Parallel approach for solution-phase synthesis of 2-quinoxalinol analogues and their inhibition of LPS-induced TNF-alpha release on mouse macrophages in vitro

A parallel solution-phase synthesis of 2-quinoxalinol analogues is described. The key step-simultaneous reductions of m-Ar(NO(2))(2) to m-Ar(NH(2))(2) was investigated extensively. We obtained preliminary pharmacological activity of those analogues for the inhibition of LPS-induced TNF-alpha release on mouse macrophage in vitro. Two compounds revealed inhibitory activity, with IC(50) values of 0.40 microM (7-amino-6-[(3-methoxypropyl)amino]-3-methyl-2-quinoxalinol) and 2.2 microM (7-amino-6-[(3-butoxypropyl)amino]-3-methyl-2-quinoxalinol), respectively.     

Design, synthesis and biological activity of new CDK4-specific inhibitors, based on fascaplysin

We present the design, synthesis, and biological activity of three classes of tryptamine derivatives, which are non-planar analogues of the toxic anti-cancer agent fascaplysin. We show these compounds to be selective inhibitors of CDK4 over CDK2, the most active compound has an IC50 for the inhibition of CDK4 of 6 microM.     

Rational design,synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid: a novel conformationally restricted glutamic acid analogue

The design and synthesis of conformationally restricted analogues of alpha-amino acids is an often used strategy in medicinal chemistry research. Here we present the rational design, synthesis, and pharmacological evaluation of 2-azanorbornane-3-exo,5-endo-dicarboxylic acid (1), a novel conformationally restricted (S)-glutamic acid (Glu) analogue intended as a mimic of the folded Glu conformation. The synthesis of 1 was completed in its racemic form in eight steps from commercially available starting materials. As a key step, the first facially selective hydroboration of a 5-methylidene[2.2.1]bicyclic intermediate was investigated. In this transformation, the catalytic methodology of Wilkinson's/catechol borane proved superior to stoichiometric borane or dialkyl borane reagents, in terms of higher diastereomeric excess and chemical yield. To our surprise (+/-)-1 did not show affinity in binding studies on native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) (IC(50) > 300 microM, [(3)H]AMPA) or kainic acid (IC(50) > 160 microM, [(3)H]kainic acid) receptors nor in binding studies on the cloned iGluR5,6 subtypes (IC(50) > 300 microM, [(3)H]kainic acid).     

Synthesis of novel curcumin analogues and their evaluation as selective cyclooxygenase-1 (COX-1) inhibitors

Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Recent studies have indicated that cyclooxygenase-1 (COX-1) plays an important role in inflammation and carcinogenesis. In order to find more selective COX-1 inhibitors a series of novel curcumin derivatives was synthesized and evaluated for their ability to inhibit this enzyme using in vitro inhibition assays for COX-1 and COX-2 by measuring PGE(2) production. All curcumin analogues showed a higher rate of COX-1 inhibition. The most potent curcumin compounds were (1E,6E)-1,7-di-(2,3,4-trimethoxyphenyl)-1,6-heptadien-3,5-dione (4) (COX-1: IC(50) = 0.06 microM, COX-2: IC(50) > 100 microM, selectivity index>1666) and (1E,6E)-methyl 4-[7-(4-methoxycarbonyl)phenyl]-3,5-dioxo-1,6-heptadienyl]benzoate (6) (COX-1: IC(50) = 0.05 microM, COX-2: IC(50) > 100 microM, selectivity index > 2000). Curcumin analogues therefore represent a novel class of highly selective COX-1 inhibitors and promising candidates for in vivo studies.     

Nucleosides and nucleotides. 186. Synthesis and biological activities of pyrimidine carbocyclic nucleosides with a hydroxyamino group instead of a hydroxymethyl group at the 4'-position of the sugar moiety.

