Structural Aspects of The Inhibitory Effect of Glabridin on LDL Oxidation

The inhibitory effects of glabridin, an isoflavan isolated from licorice (Glycyrrhiza glabra) root, and its derivatives on the oxidation of LDL induced by copper ions or mediated by macrophages were studied, in order to evaluate the contribution of the different parts of the isoflavan molecule to its antioxidant activity. The peak potential (E_1/2) of the isoflavan derivatives, their radical scavenging capacity toward 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical and their ability to chelate heavy metals were also analyzed and compared to their inhibitory activity on LDL oxidation. In copper ion-induced LDL oxidation, glabridin (1), 4′-O-methylglabridin (2), hispaglabridin A (3), and hispaglabridin B (4), which have two hydroxyl groups at positions 2′ and 4′ or one hydroxyl at position 2′ on ring B, successfully inhibited the formation of conjugated dienes, thiobarbituric acid reactive substances (TBARS) and lipid peroxides, and inhibited the electrophoretic mobility of LDL under oxidation. Compounds 1–3 exhibited similar activities, whereas compound 4 was less active. In macrophage-mediated LDL oxidation, the TBARS formation was also inhibited by these isoflavans (1–4) at a similar order of activity to that obtained in copper ion-induced LDL oxidation. On the other hand, 2′-O-methylglabridin (5), a synthesized compound, whose hydroxyl at 2′-position is protected and the hydroxyl at 4′-position is free, showed only minor inhibitory activity in both LDL oxidation systems. 2′,4′-O-Dimethylglabridin (6), whose hydroxyls at 2′- and 4′-positions are both protected, was inactive. Resorcinol (7), which is identical to the phenolic B ring in glabridin, presented low activity in these oxidation systems. The isoflavene glabrene (8), which contains an additional double bond in the heterocyclic C ring, was the most active compound of the flavonoid derivatives tested in both oxidation systems. The peak potential of compounds 1–5 (300 μM), tested at pH 7.4, was similar (425–530 mV), and that for compound 6 and 8 was 1078 and 80 mV, respectively. Within 30 min of incubation, compounds 1, 2, 3, 4, 8 scavenged 31%, 16%, 74%, 51%, 86%, respectively, of DPPH radical, whereas compounds 5 and 6, which almost did not inhibit LDL oxidation, also failed to scavenge DPPH. None of the isoflavan derivatives nor the isoflavene compound were able to chelate iron, or copper ions. These results suggest that the antioxidant effect of glabridin on LDL oxidation appears to reside mainly in the 2′ hydroxyl, and that the hydrophobic moiety of the isoflavan is essential to obtain this effect. It was also shown that the position of the hydroxyl group at B ring significantly affected the inhibitory efficiency of the isoflavan derivatives on LDL oxidation, but did not influence their ability to donate an electron to DPPH or their peak potential values.     

A new method for selective N-acylation of aminoglycoside antibiotics

Per-N-formylation of aminoglycoside (aminocyclitol) antibiotics followed by mild hydrolysis with aqueous ammonia gave mono-N-deformylated derivatives. Each positional isomer of the mono-N-deformylated derivatives thus obtained was separated by column chromatography on Amberlite CG-50 (NH₄⁺ ). Acylation of mono-N-deformylated derivatives gave the corresponding mono-N-acylated derivatives. The N-formyl groups of the mono-N-acylates were removed by the treatment with dilute aqueous hydrazine acetate, whereas the newly introduced N-acyl group was stable under these conditions. The 1-N-formyl group of the deoxystreptamine moiety of per-N-formylated aminoglycoside antibiotics containing neamine (or 3′-deoxyneamine) is more readily deformylated than the 3-N-formyl group. In this report, isolation and structural-elucidation studies, including ¹³C-n.m.r. spectral assignments, of positional isomers of tri-N-formyl derivatives of xylostasin (1), 3′-deoxyxylostasin (2), kanamycin A (3), and neamine (4) are described. This selective N-acylation provides a useful method for the preparation of 1-N-modified derivatives, and the synthesis of 3′-deoxybutirosin A (2f) from 2 is described in detail as an example.     

