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At least 55 records · Page 3Linked to original sources
PubMed2006

The benzophenanthridine alkaloid sanguinarine perturbs microtubule assembly dynamics through tubulin binding. A possible mechanism for its antiproliferative activity.

Sanguinarine has been shown to inhibit proliferation of several types of human cancer cell including multidrug-resistant cells, whereas it has minimal cytotoxicity against normal cells such as neutrophils and keratinocytes. By analyzing the antiproliferative activity of sanguinarine in relation to its effects on mitosis and microtubule assembly, we found that it inhibits cancer cell proliferation by a novel mechanism. It inhibited HeLa cell proliferation with a half-maximal inhibitory concentration of 1.6 +/- 0.1 microM. In its lower effective inhibitory concentration range, sanguinarine depolymerized microtubules of both interphase and mitotic cells and perturbed chromosome organization in mitotic HeLa cells. At concentrations of 2 microM, it induced bundling of interphase microtubules and formation of granular tubulin aggregates. A brief exposure of HeLa cells to sanguinarine caused irreversible depolymerization of the microtubules, inhibited cell proliferation, and induced cell death. However, in contrast with several other microtubule-depolymerizing agents, sanguinarine did not arrest cell cycle progression at mitosis. In vitro, low concentrations of sanguinarine inhibited microtubule assembly. At higher concentrations (> 40 microM), it altered polymer morphology. Further, it induced aggregation of tubulin in the presence of microtubule-associated proteins. The binding of sanguinarine to tubulin induces conformational changes in tubulin. Together, the results suggest that sanguinarine inhibits cell proliferation at least in part by perturbing microtubule assembly dynamics.

Alkaloids↗
PubMed1998

The role of the iminium bond in the inhibition of reverse transcriptase by quaternary benzophenanthridines.

The quaternary benzo[c]phenanthridines fagaronine, nitidine and O-methylfagaronine have been reviewed as potential antitumour and antiviral agents. Their mode of action has not been established, but their ability to bind with DNA by intercalation is believed to be involved. Of the three synthetic analogues of O-methylfagaronine which we have synthesized, methoxidine and ethoxidine are active against HIV-1 reverse transcriptase (IC50 values 2.8 microM and 2.4 microM respectively) whereas hydroxidine is inactive. One of the prerequisites for the enzyme inhibitory activity of this class of molecule is the presence of an iminium group--it is well known that a positive charge on a polyaromatic nucleus facilitates intercalative binding with DNA. Through UV spectrophotometric and modelling studies, we have shown that the iminium bond plays a more fundamental role in enzyme inhibition through its susceptibility to nucleophilic attack--the inactive analogue hydroxidine has a non-electrophilic iminium bond. Consequently, we have demonstrated that iminium bond electrophilicity is a parameter which needs to be considered in ternary complex formation with reverse transcriptase.

Alkaloids↗
PubMed1985

Synthesis and antitumor activity of structural analogues of the anticancer benzophenanthridine alkaloid fagaronine chloride.

The indenoisoquinoline analogue 4 of fagaronine chloride (2) has been prepared, as well as its positional isomer 20 and the corresponding mesylated derivatives 16 and 19. Compounds 4, 16, and 20 were tested against P388 lymphocytic leukemia and found to possess significant activity. A tricyclic analogue 24 was also synthesized and was devoid of cytotoxicity in the KB cancer cell culture system. The change in the substitution pattern of the A-ring on going from 4 to 20 was tolerated without producing a significant decrease in antitumor activity.

Alkaloids↗
PubMed2002

Benzophenanthridine alkaloids from Corydalis flabellata.

Four new alkaloids, characterized as 6-(2-hydroxyethyl)-5,6-dihydrosanguinarine (1), 6-acetonyl-5,6-dihydrosanguinarine (2), N-methyl-2,3,7,8-tetramethoxy-5,6-dihydrobenzophenanthridine-6-ethanoic acid (3), N-methyl-2,3,7,8-tetramethoxy-6-oxo-5,6-dihydrobenzophenanthridine (4), together with oxosanguinarine (5), spallidamine (6), 6-acetonyl-5,6-dihydrochelerythrine (7), 6-oxochelerythrine (8) and sanguidimerine (9) were isolated from the roots of Corydalis flabellata.

