Wolfgang Wiegrebe

Simple isoquinoline and benzylisoquinoline alkaloids as potential antimicrobial, antimalarial, cytotoxic, and anti-HIV agents

Twenty-six simple isoquinolines and 21 benzylisoquinolines were tested for antimicrobial, antimalarial, cytotoxic, and anti-HIV activities. Some simple isoquinoline alkaloids were significantly active in each assay, and may be useful as lead compounds for developing potential chemotherapeutic agents. These compounds include 13 (antimicrobial), 25, 26, and 42 (antimalarial), 13 and 25 (cytotoxic), and 28 and 29 (anti-HIV). A quaternary nitrogen atom of isoquinolium or dihydroisoquinolinium type may contribute to enhanced potency in the first three types of activities. In contrast, anti-HIV activity was found with tetrahydroisoquinoline and 6,7-dihydroxyisoquinolium salts.

Antimicrobial activity of 8-alkyl- and 8-phenyl-substituted berberines and their 12-bromo derivatives

The 8-alkyl- (3-6), 8-phenyl- (7), 12-bromo- (8), 8-alkyl-12-bromo- (9-12), and 12-bromo-8-phenyl- (13) berberine derivatives were prepared and tested for their antimicrobial activity in vitro to evaluate structure-activity relationships. Introduction of the alkyl or phenyl group and the bromine atom into the C-8 and C-12 positions of berberine (1), respectively, led to significant increases of the antimicrobial activity. In both the 8-alkyl- and 8-alkyl-12-bromo-berberines (3-6 and 9-12, respectively), the antibacterial activity increased as the length of the aliphatic chain increased. The exception was the activity against Candida albicans and Escherichia coli, which did not always increase as the alkyl side chain lengthened. Among the compounds tested, 12-bromo-8-n-hexylberberine (12) was 64, 256, 128, 16, and 32 times more active against Staphylococcus aureus, Bacillus subtilis, Salmonella enteritidis, E. coli, and C. albicans, respectively, in comparison to the clinically used berberine. Compound 12 was also found to be 8, 16, and 128 times more active against S. aureus, S. enteritidis, and C.albicans, respectively, than kanamycin sulfate, but was of the same order of activity against B. subtilis, and only one-fourth as active against E. coli.

LC–NMR and LC–MS analysis of 2,3,10,11-oxygenated protoberberine metabolites in Corydalis cell cultures

The metabolism of 2,3,10,11-oxygenated protoberberine alkaloids was studied in cell cultures of Corydalis species. Without prior isolation, the structures of the metabolites were determined by LC-MS and LC-NMR analyses. Tetrahydropseudocoptisine alpha-N-metho salt, pseudoprotopine, and pseudomuramine were identified for the first time, and preliminary evidence for metabolic pathways to the formation of these alkaloids were obtained.

Medicinal plants from Nepal: evaluation as inhibitors of leukotriene biosynthesis

The methanolic extracts of 25 different Nepalese medicinal plants were tested for their activity to inhibit the biosynthesis of leukotriene B(4) in bovine polymorphonuclear leukocytes. The selected indigenous plants are used in traditional herb remedies to treat inflammatory diseases such as asthma, bronchitis, rheumatism, and skin disorders presumed to be mediated by leukotrienes. The leaves of Zanthoxylum nepalensis were shown to be the most potent inhibitor with an IC(50) value of 11 microgram/ml. The extracts obtained from Astercantha longifolia and Hedychium ellipticum also exhibited potent inhibitory action with IC(50) values of 20 and 22 microgram/ml, respectively.

