Benzophenanthridine Alkaloids Research Articles

ChemInform Abstract: Palladium‐Catalyzed Tandem Reaction to Construct Benzo[c]phenanthridine: Application to the Total Synthesis of Benzo[c]phenanthridine Alkaloids.

AbstractA Pd‐catalyzed tandem ring opening—cross coupling—cyclization reaction of o‐iodobenzoates (I) with azabicycle (II) is the key step in the synthesis of benzophenanthridine alkaloids like avicine (IVa), chelerythrine (IVb) or nitidine (IVc).

Antimicrobial constituents from the African medicinal plant Zanthoxylum capense

The genus Zanthoxylum, comprising approximately 250 species, is well known for its ethnobotanical uses among Rutaceae family [1]. Previous studies have demonstrated that plants belonging to this genus are rich sources of biologically active compounds, such as alkaloids, aliphatic and aromatic amides, coumarins, as well as lignans [2]. Zanthoxylum capense (Thunb.) Harv. is a medicinal plant indigenous to Zimbabwe, South Africa, and Mozambique. Traditional healers use the decoction of its roots for snakebites, and the decoction of its root barks to treat tuberculosis, paralysis, and relief of toothache. However, until date there have been relatively few phytochemical studies on this species [3, 4]. During our search for bioactive compounds from the methanolic extract of Z. capense roots, we have isolated a new benzophenanthridine alkaloid and two new 2-arylbenzofuran neolignans. In addition, several known compounds were also isolated, including six alkaloids with the benzophenanthridine scaffold, one furoquinoline-type alkaloid and a lignan. The structures of the compounds were elucidated by means of MS, extensive 1D and 2D-NMR analyses and by comparison of their physical and spectroscopic data with those reported in the literature. All the isolated compounds were evaluated for their in vitro antibacterial activity against Gram-positive and Gram-negative bacteria. Some compounds showed inhibitory activity mainly against Staphylococcus aureus ATCC 6538 with MIC values ranging from 12.5 to 50µg/mL. These compounds might be promising leads for the development of new antimicrobials.

Inhibition of Stat3 activation by sanguinarine suppresses prostate cancer cell growth and invasion

Signal transducer and activator of transcription 3 (Stat3) is an oncogenic transcriptional factor that plays a critical role in carcinogenesis and cancer progression and is a potential therapeutic target. Sanguinarine, a benzophenanthridine alkaloid derived primarily from the bloodroot plant, was identified previously as a novel inhibitor of survivin that selectively kills prostate cancer cells over "normal" prostate epithelial cells. DU145, C4-2B, and LNCaP cells were treated with sanguinarine. The phosphorylation status of Stat3 and related proteins were measured with Western blots. Activation of transcription by Stat3 was measured with luciferase reporter assay. The effect of sanguinarine on anchorage-independent growth was examined with soft agar assay, and on cell migration and invasion of DU145 cells were measured with scratch assay and invasion assay, respectively. In this study, we identified sanguinarine as a potent inhibitor of Stat3 activation which was able to suppress prostate cancer growth, migration, and invasion. Sanguinarine inhibits constitutive as well as IL6-induced phosphorylation of Stat3 at both Tyr705 and Ser727 in prostate cancer cells. The inhibition of Stat3 phosphorylation by sanguinarine correlates with reduction of Janus-activated Kinase 2 (Jak2) and Src phosphorylation. Sanguinarine downregulates the expression of Stat3-mediated genes such as c-myc and survivin and inhibits the Stat3 responsive element luciferase reporter activity. Sanguinarine inhibits the anchorage-independent growth of DU145 and LN-S17 cells expressing constitutively activated Stat3. Migration and invasion abilities of DU145 cells were also inhibited by sanguinarine in a manner similar to the dominant negative form of Stat3. These data demonstrate that sanguinarine is a potent Stat3 inhibitor and it could be developed as a therapeutic agent for prostate cancer with constitutive activation of Stat3.