Alkaloids↗
PubMed1995

Characterization and mechanism of the berberine bridge enzyme, a covalently flavinylated oxidase of benzophenanthridine alkaloid biosynthesis in plants.

The berberine bridge enzyme ((S)-reticuline:oxygen oxidoreductase (methylene-bridge-forming), EC 1.5.3.9) catalyzes the oxidative cyclization of the N-methyl moiety of (S)-reticuline into the berberine bridge carbon, C-8, of (S)-scoulerine. This is a reaction that has neither an equivalent in organic chemistry nor a parallel in nature. The uniqueness of this catalytic reaction prompted an in depth study that began with the isolation of the cDNA encoding the berberine bridge enzyme followed by the overexpression of this cDNA in insect cell culture. The heterologously expressed enzyme has herein been shown to contain covalently attached FAD in a molar ratio of cofactor to protein of 1:1.03. Site-directed mutagenesis and laser desorption time-of-flight mass spectrometry suggest that the site of covalent attachment is at His-104. The holoenzyme exhibited absorbance maxima at 380 and 442 nm and a fluorescence emission maximum at 628 nm (310 nm excitation). Enzymic transformation of a series of (S)-reticuline derivatives modified with respect to the stereochemistry at C-1 or in the aromatic ring substitution suggests that ring closure proceeds in two steps: formation of the methylene iminium ion and subsequent ring closure via an ionic mechanism.

Alkaloids↗
PubMed1996

Heterologous expression of alkaloid biosynthetic genes--a review.

Tetrahydrobenzylisoquinoline alkaloids comprise a diverse class of secondary metabolites with many pharmacologically active members. The biosynthesis at the enzyme level of at-least two tetrahydrobenzylisoquinoline alkaloids, the benzophenanthridine alkaloid sanguinarine in the California poppy, Eschscholtzia californica, and the bisbenzylisoquinoline alkaloid berbamunine in barberry, Berberis stolonifera, has been elucidated in detail starting from the aromatic amino acid (aa) L-tyrosine. In an initial attempt to develop alternate systems for the production of medicinally important alkaloids, one enzyme from each pathway (BBE, a covalently flavinylated enzyme of benzophenanthridine alkaloid biosynthesis and CYP80, a phenol coupling cytochrome P-450-dependent oxidase of bisbenzylisoquinoline alkaloid biosynthesis) has been purified to homogeneity, a partial aa sequence determined, and the corresponding cDNAs isolated with aid of synthetic oligos based on the aa sequences. The recombinant enzymes were actively expressed in Spotloptera frugiperda Sf9 cells using a baculovirus vector, purified and then characterized. Insect cell culture has proven to be a powerful system for the overexpression of alkaloid biosynthetic genes.

Alcohol Oxidoreductases↗
PubMedDate not supplied

Inhibition of topoisomerase I function by nitidine and fagaronine.

The benzophenanthridine alkaloids nitidine and fagaronine were characterized as inhibitors of topoisomerase I function. In common with the antitumor agent camptothecin, both nitidine and fagaronine stabilized the covalent binary complex formed between calf thymus topoisomerase I and DNA. The effects of these compounds were readily apparent at 0.15-0.3 microM concentrations. Both nitidine and fagaronine inhibited the topoisomerase I-mediated relaxation of supercoiled pSP64 plasmid DNA more effectively than camptothecin; unlike camptothecin, both of these benzophenanthridine alkaloids also bound directly to and mediated the unwinding of B-form DNA. Nitidine and fagaronine were also studied in comparison with camptothecin to determine the sequence specificity of DNA breaks produced from a 32P-end-labeled duplex in the presence of topoisomerase I. All three compounds produced very similar cleavage patterns. The specificity of nitidine and fagaronine for inhibiting topoisomerase I function was studied by measuring the effects of the compounds on the unknotting of P4 DNA by calf thymus topoisomerase II. Moderate inhibition of topoisomerase II-mediated unknotting was obtained, but only in the presence of high (i.e., 40 microM) concentrations of nitidine and fagaronine. In comparison, doxorubicin inhibited topoisomerase II to the same extent as nitidine and fagaronine when it was employed at 2.5 microM concentration and was strongly inhibitory when employed at 10 microM concentration.

Alkaloids↗
PubMed1996

Influence of sanguinarine on the GABA synthesizing enzyme glutamate decarboxylase in vitro.

