Synthesis and Anti-HIV-1 Activity of 4- and 5-Substituted 1,2,3-Triazole-TSAO Derivatives

Abstract

Several 4- or 5-monosubstituted and 4,5-disubstituted 1,2,3-triazole analogues of the anti-HIV-1 lead compound [1-[2′,5′-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]thymine]-3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide) (TSAO-T) have been prepared and evaluated for their inhibitory effect against HIV-1-induced cytopathicity.     

Isoflavones from Lupinus angustifolius root

Two novel isoflavones, 5,7,2′-trihydroxy-6-(3,3-dimethylallyl)-[6″,6″-dimethylpyrano(2″,3″:4′,3′) ]-isoflavone and 5,2′,4′-trihydroxy-3′-(3,3-dimethylallyl)-[6″,6″-dimethylpyrano(2″,3″:7,6)]isoflavone, have been isolated from the roots of Lupinus angustifolius cv. Uniharvest. Structures were established by analysis of ¹³C NMR and other spectral data, and by chemical conversion of one of the compounds to a coumaronochromone.     

Dibenzylbutyrolactone lignans from Piper cubeba

Six more lignans have been isolated from the hot petrol extract of Piper cubeba fruits. Of these, three compounds which have been isolated from a natural source for the first time were characterized as (2R,3R)-2-(5″-methoxy-3″,4″-methylenedi [(−)-cubebinone], (2R,3R)-2-(3″,4″-methylenedioxybenzyl)-3-(3′,4′,5′-trimethoxybenzyl)butyrolactone [(−)-isoyatein] and (2R,3R)-2-(3″,4″,5″-trimethoxybenzyl)-3-(3′,4′-dimethoxybenzyl)butyrolactone [(−)-di-O-methyl thujaplicatin methyl ether, i.e. (−)-thujaplicatin trimethyl ether]. The other three compounds were identified as (−)-yatein, (−)-cubebininolide and (2R,3R)-2-(3″,4″-methylenedioxybenzyl)-3-(3′,4′-dimethoxybenzyl) butyrolactone.     

Fully relativistic rovibrational energies and spectroscopic constants of the lowest {\text{X}}:(1)0_g^{ + } , A′:(1)2 u , A:(1)1 u , {\text{B}}\prime :(1)0_u^{ - } and {\text{B}}:(1)0_u^{ + } states of molecular chlorine

The main goal of this paper is to present the rovibrational energies and spectroscopic constants of the Cl(2) molecular system in the relativistic states [Formula: see text], A':(1)2( u ), A:(1)1( u ), [Formula: see text] and [Formula: see text]. More precisely, we have evaluated the Cl(2) ω ( e ), ω ( e ) x ( e ), ω ( e ) y ( e ), α ( e ), γ ( e ) and B ( e ) rovibrational spectroscopic constants using two different procedures. The first was obtained by combining the rovibrational energies, calculated through solving Schr?dinger's nuclear equation and the diatomic rovibrational energy equation. The second was obtained by using the Dunham method. The calculated properties are in good agreement with available experimental data.     

Thonningine-A and thonningine-B: two 3-phenylcoumarins from the seeds of Millettia thonningii

The seeds of Millettia thonningii have yielded four isoflavones and three 4-hydroxy-3-phenylcoumarins, of which two are novel. On the basis of spectral analyses the novel compounds have been identified as 4-hydroxy-5,8-dimethoxy-3-(3′,4′-methylenedioxy)phenyl-2″-isopropenylfurano (4″,5″:6,7)coumarin (thonningine-A) and 4-hydroxy-5,8-dimethoxy-3-(4′-methoxy)phenyl-2″-isopropenylfurano(4″, 5″: 6,7)coumarin (thonningine-B).     

Toddasin,a new dimeric coumarin from Toddalia asiatica

A new dimeric coumarin, named toddasin and possessing a cyclohexene ring with a vinylic side-chain interposed between the two coumarin moieties has been isolated from the roots of Toddalia asiatica. It has been characterized as (E)-8,8′-[1″,4″-dimethyl-3″ -cyclohexen-1″,2″-ylene vinylene]-bis-[5,7-dimethoxycoumarin] (1). The proposed structure is supported by the mass fragmentation of its dihydro derivative (2).     