Synthesis and serotonin receptor binding properties of 5-substituted 3-(1′,2′,5′,6′-tetrahydropyridin-3′-yl) indoles

A semi-rigid 5-hydroxytryptamine (5-HT) analogue, RU28253 [5-methoxy-3-(1′,2′,5′,6′-tetrahydropyridin-3′-yl) indole], is a potent 5-HT₁ and 5-HT₂ agonist. It is isomeric to RU24969 [5-methoxy-3-(1′,2′,5′,6′-tetrahydropyridin-4′-yl) indole], a conformationally restricted 5-HT homologue, which has been extensively used in the study and classification of 5-HT receptors. A series of RU28253 derivatives with diverse substituents on indole 5-position were synthesized and their dissociation constants determined at the 5-HT₁ and 5-HT₂ receptors.     

Synthesis and opioid activity of N,N-dimethyl-Dmt-Tic-NH-CH(R)-R' analogues: acquisition of potent delta antagonism

N,N-Dimethylation of the H-Dmt-Tic-NH-CH(R)-R′ series of compounds produced no significant affect on the high δ-opioid receptor affinity (K_i=0.035–0.454 nM), but dramatically decreased that for the μ-opioid receptor. The effect of N-methylation was independent of the length of the linker (R); however, the bioactivities were affected by the chemical composition of the third aromatic group (R′): phenyl (Ph) (5′–8′) elicited a greater reduction in μ-affinity (40–70-fold) compared to analogues containing 1H-benzimidazole-2-yl (Bid) (9-fold). The major consequences of N,N-dimethylation on in vitro bioactivity were: (i) a loss of δ-agonism coupled with the appearance of potent δ antagonism (4′–7′) (pA₂=8.14–9.47), while 1 exhibited only a 160-fold decreased δ agonism (1′) and the δ antagonism of 8 enhanced >10-fold (pA₂=10.62, 8′); and (ii) a consistent loss of μ-affinity resulted in enhanced δ-opioid receptor selectivity. With the exception of compound 1′, the change in the hydrophobic environment at the N-terminus and formation of a tertiary amine by N,N-dimethylation in analogues of the Dmt-Tic pharmacophore produced potent δ-selective antagonists.     

Polychlorinated biphenyls as inducers of hepatic microsomal enzymes: Structure-activity rules

A number of highly purified polychlorinated biphenyl (PCB) isomers and congeners were synthesized and administered to male Wistar rats at dosage levels of 30 and 150 μmol · kg⁻¹. The effects of this in vivo treatment on the drug-metabolizing enzymes were determined by measuring the microsomal benzo[a]pyrene (B[a]P) hydroxylase, dimethylaminoantipyrine (DMAP) N-demethylase and NADPH-cytochrome c reductase enzyme activities, the cytochrome b₅ content and the relative peak intensities and spectral shifts of the reduced microsomal cytochrome P-450: CO and ethylisocyanide (EIC) binding difference spectra. The results were compared to the effects of administering phenobarbitone (PB), 3-methylcholanthrene (MC) and PB plus MC (coadministered) to the test animals. The synthetic PCB congeners used in this study included 3,4,4′,5-tetrachlorobiphenyl (TCBP-1), 2,3′,4,4′-tetrachlorobiphenyl (TCBP-2), 2,3′,4,4′,5′-pentachlorobiphenyl (PCBP-1), 2,3,4,4′,5-pentachlorobiphenyl (PCBP-2), 2,3,3′,4,4′,5-hexachlorobiphenyl (HCBP-1), 2,3,3′,4′,5,6-hexachlorobiphenyl (HCBP-2), 2,3,3′,5,5′,6-hexachlorobiphenyl (HCBP-3), 2,2′,3,5,5′,6-hexachlorobiphenyl (HCBP-4) and 2,3,3′,4,5,5′-hexachlorobiphenyl (HCBP-5) and were used to reappraise the structure-activity rules for PCBs as hepatic microsomal enzyme inducers. The results suggested that (a) PCBs which induce MC or mixed-type activity must be substituted at both para positions, at least two meta positions but not necessarily on the same phenyl ring and can also contain one ortho chloro substituent; (b) due to the considerable structural diversity of the PB-type inducers the rules for induction of this activity by PCB congeners are not readily defined.     

Gold in organic synthesis Part 2. Preparation of benzyl-alkyl and-arylketones via C---C coupling

Reaction of [Au(η²-Ar){CH₂C(O)R}Cl] (Ar=C₆H₄N=N- Ph-₂, R=Me, C₆H₂(OMe)₃-3′,4′,5′; Ar=C₆H₃(N=NC₆H₄Me- 4′)-2, Me-5, R=Me) with PPh₃ and NaClO₄·H₂O (1:2:1) at room temperature, leads to reductive elimination giving [Au(PPh₃)₂]ClO₄ and the corresponding carbon-carbon coupling product ArCH₂C(O)R. A similar process takes place when complexes [Au(η²-Ar){CH₂C(O)R}(PPh₃)Cl] are refluxed in tetrahydrofuran, through elimination of [Au(PPh₃)Cl].     