Differential effect of the benzophenanthridine alkaloids sanguinarine and chelerythrine on glycine transporters

Glycine transporter inhibitors modulate the transmission of pain signals. Since it is well known that extracts from medicinal plants such as Chelidonium majus exhibit analgesic properties, we investigated the effects of alkaloids typically present in this plant on glycine transporters. We found that chelerythrine and sanguinarine selectively inhibit the glycine transporter GlyT1 with comparable potency in the low micromolar range while berberine shows no inhibition at all. At this concentration both alkaloids only minimally affected transport of the closely related glycine transporter GlyT2, suggesting that the effect is not mediated by the inhibitory activity of these alkaloids on the Na +/K + ATPase. GlyT1 inhibition was time-dependent, noncompetitive and increased with glycine concentration. While chelerythrine inhibition was reversible, the effect of sanguinarine was resistant to wash out. These results suggest that benzophenanthridine alkaloids interact with glycine transporters and at low micromolar range selectively target glycine transporter GlyT1.

Inclusion complex formation of sanguinarinealkaloid with cucurbit[7]uril: inhibition of nucleophilic attack and photooxidation

The inclusion of sanguinarine, a biologically active natural benzophenanthridine alkaloid, in cucurbit[7]uril (CB7) was studied by NMR and ground-state absorption spectroscopy, as well as steady-state and time-resolved fluorescence measurements in aqueous solution. The iminium form of sanguinarine (SA(+)) produces very stable 1 : 1 inclusion complex with CB7 (K = 1.0 × 10(6) M(-1)), whereas the equilibrium constant for the binding of the second CB7 is about 3 orders of magnitude smaller. Marked fluorescence quantum yield and fluorescence lifetime enhancements are found upon encapsulation of SA(+) due to the deceleration of the radiationless deactivation from the single-excited state, but the fluorescent properties of 1 : 1 and 1 : 2 complexes barely differ. The equilibrium between the iminium and alkanolamine forms is shifted 3.69 pK unit upon addition of CB7 as a consequence of the preferential encapsulation of the iminium form and the protection of the 6 position of sanguinarine against the nucleophilic attack by hydroxide anion. On the basis of thermodynamic cycle, about 225 M(-1) is estimated for the equilibrium constant of the complexation between the alkanolamine form of sanguinarine (SAOH) and CB7. The confinement in the CB7 macrocycle can be used to impede the nucleophilic addition of OH(-) to SA(+) and to hinder the photooxidation of SAOH.

The mechanism of action of sanguinarine against methicillin-resistant Staphylococcus aureus

Sanguinarine is a benzophenanthridine alkaloid derived from the root of Sanguinaria canadensis. It is known to perform a wide spectrum of biological activities. The aim of this study is to examine the antimicrobial actions of sanguinarine against methicillin-resistant Staphylococcus aureus (MRSA). Sanguinarine antimicrobial activity was assessed by broth dilution method; its mechanism of action was investigated by bacteriolysis, detergent or ATPase inhibitors and transmission electron microscopy were used to monitor the survival characteristics and the changes in bacteria morphology. The activity of sanguinarine against MRSA strains ranged from 3.12 to 6.25 µg/ml, while the minimum inhibitory concentrations of the two reference strains are 3.12 µg/ml and 1.56 µg/ml. The treatment of the cells with sanguinarine induced the release of membrane-bound cell wall autolytic enzymes, which eventually resulted in lysis of the cell. The OD(600s) of the suspensions treated with the combination of Tris-(hydroxymethyl) aminomethane and Triton X-100 with sanguinarine were reduced to 40% and 8%, respectively. Transmission electron microsco-py of MRSA treated with sanguinarine showed alterations in septa formation. The predisposition of lysis and the altered morphology seen by transmission electron microscopy suggest that sanguinarine compromises the cytoplasmic membrane.