Minor xanthones from Rheedia gardneriana

8-Deoxygartanin and two new xanthones, 1,5-dihydroxy-6′,6′-dimethyl-2H-pyrano(2′,3′:3,2)-6″,6″-dimethyl-2H-pyrano(2″,3″:6,7)xanthone and 1,5,6-trihydroxy-6′,6′-dimethyl-2H-pyrano(2′,3′:3,2)-7-(3-methylprop-2-enyl)xanthone, have been isolated from the roots of Rheedia gardneriana. The latter of the two new xanthones has been assigned the trivial name 7-prenyljacareubin while the former has the structure erroneously assigned to pyranojacareubin reported from Garcinia densivenia. The correct identity of the G. densivenia xanthone has been shown to be rheediaxanthone-A.     

Diarylpropanoids from Iryanthera polyneura

The trunk wood of Iryanthera polyneura Ducke (Myristicaceae) contains pinocembrin, 1-(2′,4′-dihydroxyphenyl)-3-(3″,4″-methylenedioxyphenyl)-propane, 1-(2′,4′-dihydroxy-3′-methylphenyl)-3-(2″-methoxy-4″, 5″-methylenedioxyphenyl)-propane and 4,2′,4′-trihydroxy-3-methoxydihydrochalcone.     

18-Norspirostanol derivatives from Trillium tschonoskii

Three 18-norspironstanol oligoglycosides partly acylated in their sugar moieties were isolated from the underground parts of Trillium tschonoskii. Their structures were characterized, as 1-O-[2″,3″,4″-tri-O-acetyl-α-l-rhamnopyranosyl-(1 → 2)-α-l-arabinopyranosyl]-epitrillenogenin-24-O-acetate, 1-O-[2″,3″,4″-tri-O-acetyl-α-l-rhamno-pyranosyl-(1 → 2)-α-l-arabinopyranosyl]-epitrillenogenin and 1-O-[2″,4″-di-O-acetyl-α-l-rhamnopyranosyl-(1 → 2)-α-l-arabinopyranosyl]-epitrillenogenin-24-O-acetate.     

Lignans from Piper cubeba

From the hot petrol extract of Piper cubeba ftuits, six lignans were isolated. Two of these, which have been obtained from a natural source for the first time, have been characterized as (2R,3R)-2-(3″,4″,5″-trimethoxybenzyl)-3-(3′,4′-methylenedioxybenzyl)-1,4-butanediol [(?)-dihydroclusin] and (3R,4R)-3,4-bis-(3,4,5-trimethoxybenzyl)tetra-hydro-2-furanol [(?)-cubebinin]. (?)Cubebin, (?)-hinokinin, (?)-clusin and (?)-dihydrocubebin were also found in this plant. Only (?)-cubebin has been reported so far from this source.     

Isolation of novel phenolic compounds with multidrug resistance (MDR) reversal properties from Onychium japonicum

We isolated seven novel compounds, namely, 3',4',6-trihydroxy-2,4-dimethoxy-3-(3″,4″-dihydroxybenzyl)chalcone (1), 3',6-dihydroxy-2,4,4'-trimethoxy-3-(3″,4″-dihydroxybenzyl)chalcone (2), α,β-dihydro-3',6-dihydroxy-2,4,6'-trimethoxy-3-(3″,4″-dihydroxybenzyl)chalcone (3), 3',4,4'-trihydroxy-2,6-dimethoxychalcone (4), 4',5,7-trihydroxy-6-(3″,4″-dihydroxybenzyl)flavone (5), 3-(3',4'-dihydroxybenzyl)-6,7-dihydroxycoumarin (6), 3-(3',4'-dihydroxyphenyl)-3,4-dihydroisocoumarin (7), as well as a known compound, 3',4',7-trihydroxy-5-methoxyflavanone (8) from the whole grass of Onychium japonicum, and elucidated their structures by spectroscopic methods. Compounds 1-3 exhibited significant multidrug resistance (MDR) reversal effects on MCF-7/ADR and Bel-7402/5-Fu cell lines.     