Assessment of substitution in the second pharmacophore of Dmt-Tic analogues

The Dmt-Tic pharmacophore exhibits potent δ-opioid receptor antagonism. Analogues with substitutions in the second pharmacophore with (1, 1′) or without a COOH function (2–9) were synthesized: several had high δ affinity (1′, 2, 7, and 9), but exhibited low to non-selectivity toward μ receptors similar to H-Dmt-Tic-amide and H-Dmt-Tic-ol. Functional bioactivity indicated high δ antagonism (pA₂ 7.4–7.9) (1′, 2, and 9) and modest μ agonism, pEC₅₀ (6.1–6.3) (1′, 2, 8, and 9), but with E_max values analogous to dermorphin. These Dmt-Tic analogues with mixed δ antagonist/μ agonist properties would appear to be better candidates as analgesics than pure μ agonists.     

Synthesis and evaluation of novel daunomycin-phosphate-sulfate -β-glucuronide and -β-glucoside prodrugs for application in adept

The synthesis, antiproliferative effect and enzymatic hydrolysis of daunomycin-3′-N- and -4′-O-phosphate and -sulfate derivatives and of daunomycin-3′-N-CO-β-glucuronide and -β-glucoside, designed to be prodrugs in ADEPT are described. The phosphate derivatives were almost as toxic as the parent drug whereas the sulfates were not hydrolyzed by aryl sulfatases. Glucuronyl and glucosyl prodrugs were found to be useful for application in ADEPT.     

Synthèse de nucléosides pyrimidiques non protégés en O-2′ à partir de sulfites cycliques en C-1—C-2

Treatment of 3,5,6-tri-O-benzoyl-- -glucofuranose 1,2-sulfite with an excess of bis(trimethylsil) uracil, in fusion processes without any catalyst, afforded an excellent yield of 1-(3,5,6-tri-O-benzoyl-2-O-trimethylsilyl-β- -glucofuranosyl)uracil, which was readily hydrolyzed in slightly acid conditions to give in almost quantitative yield 1-(3,5,6-tri-O-benzoyl-β- -glucofuranosyl)uracil. This new synthetic method for nucleosides unprotected at O-2′ was also tested in other sugar series. In some cases, only the 1′,2′-trans-nucleosides were obtained, but in others, small yields (3–10%) of 1′,2′-cis-nucleosides were detected. The -to-β ratio seems to be dependent on the reaction temperature. 2,4-Dimethoxypyrimidine also reacted with sugar 1,2-sulfites and 4-O-methyl-1-(3,5,6-tri-O-benzyl-β- -glucopyranosyl)-2-pyrimidinone was prepared in 85% yield from 3,5,6-tri-O-benzyl-- -glucopyranose 1,2-sulfite.     

Isolation, structural elucidation, and partial synthesis of lutein dehydration products in extracts from human plasma

All-E-(3R,6′R)-3-hydroxy-3′,4′-didehydro-β,γ-carotene (anhydrolutein I) and all-E-(3R,6′R)-3-hydroxy-2′,3′-didehydro-β,ε-carotene (2′,3′-anhydrolutein II) have been isolated and characterized from extracts of human plasma using semipreparative high-performance liquid chromatography (HPLC) on a C₁₈ reversed-phase column. The identification of anhydroluteins was accomplished by comparison of the UV-Vis absorption and mass spectral data as well as HPLC-UV-Vis-mass spectrometry (MS) spiking experiments using fully characterized synthetic compounds. Partial synthesis of anhydroluteins from the reaction of lutein with 2% H₂SO₄ in acetone, in addition to anhydrolutein I (54%) and 2′,3′-anhydrolutein II (19%), also gave (3′R)-3′-hydroxy-3,4-dehydro-β-carotene (3′,4′-anhydrolutein III, 19%). While anhydrolutein I has been shown to be usually accompanied by minute quantities of 2′,3′-anhydrolutein II (ca. 7–10%) in human plasma, 3′,4′-anhydrolutein III has not been detected. The presence of anhydrolutein I and II in human plasma is postulated to be due to acid catalyzed dehydration of the dietary lutein as it passes through the stomach. These anhydroluteins have also been prepared by conversion of lutein diacetate to the corresponding anhydrolutein acetates followed by alkaline hydrolysis. However, under identical acidic conditions, loss of acetic acid from lutein diacetate proceeded at a much slower rate than dehydration of lutein. The structures of the synthetic anhydroluteins, including their absolute configuration at C(3) and C(6′) have been unambiguously established by ¹H NMR and in part by ¹³C NMR, and circular dichroism.     