The actions of benzophenanthridine alkaloids, piperonyl butoxide and (S)-methoprene at the G-protein coupled cannabinoid CB1 receptor in vitro

This investigation focused primarily on the interaction of two benzophenanthridine alkaloids (chelerythrine and sanguinarine), piperonyl butoxide and (S)-methoprene with G-protein-coupled cannabinoid CB1 receptors of mouse brain in vitro.Chelerythrine and sanguinarine inhibited the binding of the CB1 receptor agonist [3H]CP-55940 to mouse whole brain membranes at low micromolar concentrations (IC50s: chelerythrine 2.20μM; sanguinarine 1.10μM). The structurally related isoquinoline alkaloids (berberine and papaverine) and the phthalide isoquinoline ((−)-β-hydrastine) were either inactive or considerably below IC50 at 30μM. Chelerythrine and sanguinarine antagonized CP-55940-stimulated binding of [35S] GTPγS to the G-protein (IC50s: chelerythrine 2.09μM; sanguinarine 1.22μM). In contrast to AM251, both compounds strongly inhibited basal binding of [35S]GTPγS (IC50s: chelerythrine 10.06μM; sanguinarine 5.19μM).Piperonyl butoxide and S-methoprene inhibited the binding of [3H]CP-55940 (IC50s: piperonyl butoxide 8.2μM; methoprene 16.4μM), and also inhibited agonist-stimulated (but not basal) binding of [35S]GTPγS to brain membranes (IC50s: piperonyl butoxide 22.5μM; (S)-methoprene 19.31μM). PMSF did not modify the inhibitory effect of (S)-methoprene on [3H]CP-55940 binding.Our data suggest that chelerythrine and sanguinarine are effacacious antagonists of G-protein-coupled CB1 receptors. They exhibit lower potencies compared to many conventional CB1 receptor blockers but act differently to AM251. Reverse modulation of CB1 receptor agonist binding resulting from benzophenanthridines engaging with the G-protein component may explain this difference. Piperonyl butoxide and (S)-methoprene are effacacious, low potency, neutral antagonists of CB1 receptors. Certain of the study compounds may represent useful starting structures for development of novel/more potent G-protein-coupled CB1 receptor blocking drugs.

Microarray Analysis of the Chelerythrine-Induced Transcriptome of Mycobacterium tuberculosis

Chelerythrine (a natural quaternary benzophenanthridine alkaloid) is an extract from the roots of Chelidonium majus with potential antimycobacterial activity. To reveal the possible mechanism of action of chelerythrine against Mycobacterium tuberculosis (M. tuberculosis), commercial oligonucleotide microarrays were used to analyze the genome-wide transcriptional changes triggered by treatment with subinhibitory concentrations of chelerythrine. Quantitative real-time RT-PCR was performed for selected genes to verify the microarray results. We interpreted our microarray data using Agilent software. Analysis of the microarray data revealed that a total of 759 genes were differentially regulated by chelerythrine. Of these, 372 genes were upregulated, and 387 genes were downregulated. Some of the important genes that were significantly regulated are related to different pathways (such as urease), methoxy-mycolic acid synthase, surface-exposed lipids, the heat shock response, and protein synthesis. This genome-wide transcriptomics approach produced the first insights into the response of M. tuberculosis to a chelerythrine challenge.

Overproduction of Alkaloid Phytoalexins in California Poppy Cells Is Associated with the Co-Expression of Biosynthetic and Stress-Protective Enzymes

Many plant cells respond to pathogens by the induction of phytoalexin biosynthesis, but the underlying changes of gene expression are often obscured by their close linkage to the complex rearrangements during pathogen defense, especially the hypersensitive cell death. In root-derived cell cultures of Eschscholzia californica, the overproduction of cytotoxic benzophenanthridine alkaloids can be triggered by a minimum of pathogen pressure that does not evoke hypersensitive reactions. Such conditions activate a signal chain that is initiated by a short contact to low concentrations of yeast glycoprotein elicitor and includes a transient acidification of the cytoplasm. In contrast, high elicitor concentrations signal via an increase of jasmonate and trigger hypersensitive cell death, preceded by a drastic decay of translatable mRNAs. The main changes in protein and mRNA patterns caused by either signal path were compared by 2D proteomic separation, MS/MS sequencing and mRNA-in vitro translation. The four proteins showing the highest overexpression were identical between cells that received low or high-elicitor treatment and overlapped with the three proteins most up-regulated by artificial pH shifts. They comprised one biosynthetic enzyme (norcoclaurine:SAM 4' O-methyl-transferase) plus a unique combination of stress-protective proteins: a heat shock protein (hsp 70); a peptidyl-prolyl-cis/trans isomerase (cyclophilin); and a glyceraldehyde-3-phosphate dehydrogenase. It appears that overproduction of the benzophenanthridine phytoalexins requires the up-regulation of a rate-limiting biosynthetic enzyme plus the coordinated expression of a specific set of protective enzymes and thus is managed like an oxidative stress.