The major flavonoids of the seed of Tephrosia apollinea

A total of six complex 7-oxygenated-8-prenylflavones have been isolated from the seeds of Tephrosia apollinea and identified as the diastereoisomers (?)-semiglabrin and (?)-pseudosemiglabrin, (+)-glabratephrin, (+)-glabratephrinol, appollinine (7-methoxy-8-[3″-(2″,5″-dihydro-5″,5″-dimethyl-2″-oxofuryl)]-flavone and lanceolatin-A. The use of ¹³C NMR in the structure elucidation of flavones of this type is discussed. The potential chemotaxonomic value of Tephrosia flavones of the type isolated from T. apollinea is explored.     

An alkaloid from Haplophyllum tuberculatum

A new alkaloid (+)-tuberine was isolated from Haplophyllum tuberculatum. Physicochemical and spectral evidence established its structure and stereochemistry as N- benzoyl-4′-[(2″S,3″S,6″S)-(+)-7″-acetoxy-2″-hydroxy-3″,7″-dimethyl-3″,6″-epoxyoctyloxy]phenethylamine.     

Les Flavonols d'Asclepias Syriaca

Eight flavonoids are present in the leaves of Asclepias syriaca. Three have been identified as quercetin, kaempferol, isorhamnetin; a structure of a fourth, 3,5,3′,4′-tetrahydroxy-7,8-(2″,2″-dimethyl-4″-methyl-5″,6″) pyranoflavone(I), has been established by study of its spectral properties (UV, IR, MS, NMR) and those of its acetate.     

Design of novel cationic ligands for the purification of trypsin-like proteases by affinity chromatography

A number on new cationic ligands have been designed and synthesized for the selective resolution an purification of the trypszin-like proteases. A series of ligands based on 4-[2′-methyl-4′-(2″,4″-dichloro-1″,3″,5″-triazin-6-ylamino) phenylazo]benzamidine were able to bind to trypsin and the trypsin-like proteases, thrombin and urokinase, but bound pancreatic kallikrein only weakly. Ligands possessing a second cationic group (either 4-aminophenyltrimethylammonium or 4-aminobenzamidine) substituted onto the triazine ring displayed higher affinities than the parent compound for trypsin in solution but bound the enzyme weakly or not at all after immobilization. In contrast, these bis-cationic ligands bound pancreatic kallikrein in solution ad following immobilization. The presence of the second cationic group was crucial, since its replacement by neutral or anionic groups led to loss of affinity for pancreatic kallikrein. One of the bis-cationic ligands was used to purify pancreatic kallikrein 9.5-fold from a crude pancreatic extract in 79% yield, to generate a product 99.9% free of contaminating trypsin activity.     

Xanthones and biflavonoids from Garcinia densivenia stem bark

The stem bark of a species of Garcinia (Guttiferae), provisionally identified as G. densivenia, has yielded a xanthone and two biflavonoids. The xanthone has been characterized as a novel 1,3,5,6-tetraoxygenated compound and has been assigned the trivial name pyranojacareubin (1,5-dihydroxy-6′,6′-dimethylpyrano (2′,3′:3,2)-6″,6″-dimethylpyrano (2″,3″:6,7)-xanthone). The biflavonoids were identified as morelloflavone and its methyl ether derivative, O-methyl fukugetin.     

Chemical modification of the nonreducing,terminal group of maltotriose

O-α-d-Galactopyranosyl-(1→4)-O-α-d-glucopyranosyl-(1→4)-d-glucopyranose (12) was prepared by inversion of configuration at C-4″ of 2,3,2′,3′,6′,2″,3″-hepta-O-acetyl-1,6-anhydro-4″,6″-di-O-methylsulfonyl-β-maltotriose (7), followed by O-deacylation, acetylation, acetolysis, and de-O-acetylation. The intermediate 7 was obtained by treatment of 1,6-anhydro-β-maltotriose (2) with benzal chloride in pyridine, followed by acetylation, removal of the benzylidene group, and methane-sulfonylation. Selective tritylation of 2 and subsequent acetylation afforded 2,3,2′,3′,6′,2″,3″,4″-octa-O-acetyl-1,6-anhydro-6″-O-trityl-β-maltotriose (6), which was O-detritylated and p-toluenesulfonylated to give 2,3,2′,3′,6′,2″,3″,4″-octa-O-acetyl-1,6-anhydro-6″-O-p-tolylsulfonyl-β-maltotriose (13). Nucleophilic displacement of 13 with thioacetate, iodide, bromide, chloride, and azide ions gave 6″-S-acetyl- (14), 6″-iodo- (15), 6″-bromo- (16), 6″-chloro- (19), and 6″-azido- (20) 1,6-anhydro-β-maltotriose octaacetates, respectively. 6″Deoxy- (18) and 6″-acetamido-6″-deoxy (21) derivatives of 1,6-anhydro-β-maltotriose decaacetates were also prepared from 15 and 16, and 20, respectively. Acetolysis of 14, 15, 16, 18, 19, and 21 afforded 1,2,3,6,2′,3′,6′,2″,3″,4″-deca-O-acetyl-6″-S-acetyl (22), -6″-iodo (23), -6″-bromo (24), -6″-deoxy (25), -6″-chloro (26), and -6″-acetamido-6′-deoxy (27) derivatives of α-maltotriose, respectively. O-Deacetylation of 24, 25, and 26 furnished 6″-bromo-(28), 6″-deoxy- (29), and 6″-chloro- (30) maltotrioses, respectively, which on acetylation gave the corresponding β-decaacetates.     