The inhibitory activity of the quaternary benzophenanthridine alkaloid sanguinarine on rat brain glutamate decarboxylase (GAD; EC 4.1.1.15) was studied in vitro. A value of Ki 7.10(-4) mol.1(-1) for sanguinarine was found. The inhibition was irreversible and increased during the preincubation time of sanguinarine with the GAD preparation. The results suggest that reaction of the iminium bond in the benzophenanthridine molecule with thiol groups of the enzyme participates in GAD inhibition. As GAD catalyzes the rate-limiting step of GABA synthesis, its inhibition by sanguinarine may contribute to its physiological action in vivo.

Alkaloids↗
PubMed1992

Inhibition of nonenzymic lipid peroxidation by benzylisoquinoline alkaloids.

A group of benzylisoquinoline alkaloids, including five simple benzylisoquinolines, three phtalideisoquinolines, six aporphines, three protoberberines, and two benzophenanthridines, have been studied as inhibitors of lipid peroxidation stimulated by Fe2+/cysteine in rat liver microsomal fractions. Protopapaverine, apomorphine, laudanosoline, tetrahydroberberine, isoboldine, bulbocapnine, boldine, anonaine, glaucine, and stepholidine showed antiperoxidative effects, and structure-activity relationships were established. In simple benzylisoquinolines, the presence of phenolic hydroxyls or similar reactive groups is necessary for inhibition of peroxidation, while in aporphines and protoberberines nonhydroxylated compounds can exert antiperoxidative effects. The phtalideisoquinolines and benzophenanthridines tested were inactive.

Alkaloids↗
PubMedDate not supplied

Analysis of secondary metabolites from eschscholtzia californica by high-performance liquid chromatography.

A rapid and precise analytical HPLC method has been developed for screening the major benzophenanthridine alkaloids produced by cell cultures of Eschscholtzia califomica, namely, sanguinarine, chelirubine, macarpine, chelerythrine and chelilutine. Separation was achieved on a C18, reversed-phase column with gradient elution using acetonitrile and 50 mM phosphoric acid. Detection was performed by both fluorescence (lambda(ex) 330 nm, lambda(em) 570 nm) and photodiode array, leading to good selectivity and precision in determining peak purity. A simple and quick sample preparation protocol was elaborated involving a methanolic extraction for the measurement of intracellular concentrations of the alkaloids and a solid phase extraction for their quantification in culture medium. Owing to the non-availability of commercially standards, a method for the purification of chelirubine, macar pine and chelilutine by semi-preparative HPLC was developed. Coupled together, the isolation method and the analytical method were highly reliable for screening the alkaloids of interest produced by E. califomica.

Alkaloids↗
PubMed2001

Inhibitory effects of sanguinarine on monoamine oxidase activity in mouse brain.

The effects of benzophenanthridine alkaloids, such as sanguinarine and chelidonine, on monoamine -oxidase (MAO) activity in mouse brain were investigated. Sanguinarine showed an inhibitory effect on MAO activity in a concentration dependent manner (53.4% inhibition at 25 microM). However, chelidonine did not inhibit MAO activity. The IC(50) value of sanguinarine was 24.5 microM. Sanguinarine inhibited non-competitively MAO activity using kynuramine as a substrate. The K(i) value for sanguinarine was 22.1 microM. These results suggest that sanguinarine partially contributes to the regulation of catecholamine content.

Alkaloids↗
PubMed2004

Apoptosis inducing effects of 6-methoxydihydrosanguinarine in HT29 colon carcinoma cells.

6-methoxydihydrosanguinarine (6ME), a benzophenanthridine alkaloid derived from the methanol extracts of Hylomecon hylomeconoides, showed a dose-dependent effect at 1-10 microM on causing apoptotic cell death in HT29 colon carcinoma cells (IC50 = 5.0+/-0.2 microM). Treatment of HT-29 cells with 6ME resulted in the formation of internucleosomal DNA fragmentation. Treatment of the cells with 6ME caused activation of caspase-3, -8 and 9 protease and subsequent proteolytic cleavage of poly(ADP-ribose)polymerase. 6ME increased the expression of p53 and Bax and decreased the expression of Bid. These results indicate that p53 and proapoptotic Bcl-2 family proteins might participate in the antiproliferative activity of 6ME in HT29 cells.

Alkaloids↗