Production of Nitidine from Callus Cultures of Toddalia asiatica

Toddalia asiatica(Rutaceae) is a woody liana used traditionally in the treatment of malaria, sprains, cough, fever, neuralgia, epilepsy, dyspepsia and other disease conditions. The extracts of the plant have been reported to have anticancer and anti-HIV activities. These activities are mainly attributed to benzophenanthridine alkaloid i.e., nitidine. The yield of the nitidine in intact plant is too low (0.002% w/w). Plant tissue culture has been used as an alternative method for increasing the production of secondary metabolites such as nitidine. In similar attempt the present study was carried out to initiate callus cultures from T.asiatica and evaluate further strategies to improve the production of nitidine. The leaves of T. asiatica were incubated in MS medium supplemented with different combinations of growth hormones. MS medium containing NAA (2mg/L) and Kinetin (1mg/L) was found to yield good friable callus after six weeks of incubation. The pooled callus was extracted and observed for the presence of nitidine. The identification was done by TLC and HPLC by using the standard sample. The callus was found to produce 0.026% w/w of nitidine which was 10 fold more than that of intact plant. The conditions required for growth of callus and production of nitidine were optimized and it is the first report.

Shotgun Proteomic Analysis of Yeast-Elicited California Poppy (Eschscholzia californica) Suspension Cultures Producing Enhanced Levels of Benzophenanthridine Alkaloids

The California poppy, Eschscholzia californica, produces benzophenanthridine alkaloids (BPAs), an important class of biologically active compounds. Cell cultures of E. californica were investigated as an alternative and scalable method for producing these valuable compounds; treatment with yeast extract increased production from low levels to 23 mg/g dry weight (DW) of BPAs. A shotgun proteomic analysis of E. californica cell cultures was undertaken to explore changes in metabolism associated with enhanced BPA production. We implemented differential centrifugation and then shotgun proteomics based on nanoliquid chromatography/mass spectrometry (nano-LC-MS/MS) for peptide separation and analysis. A unigene database available for E. californica was translated and utilized for protein identification. Approximately 646 proteins (3% false discovery rate at the protein level) were identified. Differentially abundant proteins observed with elicitation included enzymes involved in (S)-adenosyl methionine (SAM) biosynthesis and BPA biosynthesis. These results demonstrate (1) the identification of proteins from a medicinal plant using shotgun proteomics combined with a well-annotated, translated unigene database and (2) the potential utility of proteomics for exploring changes in metabolism associated with enhanced secondary metabolite production.

Structure and Mechanism of Sanguinarine Reductase, an Enzyme of Alkaloid Detoxification

Sanguinarine reductase is a plant enzyme that prevents the cytotoxic effects of benzophenanthridine alkaloids, which are the main phytoalexins of Papaveraceae. The enzyme catalyzes the reduction of sanguinarine, the most toxic benzophenanthridine, which re-enters the cytoplasm after its primary accumulation in the cell wall region has reached a threshold concentration. We present the sequence of the gene and protein of sanguinarine reductase isolated from cell cultures of Eschscholzia californica. High sequence similarities indicate that the enzyme evolved from a plant-specific branch of the ubiquitous Rossmann fold NAD(P)H/NAD(P)(+) binding reductases, with NADP-dependent epimerases or hydroxysteroid reductases as the most likely ancestors. Based on the x-ray structure of a close homolog, a three-dimensional model of the spatial conformation and catalytic site of sanguinarine reductase was established and used for in silico screening of known three-dimensional structures. Surprisingly, the enzyme shares high structural similarity with enzymes of human and bacterial origin, which have similar functions as the plant homologs but bear little amino acid sequence similarity. Using site-directed mutagenesis, a series of recombinant enzymes was generated and assayed to reveal the impact of individual amino acids and peptides in the catalytic process. It appears that relatively few innovations were required to generate this selective catalyst for alkaloid detoxication, notably an insertion of 13 amino acids and the generation of a novel catalytic triad of Cys-Asp-His were sufficient.