Olefin versus sulfur coordination of benzo[b]thiophene (BT) in Cp(CO)2Re(η:η-μ2-BT)Cr(CO)3

Reactions of Cr(CO)₃(η⁶-BT), in which the Cr is π-coordinated to the benzene ring of benzo[b]thiophene (BT), with Cp′(CO)₂Re(THF), where Cp′ = η⁵-C₅H₅ or η⁵-C₅Me₅, give the products Cp′(CO)₂Re(η²:η⁶-μ₂-BT)Cr(CO)₃ in which the Cr remains coordinated to the benzene ring and Re is bound to the C(2)=C(3) double bond. An X-ray diffraction study of Cp(CO)₂Re(η²:η⁶-μ₂-BT)Cr(CO)₃ (3) provides details of the geometry. This structure contrasts with that of the Cp′(CO)₂Re(BT) complexes that exist as mixtures of isomers in which the BT is coordinated to the Re through either the double bond (2,3-η²) or the sulfur (η¹(S)). Thus, the electron-withdrawing Cr(CO)₃ group in 3 stabilizes the 2,3-η² mode of BT coordination to the Cp′(CO)₂Re fragment. Implications of these results for catalytic hydrodesulfurization of BT are discussed. Crystal data for 3: triclinic, space group

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Reactions of tungsten phosphonium carbyne complexes with aryloxide nucleophiles to form aryloxycarbyne and η-ketenyl complexes

Tungsten phosphoranylideneketene complexes of the type Tp′(CO)(p-OC₆H₄R)W(η²-(C,C)---O=CC---PR′₂Ph) (R=NO₂, R′=Me (6a); R=NO₂, R′=Ph (6b); R=CN, R′=Me (7a); R=CN, R′=Ph (7b); R=Cl, R′=Ph (8b)) have been synthesized from phosphonium carbyne precursors in a reaction that reflects coupling of carbonyl and carbyne ligands. In addition to these products, aryloxycarbyne complexes Tp′(CO)₂WCO(p-C₆H₄NO₂) (9a), Tp′(CO)₂WCO(p-C₆H₄CN) (9b), and Tp′(CO)₂WCO(p-C₆H₄Cl) (9c)) have been prepared via substitution of the phosphonium carbyne phosphine with an aryloxide nucleophile. The product ratio of substitution at the carbyne carbon to carbonyl–carbyne coupling can be tuned by variation of the aryloxide para-substituent. Aryloxy carbyne complexes are the favored products with stronger nucleophiles, while weaker nucleophiles result in a mixture of aryloxy carbyne complexes and η²-ketenyl coupled complexes. Formation of η²-ketenyl complexes is favored for the least nucleophilic aryloxides. Ketenyl complexes 6a and 6b were methylated at the ketenyl oxygen to form cationic alkyne complexes [Tp′(CO)(p-OC₆H₄NO₂)W(η²-(C,C)---CH₃OCCPR₂Ph)][OTf] (R=Me (10a), R=Ph (10b)). The structures of η²-ketenyl complexes 6a and 7b and the structure of cationic alkyne complex 10a were determined by X-ray crystallography.     

Design, synthesis and preliminary evaluation of novel 3′-Substituted carboxycyclopropylglycines as antagonists at group 2 metabotropic glutamate receptors

Two novel 3′-substituted carboxycylopropylglycines, (2S,1′S,2′S,3′R)-2-(3′-xanthenylmethyl-2′-carboxycyclopropyl)glycine (8a) and (2S,1′S,2′S,3′R)-2-(3′-xanthenylethyl-2′-carboxycyclopropyl)glycine (8b), were synthesized and evaluated as mGluR ligands. Compound 8b showed to be a potent group II antagonist with submicromolar activity.     