Pyrimidine carbocyclic nucleosides with a hydroxyamino group instead of a hydroxymethyl group at the 4'-position of the sugar moiety were designed as potential antitumor and/or antiviral agents. Pd (O)-catalyzed reactions of enantiomerically pure (+)-(1R,4S)-4-[(tert-butyldiphenylsilyl)oxy]-1-(ethoxycarbonylo xy)-2- cyclopentene (9) with N3-benzoylthymine and -uracil gave carbocyclic nucleosides 10 and 11. Subsequent Pd (O)-catalyzed reactions of N3-benzoyl-1-[(1R,4S)-4-(ethoxycarbonyloxy)-2-cyclopenten-1- yl]thymine (14) and -uracil (15) with O-benzylhydroxylamine smoothly gave the hydroxyamino-substituted carbocyclic nucleosides 16 and 17. From these nucleosides, the target compounds were prepared after deprotection or further reactions. The 2',3'-didehydro-2',3'-dideoxythymidine (D4T) analogue 20 was the most effective compound, with IC50 values of 27.3 and 34.5 microM against KB and L1210 cells in vitro. Carbocyclic analogues of uridine and cytidine (29 and 32) were less effective than 20 against both cell lines.     

Synthesis of natural flutimide and analogous fully substituted pyrazine-2,6-diones, endonuclease inhibitors of influenza virus

Flutimide, a fully substituted 1-hydroxy-3H-pyrazine-2,6-dione, is a fungal metabolite isolated from a new species of Delitschia cofertaspora. It has been shown to selectively inhibit cap-dependent endonuclease activity of influenza virus A. The inhibition of this activity is a target for the potential development of a therapeutic agent to treat influenza infections. A convergent total synthesis of flutimide starting from L-leucine has been described. The synthetic methodology has been extended to include the synthesis of specifically designed aromatic analogues of flutimide, some of which exhibited greater than 7-fold improvement in activity. The most potent compounds were those with p-fluorobenzylidene or p-methoxybenzylidene substitutions at C-5 of 3H-pyrazine-2,6-dione and showed IC(50) values of 0.9 and 0.8 microM, respectively. The details of the rationale for the synthetic design, syntheses, and biological activities of these analogues are described.     

Inhibition of chitin synthase by a series of 7-deoxycasuarine stereoisomers designed as constrained analogues of the potent inhibitor 6-deoxyhomoDMDP

A series of polyhydroxy-pyrrolizidines were designed as constrained analogues of 6-deoxyhomoDMDP, a potent naturally occurring inhibitor of chitin synthase. Enzymatic evaluation revealed that 7-deoxycasuarine was the best inhibitor of the series (IC50 = 820 microM) displaying a non-competitive inhibition pattern, whereas the other tested compounds had IC50 in the range 4.3-18.9 mM. This is the first report of pyrrolizidine-type iminosugars inhibiting a glycosyltransferase. In addition, the biological evaluation towards glycosidases of these synthetic casuarine analogues is also disclosed.     

Inhibition of chitin synthase by a series of 7-deoxycasuarine stereoisomers designed as constrained analogues of the potent inhibitor 6-deoxyhomoDMDP

A series of polyhydroxy-pyrrolizidines were designed as constrained analogues of 6-deoxy-homoDMDP, a potent naturally occurring inhibitor of chitin synthase. Enzymatic evaluation revealed that 7-deoxycasuarine was the best inhibitor of the series (IC50 = 820 microM) displaying a noncompetitive inhibition pattern, whereas the other tested compounds had IC50 in the range 4.3-18.9 mM. This is the first report of pyrrolizidine-type iminosugars inhibiting a glycosyltransferase. In addition, the inhibitory potencies towards glycosidases of these synthetic casuarine analogues is also disclosed.     

A model study to carbocyclic formycin A and B analogues

An efficient synthesis of carbocyclic formycin analogues has been developed to serve as the foundation for the preparation of a variety of formycin-based antiviral agents.     

Tyrosinase inhibitors from Rhododendron collettianum and their structure-activity relationship (SAR) studies

A new coumarinolignoid 8'-epi-cleomiscosin A (1) together with the new glycoside 8-O-beta-D-glucopyranosyl-6-hydroxy-2-methyl-4H-1-benzopyrane-4-one (2) have been isolated from the aerial parts of Rhododendron collettianum and their structures determined on the basis of spectroscopic evidences. Tyrosinase inhibition study of these compounds and their structure-activity relationship (SAR) were also investigated. The compounds exhibited potent to mild inhibition activity against the enzyme. Especially, the compound 1 showed strong inhibition (IC50=1.33 microM) against the enzyme tyrosinase, as compared to the standard tyrosinase inhibitors kojic acid (IC50=16.67 microM) and L-mimosine (IC50=3.68 microM), indicating its potential used for the treatment of hyperpigmentation associated with the high production of melanocytes.     