Treatment of Psoriasis with Anthrones – Chemical Principles, Biochemical Aspects, and Approaches to the Design of Novel Derivatives

Antipsoriatic anthrones are probably the most commonly used topical agents in the treatment of psoriasis. There is growing evidence that the biochemical basis for their mechanism of action at the molecular level is related to their redox activity leading to the production of active oxygen species, which include singlet oxygen, superoxide anion radical, and hydroxyl radical. These species are involved in a variety of oxidative effects affecting cellular targets that have been implicated both in the mode of action and the skin-irritating properties of antipsoriatic anthrones: interaction with DNA, inhibition of various enzyme systems associated with cell proliferation and inflammation, such as glucose-6-phosphate dehydrogenase and inflammation, such as glucose-6-phosphate dehydrogenase and 5-lipoxygenase, and destruction of membrane lipids. Furthermore, the application of this information to the design of novel derivatives is discussed. In particular, compounds with diminished oxygen radical-generating properties have been developed, which may permit a separation of antipsoriatic and inflammatory effects. Some of the novel anthrone analogs which produced significantly less amounts of oxygen radicals than dithranol compared favorably in biological tests with this known antipsoriatic drug as an alternative method of treating psoriasis.

A NOVEL APPROACH TO 4-BENZYLISOQUINOLINES

Abstract The reaction of quinone methides with 3.4-dihydroisoquinoline or isoquinoline leads to benzylisoquinoline derivatives. NMR and ms investigations as well as chemical degradation prove that benzylation takes place at C-4 of the isoquinoline nucleus. Spectroscopic data are given for all new compounds.

Modification of DNA bases by anthralin and related compounds

Modification of bases in calf thymus DNA by treatment with the antipsoriatic drug anthralin was studied. The products of DNA bases were identified and their yields measured by gas chromatography-mass spectrometry with selected ion monitoring. Treatment of calf thymus DNA with anthralin significantly enhanced the amount of modified bases above control levels. Purine bases were modified to products identical with those known to be typical of DNA damage induced by hydroxyl radicals. The yields of Fapy-adenine, 8-hydroxyadenine, Fapy-guanine, and 8-hydroxyguanine were maximally increased at an anthralin concentration of 75 microM. A variety of structural analogues of anthralin were also tested at 75 microM were either weaker or stronger hydroxylating agents. It is likely that damage to DNA bases induced by anthrones contributes to their antiproliferative activity. The pharmacological implications of these characteristics of the action of anthralin on DNA bases are discussed.

Elektronenstoß-induzierte Spaltung der Stilben-Doppelbindung

Syntheses ofo-(β-aminoethyl)-stilbene-urethanes (types1, 2 and3) ando-(β-phenethyl)-stilbenes4 are described. The urethanes are obtained by degradation of 1-benzyl-1,2,3,4-tetrahydroisoquinolines with ethylchloroformate;4 is synthesized by reduction of desoxybenzoines, followed byo-formylation andWittig-reaction. The deuteriated isotopomers were obtained via the corresponding deuteriated precursors.

SYNTHESE EINES 3-PHENYLISOCHROMANS

Zusammenfassung Es wird eine unabhangige Synthese des 3-Phenylisochromans II beschrieben, die uber das Desoxybenzoin XIV fuhrt. In diesem Zusammenhang werden einfache Darstellungsweisen fur mehrfach substituierte Desoxybenzoine und 3-Phenyl-α-naphthol-Derivate mitgeteilt.

1,3-Diphenylpropane-1,3-diamines, VIII. Reactions of lithiated oximes and oxime ethers with C=N-electrophiles

SummaryThe reaction of lithiated acetophenone oximes and their O-methyl ethers with benzylideneamines affords (1,3-diphenyl-3-hydroxyimino-1-propyl)-amines or their O-methyl derivatives, respectively, which are precursors of 1,3-diphenylpropane-1,3-diamines.ZusammenfassungDie Reaktion lithiierter Acetophenonoxime bzw. ihrer O-Methylether mit Benzylidenaminen führt zu (1,3-Diphenyl-3-hydroxyimino-1-propyl)-aminen bzw. zu deren O-Methylderivaten. Diese Verbindungen sind Vorstufen für 1,3-Diphenylpropan-1,3-diamine.