Synthesis of monofluorinated isofagomine analogues and evaluation as glycosidase inhibitors

The straightforward synthesis of monofluorinated isofagomine analogues 1-3 was described. The synthetic strategy featured that the chiral carbon center bearing fluorine atom was constructed stereoselectively via silicon-induced Reformatskii-Claisen rearrangement of allyl bromofluoroacetate. These compounds were tested for inhibition of five glycosidases. The 3S,4R,5R isomer 3 has been found to be a potent inhibitor against β-glucosidase from almonds with K_i value of 11.9 μM.     

Synthesis,characterization and biological evaluation of purine nucleoside analogues

We present a convenient route for the synthesis of C6-amino-C5′-N-cyclopropyl carboxamido-C2-alkynylated purine nucleoside analogues 11a–g via Sonogashira coupling reaction. The nine step synthesis is easy to perform, employing commercially available reagents. Compound 9 is used as key intermediate for the synthesis of analogues 11a–g. Synthetic intermediates and final products are appropriately characterized by IR, ¹H NMR, ¹³C NMR and Mass. The modified nucleoside analogues 11a–g is evaluated for in vitro anticancer activity against MDA-MB-231 and Caco-2 cell lines. Screening data reveals that compounds 11b and 11e displayed potent IC₅₀ value of 7.9, 6.8 µg/mL respectively against MDA-MB-231 and of 7.5, 8.3 µg/mL respectively against Caco-2 than the standard drug doxorubicin, thus establishing the potential anti-cancer properties of these newer derivatives.     

Synthesis and evaluation of calystegine B2 analogues as glycosidase inhibitors.

A practical synthesis of polyhydroxylated 6-oxa-nor-tropanes incorporating the essential structural features of calystegine B(2) from 5-deoxy-5-thioureido and 5-ureido-L-idofuranose precursors is presented. The methodology relies on the ability of pseudoamide-type nitrogen atoms (thiourea, urea, and carbamate) to undergo nucleophilic addition to the masked aldehyde group of the monosaccharide. The generated hemiaminal functionality may further undergo in situ intramolecular glycosidation to give the bicyclic aminoacetal compounds, the whole process being favored by the anomeric effect. A series of derivatives bearing different substituents at nitrogen has been prepared and screened against several glycosidases in comparison with xylonojirimycin-type piperidine analogues. Interestingly, strong and highly specific inhibition of bovine liver beta-glucosidase was observed for 6-oxacalystegine B(2) analogues incorporating aromatic pseudoaglyconic groups. On the basis of these data, a 1-azasugar inhibition mode is proposed for this family of glycomimetics.     

Synthesis of nitrogen analogues of salacinol and their evaluation as glycosidase inhibitors.

The syntheses of two nitrogen analogues (11 and 12) of the naturally occurring sulfonium ion, salacinol (7) are described. The latter compound is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The synthetic strategy relies on the nucleophilic attack of a 1,4-dideoxy-1,4-imino-D- or L-arabinitol at the least hindered carbon of 2,4-O-benzylidene D- or L-erythritol-1,3-cyclic sulfate. The nitrogen analogues bear a permanent positive charge and serve as mimics of the sulfonium ion. We reasoned that these ammonium derivatives should function in a manner similar to that of known glycosidase inhibitors of the alkaloid class such as castanospermine (4) and deoxynojirimycin (5). Enzyme inhibition assays indicate that salacinol (7) is a weak (K(i) = 1.7 mM) inhibitor of glucoamylase, whereas compounds 11 and 12 inhibit glucoamylase with K(i) values in the range approximately 10-fold higher. The nitrogen analogues 11 and 12 showed no significant inhibitory effect of either barley alpha-amylase (AMY1) or porcine pancreatic alpha-amylase (PPA) at concentrations of 5 mM. In contrast, salacinol (7) inhibited AMY1 and PPA in the micromolar range, with K(i) values of 15 +/- 1 and 10 +/- 2 microM, respectively.     

Synthesis of stemofoline analogues as acetylcholinesterase inhibitors

Thirty-two new stemofoline analogues were prepared from didehydrostemofoline for studies as AChE inhibitors. C-3 Side-chain modified amino, carbamate, triazole and oxazole stemofoline derivatives were prepared. In general the amine derivatives were found to be stronger inhibitors of AChE than their alcohol analogues that we previously reported. Compounds 5 and 26, with small C-3 side-chain substituents, were two of the most active inhibitors. Preliminary molecular docking studies suggested that these compounds may inhibit AChE by binding horizontally along the passage of the active-site gorge and block access to acetylcholine.     