Formation of Human Telomeric G‐quadruplex Structures Induced by the Quaternary Benzophenanthridine Alkaloids: Sanguinarine, Nitidine, and Chelerythrine

AbstractThe ligands which can facilitate the formation and stabilize G‐quadruplex structures have attracted enormous attention due to their potential ability of inhibiting the telomerase activity and halting tumor cell proliferation. It is noteworthy that the abilities of the quaternary benzophenanthridine alkaloids (QBAs), the very important G‐quadruplex binders, in inducing the formation of human telomeric DNA G‐quadruplex structures, have not been reported. Herein, the interaction between single‐strand human telomeric DNA and three QBAs: Sanguinarine (San), Nitidine (Nit) and Chelerythrine (Che), has been investigated. Although these molecules are very similar in structure, they exhibit significantly different abilities in inducing oligonucleotide d(TTAGGG)4 (HT4) to specific G‐quadruplex structures. Our experimental results indicated that the best ligand San could convert HT4 into antiparallel G‐quadruplex structure completely, followed by Nit, which could transform to mixed‐type or hybrid G‐quadruplex structure partially, whereas Che could only transform to antiparallel G‐quadruplex structure in small quantities. The relative QBAs' inducing abilities as indicated by the CD data are in the order of San>Nit>Che. Further investigation revealed that the G‐quadruplex structures from HT4 induced by QBAs are of intramolecular motif. And only sequences with certain length could be induced by QBAs because of their positive charges which could not attract short chain DNA molecules to close to each other and form intermolecular G‐quadruplex. In addition, the factors that affect the interaction between HT4 and QBAs were discussed. It is proposed that the thickness of the molecular frame and the steric hindrance are the primary reasons why the subtle differences in QBAs' structure lead to their remarkable differences in inducing the formation of the G‐quadruplex structures.

Metabolic Diversification of Benzylisoquinoline Alkaloid Biosynthesis Through the Introduction of a Branch Pathway in Eschscholzia californica

Higher plants produce a diverse array of secondary metabolites. These chemicals are synthesized from simple precursors through multistep reactions. To understand how plant cells developed such a complicated metabolism, we examined the plasticity of benzyl isoquinoline alkaloid biosynthesis in transgenic Eschscholzia californica cells with the ectopic expression of Coptis japonica scoulerine-9-O-methyltransferase (CjSMT). CjSMT catalyzes the O-methylation of scoulerine to produce tetrahydrocolumbamine (THC) in berberine biosynthesis and is not involved in benzophenanthridine alkaloid biosynthesis in E. californica. While a preliminary characterization confirmed that columbamine (oxidized product of THC) was produced in transgenic E. californica cells, many newly found peaks were not identified. Here, we report the identification of novel products, including allocryptopine and 10-hydroxychelerythrine. This result indicates that CjSMT reaction products were further converted by endogenous enzymes to produce double O-methylated compounds instead of a methylenedioxy ring at the 7,8-position of the original benzophenanthridine alkaloids. Further metabolite profiling revealed the enhanced diversification of the alkaloid profile in transgenic cells. Metabolic plasticity and the enzymes involved in metabolic diversity are discussed.