Four New Acylated Iridoid Glycosides from the Aerial Part of Veronicastrum sibiricum and Their Antioxidant Response Element‐Inducing Activity

Four new ( 1 – 4 ) and one known ( 5 ) acylated iridoid glycosides were isolated from the aerial parts of Veronicastrum sibiricum (L.) Pennell . The chemical structures of the isolated compounds were determined to be 3″,4″‐dicinnamoyl‐6‐O‐rhamnopyranosyl‐10‐O‐bergaptol‐5,7‐bisdeoxycynanchoside ( 1 ), 3″,4″‐dicinnamoyl‐6‐O‐rhamnopyranosylpaulownioside ( 2 ), 2″,4″‐dicinnamoyl‐6‐O‐rhamnopyranosylcatalpol ( 3 ), 3″,4″‐dicinnamoyl‐6‐O‐rhamnopyranosylaucubin ( 4 ), and 3″,4″‐dicinnamoyl‐6‐O‐rhamnopyranosylcatalpol ( 5 ) using spectroscopic techniques. Among these compounds, compound 5 increased antioxidant response element (ARE) luciferase activity.     

Quinoline alkaloids and cytotoxic lignans from Haplophyllum tuberculatum

Three quinoline alkaloids and two lignan lactones were isolated from Haplophyllum tuberculatum. Physicochemical and spectral evidence established the structures of two of the alkaloids as a new quinoldione, 3-(1′,1′-dimethylallyl)-3-(3″,3″-dimethylallyl)-1,2,3,4-tetrahydro-2,4-quinoldione and the known 4-(3′,3′-dimethylallyloxy)-3-(3″,3″-dimethylallyl)-2(1H)-quinolone. The former was shown to undergo facile [3,3]-sigmatotropic transformation into the latter. The remaining compounds were identified as the known Polygamain, kusunokinin and 1-methyl-2-n-nonyl-4(1H)-quinolone.     

Four isoflavanones from the stem bark of Platycelphium voënse

From the stem bark of Platycelphium voënse (Leguminosae) four new isoflavanones were isolated and characterized as (S)-5,7-dihydroxy-2′,4′-dimethoxy-3′-(3″-methylbut-2″-enyl)-isoflavanone (trivial name platyisoflavanone A), (±)-5,7,2′-trihydroxy-4′-methoxy-3′-(3″-methylbut-2″-enyl)-isoflavanone (platyisoflavanone B), 5,7-dihydroxy-4′-methoxy-2″-(2?-hydroxyisopropyl)-dihydrofurano-[4″,5″:3′,2′]-isoflavanone (platyisoflavanone C) and 5,7,2′,3″-tetrahydroxy-2″,2″-dimethyldihydropyrano-[5″,6″:3′,4′]-isoflavanone (platyisoflavanone D). In addition, the known isoflavanones, sophoraisoflavanone A and glyasperin F; the isoflavone, formononetin; two flavones, kumatakenin and isokaempferide; as well as two triterpenes, betulin and β-amyrin were identified. The structures were elucidated on the basis of spectroscopic evidence. Platyisoflavanone A showed antibacterial activity against Mycobacterium tuberculosis in the microplate alamar blue assay (MABA) with MIC = 23.7 μM, but also showed cytotoxicity (IC₅₀ = 21.1 μM) in the vero cell test.