Synthesis of non-immunosuppressive cyclophilin-Binding cyclosporin A derivatives as potential anti-HIV-1 drugs

Original cyclosporin A (CsA) derivatives bearing various alkylthio side chains at the sarcosine residue 3 (R configuration) and for the most potent and selective compounds a 4′-hydroxyl group at the Me-Leucine residue 4 were prepared in one or two steps from commercially available CsA. The [2-(dimethyl or diethylamino)-ethylthio-Sar]³-[(4′-OH)MeLeu]⁴-CsA derivatives 3k and 3l displayed potent in vitro anti-HIV-1 (IC₅₀ 46 nM) and low immunosuppressive activities (IC₅₀≥1500 nM).     

Further farnesyl-homogentisic acid derivatives from Otoba parvifolia

The seeds of Otoba parvifolia contain three novel compounds apparently derived from homogentisic acid, rel-(1′R,5′R)-2-(1′-farnesyl-5′-hydroxy-2′-oxocyclohex-3′-en-1′-yl)-acetic acid and its acetate as well as rel-(1′R,4′S,5′R)-2-(1′-farnesyl-4′,5′-dihydroxy-2′-oxocyclohexan-1′-yl)-acetic acid δ-lactone. The structure of an additional isolate, previously described as 2-(1′-farnesyl-2′-hydroxy-5′-oxocyclohex-3′-en-1′-yl)-acetic acid γ-lactone was revised to rel-(1′R,5′R)-2-(1′-farnesyl-5′-hydroxy-2′-oxocyclohex-3′-en-1′-yl)-acetic acid δ-lactone.     

A pterocarpan and two isoflavans from alfalfa

(−)6aR,11aR-Dihydro-3-hydroxy-9,10-dimethoxy-6H-benzofuro[3,2c] [1]-benzopyran (10-methoxymedicarpin), (+)-(2,3,4,-trimethoxyphenyl)-2,3-dihydro-7-hydroxy-4H-1-benzopyran (7-hydroxy-2′,3′,4′-trimethoxyisoflavan) and (+)-(2,3,4-trimethoxy-5-hydroxyphenyl)-2,3-dihydro-7-hydroxy-4H-1-benzopyran (7,5′-dihydroxy-2′,3′,4′-trimethoxyisoflavan) were isolated for the first time from dried Medicago sativa hay. Structural assignments were based on ¹H NMR and mass spectra, X-ray crystallography, and optical rotations.     

Alkaloids from Heimia salicifolia

Two alkaloids, 9β,2′-dihydroxy-4′′,5′′-dimethoxy-lythran-12-one or 9β-hydroxyvertine (1) and (2S,4S,10R)-4-(3-hydroxy-4-methoxyphenyl)-quinolizidin-2-acetate (2), as well as seven known alkaloids, lythrine (3), dehydrodecodine (4), lythridine (5), vertine (6), heimidine (7), lyfoline (8) and epi-lyfoline (9), were isolated from Heimia salicifolia. The structures of these compounds were elucidated by extensive spectroscopic techniques. Furthermore, the structures of 2, 3, and 6 were confirmed by X-ray crystallography, including absolute configuration determination of 2 and 6. Compounds 6 and 9 showed moderate antimalarial activity.     

Relationship between pKa of 8-quinolinol derivatives and a π-donor ability of the 8-quinolinolato oxygen in linear nitrosylruthenium(II) complexes

The relationship between the pK_a of 8-quinolinol derivatives {8-quinolinol (Hqn), 2-methyl- (H2-Meqn), 2,4-dimethyl- (H2,4-diMeqn), 5-chloro- (H5-Clqn) and 5,7-dichloro-8-quinolinols (H5,7-diClqn)} and a π-donor ability of the 8-quinolinolato oxygens has been investigated by the identification of the structures of the major products, [RuCl(QN)(QN′)NO] (HQN=8-quinolinol derivative; HQN′=different 8-quinolinol derivatives), obtained by the reaction of [RuCl₃(QN or QN′)NO]⁻ with HQN′ or HQN. The results obtained clearly showed that the oxygen of the 8-quinolinol derivative that has a higher pK_a predominantly coordinates in the trans position to the NO ligand and is a better π-electron donor. The order of the π-electron donor ability for the oxygen of the 8-quinolinol derivatives is as follows: H2-Meqn≥H2,4-diMeqn>Hqn≥H5-Clqn>H5,7-diClqn, almost agreeing with the magnitude of the pK_a values of the corresponding 8-quinolinols. The structures of cis-1 [RuCl(5,7-diClqn)₂NO] and cis-1 [RuCl(5,7-diClqn)(2-Meqn)NO] were determined by X-ray diffraction.