Abstract 23: Sanguinarine suppresses survivin expression and inhibits the growth of prostate cancer cells

Abstract Background: Prostate cancer is a frequently occurring disease and is the second leading cause of cancer related deaths of men in the United States. Current treatments have proved inadequate in curing or controlling prostate cancer and a search for agents for the management of this disease is urgently needed. Survivin plays an important role in both progression of castration-resistant prostate cancer and resistance to chemotherapy. Altered expression of survivin in prostate cancer cells is associated with cancer progression, drug/radiation resistance, poor prognosis and short patient survival. Methods: We performed a cell based rapid screen of the Prestwick Chemical Library consisting of 1120 FDA-approved compounds with known safety and bioavailability in humans to identify potential inhibitors of survivin and anti-cancer agents for prostate cancer. Results: Sanguinarine, a benzophenanthridine alkaloid derived primarily from the bloodroot plant, was identified as a novel inhibitor of survivin that selectively kills prostate cancer cells over “normal” prostate epithelial cells. We found that sanguinarine inhibits survivin protein expression through protein degradation via the ubiquitin-proteasome system. Sanguinarine induces apoptosis and inhibits tumor formation and growth of human prostate cancer cells. Administration of sanguinarine, beginning 3 days post ectopic implantation of DU145 human prostate cancer cells, reduces both tumor weight and volume by more than 70% compared to the control treated mice with no apparent toxicity. In addition, sanguinarine sensitized prostate cancer cells to paclitaxel-mediated growth inhibition and apoptosis, offering a potential therapeutic strategy for overcoming taxol resistance. Conclusions: These results suggest that sanguinarine may be developed as an agent either alone or in combination with taxol for treatment of castration-resistant prostate cancer overexpressing survivin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 23.

1186 SANGUINARINE IS A NOVEL INHIBITOR OF SURVIVIN AND INHIBITS THE GROWTH OF PROSTATE CANCER CELLS

You have accessJournal of UrologyProstate Cancer: Basic Research VI1 Apr 20101186 SANGUINARINE IS A NOVEL INHIBITOR OF SURVIVIN AND INHIBITS THE GROWTH OF PROSTATE CANCER CELLS Meng Sun, Jae Chun, Wei Lou, and Allen Gao Meng SunMeng Sun More articles by this author , Jae ChunJae Chun More articles by this author , Wei LouWei Lou More articles by this author , and Allen GaoAllen Gao More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.687AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate cancer is a frequently occurring disease and is the second leading cause of cancer related deaths of men in the United States. Current treatments have proved inadequate in curing or controlling prostate cancer and a search for agents for the management of this disease is urgently needed. Survivin plays an important role in both progression of castration-resistant prostate cancer and resistance to chemotherapy. Altered expression of survivin in prostate cancer cells is associated with cancer progression, drug/radiation resistance, poor prognosis and short patient survival. METHODS We performed a cell based rapid screen of the Prestwick Chemical Library consisting of 1120 FDA-approved compounds with known safety and bioavailability in humans to identify potential inhibitors of survivin and anti-cancer agents for prostate cancer. RESULTS Sanguinarine, a benzophenanthridine alkaloid derived primarily from the bloodroot plant, was identified as a novel inhibitor of survivin that selectively kills prostate cancer cells over ¡°normal¡± prostate epithelial cells. We found that sanguinarine inhibits survivin protein expression through protein degradation via the ubiquitin-proteasome system. Sanguinarine induces apoptosis and inhibits tumor formation and growth of human prostate cancer cells. Administration of sanguinarine, beginning 3 days post ectopic implantation of DU145 human prostate cancer cells, reduces both tumor weight and volume by more than 70% compared to the control treated mice with no apparent toxicity. In addition, sanguinarine sensitized prostate cancer cells to paclitaxel-mediated growth inhibition and apoptosis, offering a potential therapeutic strategy for overcoming taxol resistance. CONCLUSIONS These results suggest that sanguinarine may be developed as an agent either alone or in combination with taxol for treatment of castration-resistant prostate cancer overexpressing survivin. Sacramento, CA© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e459 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Meng Sun More articles by this author Jae Chun More articles by this author Wei Lou More articles by this author Allen Gao More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Sanguinarine Suppresses Prostate Tumor Growth and Inhibits Survivin Expression