Parallel synthesis and in vitro activity of novel anthranilic hydroxamate-based inhibitors of the prostaglandin H2 synthase peroxidase activity

Currently available non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin are directed at the cyclooxygenase (COX) site, but not the peroxidase (POX) activity of prostaglandin H2 synthase (PGHS). They are thus unable to inhibit the free-radical induced tissue injury associated with PGHS peroxidase activity, which can occur independently of the COX site. A lead compound, anthranilic hydroxamic acid (AHA) was found to have significant PGHS-POX inhibitory activity (IC50= 72 microM). To define the critical parameters for PGHS-POX inhibition, we investigated 29 AHA derivatives, synthesised from their acid precursors, using solid phase synthesis. In vitro analysis demonstrated a ten-fold improvement in inhibition with 3,5-diiodoanthranilic hydroxamic acid (IC50= 7 microM).     

Synthesis of 1,1-linked galactosyl mannosides carrying a thiazine ring as mimetics of sialyl Lewis X antigen: investigation of the effect of carboxyl group orientation on P-selectin inhibition

This paper describes the synthesis of 1,1-linked galactosyl mannosides as sialyl Lewis X mimetics that contain a spiro-ring to position the carboxylate group in a well-defined orientation. It was found that compound 4 is more active as a P-selectin inhibitor (IC50 = 19 microM) than the parent disaccharide 2, which contains a flexible carboxyl group (IC50 = 193 microM). This result is consistent with that observed in the previous NMR study of sialyl Lewis X bound to P-selectin. The chemistry described here should be useful for the development of selective inhibitors of E-, P-, and L-selectins.     

Effects of anonaine on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells

The effects of anonaine, an aporphine isoquinoline alkaloid, on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells were investigated. Anonaine at concentration ranges of 0.01-0.2 microM showed a significant inhibition of dopamine content at 24 h, with an IC(50) value of 0.05 microM. Anonaine at 0.05 microM inhibited tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) activities to 38.4-40.2% and 78.4-90.2% of control levels at 12-24 h and 3-6 h, respectively. TH activity was more influenced than AADC activity. Anonaine also decreased intracellular cyclic AMP levels, but not intracellular Ca(2+) concentrations. In addition, anonaine (0.05 microM) reduced L-DOPA (50 microM and 100 microM)-induced increases in dopamine content at 24 h. However, anonaine (0.05 microM) did not enhance L-DOPA (50 microM and 100 microM)-induced cell death after 24 h. These results suggest that anonaine inhibits dopamine biosynthesis by mainly reducing TH activity without aggravating L-DOPA-induced cytotoxicity in PC12 cells.     

Cyclopentene carbocyclic nucleosides related to the antitumor nucleoside clitocine and their conversion to 8-Aza-neplanocin analogues. Synthesis and antiviral activity

Synthesis of the cyclopentene carbocyclic analogue of the naturally occurring nucleoside clitocine ( 1 ) is reported. Starting with racemic cyclopentenylamine ( 10 ), the heterocyclic moieties of the clitocine analogue 4 and related 1,6-dihydro-6-oxo, 5 , and 2-amino-1,6-dihydro-6-oxo, 6 , analogues were constructed. These compounds were respectively converted to 8-aza-neplanocin A (7) , 8-aza-neplanocin D ( 8 , the inosine analogue), and the corresponding 8-aza-guanosine analogue 9 after reduction of the nitro group followed by nitrous acid cyclization. Extensive antiviral evaluation revealed that only 8-aza-neplanocin A ( 7 ) had enough antiviral activity to warrant further studies. This compound showed weak antiviral activity against HSV-1, HSV-20 and the thymidine kinase deficient (TK-) HSV-1. However, it displayed good antiviral activity against human cytomegalovirus (HCMV) at a concentration of 0.40–2.50 μg/ml, well below the cytotoxicity threshold. This activity profile is consistent with a mechanism of action involving the inhibition of the enzyme adenosylhomo-cysteine hydrolase.     