Synthesis of new nitrogen analogues of salacinol and deoxynojirimycin and their evaluation as glycosidase inhibitors

The synthesis of two enantiomerically pure iminosugars, analogues of 1-L-deoxynojirimycin (l-DNJ) and 1-D-deoxymannojirimycin (DMJ), was achieved using cyclic sulfate substituted isoxazoline derivatives. The piperidine ring was formed via the reduction of an isoxazoline into an amine which underwent a spontaneous intramolecular cyclization by reaction with the cyclic sulfate moiety. The nucleophilic attack of these two trisubstituted piperidines and morpholine on L- and D-erythritol-1,3-cyclic sulfates gave six new nitrogen analogues of salacinol. The inhibitory properties of the synthesized salacinol analogues were evaluated on several commercial glycosidases.     

Synthesis of novel pyrimidine nucleoside analogues

Two new tetrazolopyrimidinedeoxynucleosides were synthesized and their physico-chemical data are described. Results of preliminary analyses of their biological properties are also reported.     

Synthesis of sphingomyelin carbon analogues as sphingomyelinase inhibitors

The highly efficient and stereocontrolled syntheses of sphingomyelin carbon analogues 1 and 2 were achieved by effectively utilizing Hofmann rearrangement of enantiomerically pure beta-hydroxyamide 7, which was prepared by an asymmetric hydrogenation of alpha-acyl-gamma-butyrolactone 9 and ring opening with NH(3). Intermediary isocyanate 6 was selectively trapped with the vicinal hydroxy group in an intramolecular fashion to produce an oxazolidinone derivative, 5. In the synthesis of a quite polar compound such as 1, a convenient one-pot procedure of the introduction of a benzyloxycarbonyl group into the hydroxy group resulting from the oxazolidinone ring opening is another key point, because, in addition to the efficiency, this protecting group was easily removable by a simple procedure and workup at the final step. Both synthesized compounds 1 and 2 showed moderate inhibitory activity toward sphingomyelinase from B. cereus.     

Synthesis and evaluation of substrate analogues as mechanism-based inhibitors of type II isopentenyl diphosphate isomerase

Type 2 isopentenyl diphosphate isomerase (IDI-2), which catalyzes the interconversion of isopentenyl diphosphate and dimethylallyl diphosphate, contains a tightly bound molecule of FMN. To probe the mechanism of the reaction, cyclopropyl and epoxy substrate analogues, designed to be mechanism-based irreversible inhibitors, were synthesized and evaluated with IDI-2 from Thermus thermophilus. The cyclopropyl analogues were alternative substrates. The epoxy analogue was an irreversible inhibitor, with kI = 0.37 +/- 0.07 min(-1) and KI = 1.4 +/- 0.3 microM. LC-MS studies revealed formation of an epoxide-FMN adduct.     

Synthesis and evaluation of keto-glutamine analogues as inhibitors of hepatitis A virus 3C proteinase

Hepatitis A virus (HAV) 3C enzyme is a picornaviral cysteine proteinase involved in the processing of the initially synthesized viral polyprotein and is therefore important for viral maturation and infectivity. Although it is a cysteine proteinase, this enzyme has a topology similar to those of the chymotrypsin-like serine proteinases. Since the enzyme recognizes peptide substrates with a glutamine residue at the P(1) site, a number of ketone-containing glutamine compounds analogous to nanomolar inhibitors of cathepsin K were synthesized and tested for inhibition against HAV 3C proteinase. In addition, a 3-azetidinone scaffold was incorporated into the glutamine fragment but gave only modest inhibition. However, introduction of a phthalhydrazido group alpha to the ketone moiety gave significantly better inhibitors with IC(50) values ranging from 13 to 164 microM, presumably due to the effect of intramolecular hydrogen bonding to the ketone. In addition, the tetrapeptide phthalhydrazide 24 was found to be a competitive reversible inhibitor (K(i) = 9 x 10(-6) M) and also showed no loss of inhibitory potency in the presence of dithiothreitol.     

Synthesis and biological evaluation of nucleoside dicarboxylates as potential mimics of nucleoside diphosphates

A series of nucleotide analogues wherein the diphosphate moiety has been replaced by a dicarboxylate were synthesized and tested for inhibitory activity against nucleoside diphosphate (NDP) kinase as well as several pathogenic bacterial strains.     