Prostate cancer is a frequently occurring disease and is the second leading cause of cancer-related deaths of men in the United States. Current treatments have proved inadequate in curing or controlling prostate cancer, and a search for agents for the management of this disease is urgently needed. Survivin plays an important role in both progression of castration-resistant prostate cancer and resistance to chemotherapy. Altered expression of survivin in prostate cancer cells is associated with cancer progression, drug/radiation resistance, poor prognosis, and short patient survival. In the present study, the authors performed a cell-based rapid screen of the Prestwick Chemical Library consisting of 1120 Food and Drug Administration-approved compounds with known safety and bioavailability in humans to identify potential inhibitors of survivin and anticancer agents for prostate cancer. Sanguinarine, a benzophenanthridine alkaloid derived primarily from the bloodroot plant, was identified as a novel inhibitor of survivin that selectively kills prostate cancer cells over "normal" prostate epithelial cells. The authors found that sanguinarine inhibits survivin protein expression through protein degradation via the ubiquitin-proteasome system. Sanguinarine induces apoptosis and inhibits growth of human prostate cancer cells and in vivo tumor formation. Administration of sanguinarine, beginning 3 days after ectopic implantation of DU145 human prostate cancer cells, reduces both tumor weight and volume. In addition, sanguinarine sensitized paclitaxel-mediated growth inhibition and apoptosis, offering a potential therapeutic strategy for overcoming taxol resistance. These results suggest that sanguinarine may be developed as an agent either alone or in combination with taxol for treatment of prostate cancer overexpressing survivin.

In Vitro Leishmanicidal Activity of Benzophenanthridine Alkaloids from Bocconia pearcei and Related Compounds

Leishmanicidal activities of benzophenanthridine alkaloids isolated from fruits of Bocconia pearcei and their derivatives were examined. Seven benzophenanthridine compounds were isolated from the methanolic extracts of B. pearcei. Among them, dihydrosanguinarine showed the most potent leishmanicidal activities (IC(50) value: 0.014 microg/ml, respectively). To examine the structure-activity relationship of the benzophenanthridine skeleton, the leishmanicidal activities for 32 synthetic samples were examined. The existence of bulky groups at the C(7)-C(8) position was found to enhance the activity. On the other hand, the bulkiness at the C(2)-C(3) position on the D-ring, a carbonyl group at C-6, substitution at C-6 and cleavage or saturation of the C(5)-C(6) bond reduced activity. A methyl group on nitrogen of the C-ring was thought to be necessary for significant activity.

Biophysical aspects and biological implications of the interaction of benzophenanthridine alkaloids with DNA.

Benzophenanthridine alkaloids represent a very interesting and significant group of natural products that exhibit a broad range of biological and pharmacological properties. Among this group of alkaloids, sanguinarine, nitidine, fagaronine, and chelerythrine have the potential to form molecular complexes with DNA structures and have attracted recent attention for their possible clinical and pharmacological utility. This review focuses on the interaction of these alkaloids with polymorphic DNA structures (B-form, Z-form, HL-form, and triple helical form) reported by several research groups employing various physical techniques such as spectrophotometry, spectrofluorimetry, circular dichroism, NMR spectroscopy, thermal melting, viscometry as well as thermodynamic analysis by isothermal titration calorimetry and differential scanning calorimetry to elucidate the mode and mechanism of action at the molecular level to determine the structure-activity relationship. DNA binding properties of these alkaloids are interpreted in relation to their biological activity.

Racemization of 6-methoxydihydrosanguinarine in methanol investigated by enantioselective dynamic HPLC

A biologically active benzophenanthridine alkaloid, 6-methoxydihydrosanguinarine (MS), was isolated from Hylomecon plants. Although enantiomers of MS can be separated by chiral HPLC, its isomers rapidly form a racemic mixture in methanol. The rate constants for the racemization of MS enantiomers were 9.20 × 10 −4 s −1 and 9.95 × 10 −4 s −1 for (+)-MS and (−)-MS, respectively, as determined by dynamic HPLC and chiral chromatography. This unusually rapid racemization may originate from the formation of a stable iminium ion intermediate, sanguinarine. Therefore, the variety of biological activities exhibited by MS may be attributable to a combination of (+)-MS, (−)-MS, and sanguinarine.