma cells (H22) in the abdominal cavity. The effect of EBB on survival at different concentrations as well as in combination with 5-FU were investigated in vivo. Flow cytometry analysis, dot blot hybridization, western blot, immunochemistry, enzyme-linked lectin assay (ELISA), trifluoperazine (TFP) and electron microscopic observation were used to study the effect of EBB on cell cycle process, P53 mRNA and protein levels, calmodulin content and ultrastractural changes of hepatoma cells. RESULTS: EBB exerts a very strong inhibitory effect on human hepatoma cell line 7402 and mouse hepatoma cell line H22 in vitro. The IC(50) value of EBB for the two cell lines are 3.312 microg/ml and 1.167 microg/ml, respectively. The sensitivity of H22 cells to 5-FU can be markedly enhanced: The IC(50) dosage of 5-Fu can be decreased from 0.75 microg/ml down to 0.15 microg/ml, when jointly administered with nontoxic dosages of EBB (IC(10)). In vivo, EBB can prolong the lifespan of mice with ascites H22 to more than three months. 64% of mice survived, while all animals in the control group died by the 18th day. When EBB (5 mg x kg(-1) x d(-1)) is jointly used with 5-FU (25 mg x ml(-1) x d(-1)), 73% of mice with ascites H22 survived, much higher than 27% in the 5-FU treated group. EBB can enhance the anti-hepatoma ability of 5-Fu treatment. EBB mechanism against hepatoma: P53 expression in the EBB treated group is substantially higher than that in the control group. EBB increased the translation of P53. As a calmodulin antagonist, EBB decreases amount of the CaM in hepatoma cells and blocked the hepatoma cell proliferation cycle at the G(2)M phase. Before the G(0)/G(1) phase, a diploid peak and apoptic cells in the treated groups were observed. CONCLUSIONS: The CaM antagonist, EBB, has a strong anti-hepatoma effect and enhances the effect of 5-FU, induces hepatoma cell to apoptosis, promotes the P53 protein expression and decreases the amount of CaM in the cytoplasm. All these results demonstrate that EBB is a new and potentially useful drug against hepatoma and should be researched further.

A phytochemical study on Dichocarpum auriculatum, an endangered medicinal plant peculiar to China

Objective:Dichocarpum auriculatum,an endangered perennial herb,is endemic to China and has been used as folk medicines for the treatment of cough,hepatitis,scrofula,and epilepsy.However,there is no phytochemical report on this herbal so far.For the resource development and protective importance of this endangered medicinal plant,a phytochemical study was undertaken.Methods:The chemical constituents were purified by silica gel column,Sephadex LH-20 column,and semi-preparative reversed phase HPLC.NMR and MS spectra were used for structural identification.Results:Thirteen compounds were isolated from D.auriculatum.Their structures were characterized as jatrorrhizine(1),berberine(2),steponine(3),magnoflorine(4),coclauril(5),menisdaurin(6),menisdaurilide(7),aquilegiolide(8),(6 R,9 S)-3-oxo-α-ionol-β-D-glucopyranoside(9),blumenol C glucoside(10),palmitic acid(11),dibutylphthalate(12),and auriculatum A(13).Conclusion:Compound 13 is a new diester terephthalate derivative.All the compounds are obtained from the genus Dichocarpum for the first time,and compounds 9 and 10 have potential chemotaxonomic significance to the genus Dichocarpum.

Over 100 Million Years of Enzyme Evolution Underpinning the Production of Morphine in the Papaveraceae Family of Flowering Plants

Phylogenomic analysis of whole genome sequences of five benzylisoquinoline alkaloid(BIA)-producing species from the Ranunculales and Proteales orders of flowering plants revealed the sequence and timing of evolutionary events leading to the diversification of these compounds.(S)-Reticuline is a pivotal intermediate in the synthesis of many BIAs and our analyses revealed parallel evolution between the two orders,which diverged122 million years ago(MYA).Berberine is present in species across the entire Ranunculales,and we found co-evolution of genes essential for production of the protoberberine class.The benzophenanthridine class,which includes the antimicrobial compound sanguinarine,is specific to the Papaveraceae family of Ranunculales,and biosynthetic genes emerged after the split with the Ranunculaceae family110 MYA but before the split of the three Papaveraceae species used in this study at77 MYA.The phthalideisoquinoline noscapine and morphinan class of BIAs are exclusive to the opium poppy lineage.Ks estimation of paralogous pairs indicates that morphine biosynthesis evolved more recently than 18 MYA in the Papaver genus.In the preceding 100 million years gene duplication,neofunctionalization and recruitment of additional enzyme classes,combined with gene clustering,gene fusion,and gene amplification,resulted in emergence of medicinally valuable BIAs including morphine and noscapine.