Synthesis of 4-nitromethylene-1,4-dihydropyrimidine derivatives as pyrimidine nucleoside analogues

The synthesis of 4-nitromethylene-1,4-dihydropyrimidine derivatives as pyrimidine nucleoside analogues was developed, starting from 3-nitropyran-2-one N-functionalized amidines. Primary amines were reacted with amidines yielding 4-nitromethylene-1,4-dihydropyrimidine derivatives. In an initial survey, several 4-nitromethylene-1,4-dihydropyrimidines turned into 4-nitromethylene-1,2,3,4-tetrahydropyrimidine derivatives under different reduction conditions. The reduction reaction also induced a change in the exocyclic double bond configuration from (E) to (Z), due to an intramolecular hydrogen bond.     

Synthesis of selenium analogues of the naturally occurring glycosidase inhibitor salacinol and their evaluation as glycosidase inhibitors

The syntheses of two selenium analogues (10 and 11) of the naturally occurring sulfonium ion, salacinol (3), are described. Salacinol is one of the active principles in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The synthetic strategy relies on the nucleophilic attack of a 2,3,5-tri-O-benzyl-1,4-anhydro-4-seleno-D-arabinitol at the least hindered carbon of benzyl- or benzylidene-protected D- or L-erythritol-1,3-cyclic sulfate. The use of 1,1,1,3,3,3-hexafluoro-2-propanol as a solvent in the coupling reaction proves to be beneficial. Enzyme inhibition assays indicate that 10 is a better inhibitor (K(i) = 0.72 mM) of glucoamylase than 3, which has a K(i) value of 1.7 mM. In contrast, 11 showed no significant inhibition of glucoamylase. Compounds 10 and 11 showed no significant inhibition of barley-alpha-amylase or porcine pancreatic-alpha-amylase.     

Synthesis of novel analogues of zanamivir as neuraminidase inhibitors

<正>A versatile synthesis of novel zanamivir analogues modified at C-4 and C-8 positions was described.The formation of amides from the acid with corresponding amines,followed by click chemistry generated the triazole substituted compounds as novel analogues of neuraminidase inhibitors in good yields.     

Synthesis and evaluation of 1-deoxy-D-xylulose 5-phosphate analogues as chelation-based inhibitors of methylerythritol phosphate synthase

[structures: see text] A series of 1-deoxy-D-xylulose 5-phosphate (DXP) analogues were synthesized and evaluated as inhibitors of E. coli methylerythritol phosphate (MEP) synthase. In analogues 1-4, the methyl group in DXP was replaced by hydroxyl, hydroxylamino, methoxy, and amino moieties, respectively. In analogues 5 and 6, the acetyl moiety in DXP was replaced by hydroxymethyl and aminomethyl groups. These compounds were designed to coordinate to the active site divalent metal in MEP synthase. The carboxylate (1), methyl ester (3), amide (4), and alcohol (5) analogues were inhibitors with IC50's ranging from 0.25 to 1.0 mM. The hydroxamic acid (2) and amino (6) analogues did not inhibit the enzyme.     

Synthesis and evaluation of hexitol nucleoside congeners as ambiguous nucleosides

A series of anhydrohexitol nucleoside congeners was synthesized as ambiguous or so-called universal nucleosides and was evaluated for their hybridization potential and discrimination properties. The 1,5-anhydro-2,3-dideoxy-2-(5-nitroindazol-1-yl)-d-arabino-hexitol 4e showed the lower spread in T_m values upon hybridization to the natural bases, with minimal destabilization, and therefore behaved as a true ambiguous nucleoside.     

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.     

新型类嘌呤脱氧核糖核苷类化合物的合成

以1,3,5-三-O-苯甲酰基-2-脱氧-2-β-氟-α-D-核糖为原料,通过溴代、与4-氯吡咯[2,3-d]嘧啶的钠盐偶合、4-氯的氨基化等反应,设计合成了一系列具有新型结构的4-取代-9-(2′-脱氧-2′-β-氟-β-D-呋喃糖基)吡咯[2,3-d]嘧啶类化合物,其化学结构经核磁共振、高分辨率质谱分析确证;并且初步探讨了反应条件和反应机理.结果表明,以无水四氢呋喃为溶剂,密闭高压回流反应,反应产率较高.     

Synthesis and antiviral evaluation of new 2,5-disubstituted 1,3,4-oxadiazole derivatives and their acyclic nucleoside analogues

Abstract  

A number of new 5-[(naphthalen-1-yloxy)-methyl]-1,3,4-oxadiazole derivatives were synthesized. Sugar 2-[5-[(naphthalen-1-yloxy)methyl]-1,3,4-oxadiazol-2-ylthio]acetohydrazones were prepared by condensation of the hydrazide with the corresponding monosaccharides. Cyclization of the sugar hydrazones with acetic anhydride afforded the substituted oxadiazoline derivatives. The synthesized compounds displayed different degrees of antiviral activities or inhibitory actions against HCV and HIV viruses.