Antihepatitis B virus constituents of Solanum erianthum

Eleven compounds were isolated from the methanolic extract of the leaves of Solanum erianthum D. Don, including five alpha-linolenic acid analogs, alpha-linolenic acid (1), 13S-hydroxy-9(Z),11(E)-octadecadienoic acid (2), 9S-hydroxy-10(E),12(Z), 15(Z)-octadectrienoic acid (3), 9(Z),11(E)-octadecadienoic acid (4), and octadecanoic acid (5); two benzofuran-type lactones, loliolide (6) and dihydroactinidiolide (7); two steroidal alkaloids, solasonine (8) and solamargine (9); a flavonol glycoside, camelliaside C (10); and a flavone, 5-methoxy-(3,4"-dihydro-3",4"-diacetoxy)-2",2'-dimethylpyrano-(7,8:5",6")-flavone (11). Among these isolated compounds, 9 showed the most potent activity against HBsAg, with an IC50 of 1.57 microM, followed by 8 (IC50 is 5.89 microM). In the testing against HBeAg, 11 was the only active compound with an IC50 of 36.11 microM. Compound 9 also revealed strong inhibition of DNA replication towards HBV and its IC50 was 2.17 microM. However, alpha-linolenic acid (1) showed a prominent selected index (SI), both in anti-HBsAg and inhibition of DNA replication with SI values of 7.75 and 7.18, respectively. This is the first report that unsaturated fatty acid 1, steroidal alkaloid glycoside 9 and flavone 11, all showed excellent activity against HBV. These results provide lead candidates in the development of anti-HBV drugs from natural sources.     

Inhibitory effects of constituents from Cynomorium songaricum and related triterpene derivatives on HIV-1 protease

From CH2Cl2 and MeOH extracts of the stems of Cynomorium songaricum RUPR. (Cynomoriaceae), ursolic acid and its hydrogen malonate were isolated as inhibitors of human immunodeficiency virus type 1 (HIV-1) protease, with 50% inhibitory concentrations (IC50) of 8 and 6 microM, respectively. Amongst various synthesized dicarboxylic acid hemiesters of related triterpenes, inhibitory activity tended to increase in the order of oxalyl, malonyl, succinyl and glutaryl hemiesters, for triterpenes such as ursolic acid, oleanolic acid and betulinic acid. The most potent inhibition was observed for the glutaryl hemiesters, with an IC50 of 4 microM. From the water extract of the stems of C. songaricum, flavan-3-ol polymers, consisting of epicatechin as their extender flavan units, were also found to be potent inhibitory principles against HIV-1 protease.     

Practical synthesis of D- and l-2-cyclopentenone and their utility for the synthesis of carbocyclic antiviral nucleosides against orthopox viruses (smallpox, monkeypox, and cowpox virus)

Highly efficient and practical methodology for the syntheses of D- and l-4,5-O-isopropylidene-2-cyclopentenone (9 and 22), versatile intermediates for the synthesis of carbocyclic nucleosides, have been developed via a ring-closing metathesis reaction from d-ribose in eight steps. The utility of D- and l-4,5-O-isopropylidene-2-cyclopentenone is demonstrated by their application for the preparation of D-cyclopentyl-6-azauridine 12 and D-cyclopentenyl-5-halocytosine nucleosides (33-35) using Mitsunobu reaction to introduce pyrimidine bases as potential antiviral agents. Preliminary antiviral activity against orthopox viruses (smallpox, monkeypox, and cowpox virus) of the synthesized nucleosides are described.     

Probing the structural properties,binding mode and intermolecular interactions of herbacetin against H1N1 neuraminidase using vibrational spectroscopic,quantum chemical calculation and molecular docking studies

Research on Chemical Intermediates - Herbacetin (HBN) is an antiviral agent of H1N1 influenza virus which was reported to inhibit H1N1 neuraminidase (NA) enzyme with IC50 value of...