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Polyphenols are attracting increasing attention in the discovery of useful agents for the treatment of neurodegenerative diseases. Thelesperma megapotamicum (Spreng.) Kuntze belongs to the family Asteraceae, which is known to have a high antioxidant capacity. The phytochemical investigation of T. megapotamicum revealed the presence of 1′-S-isobutyroxyeugenol isobutyrate, (1), lupeol, (2), 1′-S-acetoxyeugenol isobutyrate, (3), stigmasterol, (4), β-sitosterol, (5), eriodictyol, (6), luteolin, (7), and marein, (8), as major secondary metabolites. The neuroprotective activity of this species was studied by evaluating the inhibition in vitro of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the antioxidant capacity of the sub-extracts and of the major metabolites isolated from them. The AChE and BChE inhibition were determined by Ellman’s method and the antioxidant activity by DPPH assay. The inhibitory activity against BChE and the antioxidant capacity of the polyphenols present in T. megapotamicum highlight this species as a promising source of active metabolites for the development of agents for the treatment of neurodegenerative diseases.

Lupane-type triterpenoids have shown a potential effect against neurodegenerative disorders. Alzheimer's disease, one of the common neurodegenerative disease, is evident by the accumulation of amyloid-beta (Aβ) plaque in the extracellular regions of the brain. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a key enzyme for the Aβ formation viathe cleavage of amyloid precursor protein (APP). Therefore, to find the potent BACE1 inhibitors and furthermore to explore the role of the functional group responsible for the strong BACE1 inhibitory activity, we synthesized a series of triterpenoids with lupane skeleton starting from the natural compounds calenduladiol and lupeol. Compound 1 revealed a potent competitive BACE1 inhibitory activity (IC50 = 16.77 ± 1.16 μM; Ki = 19.38). Furthermore, the molecular docking simulation revealed the importance of Tyr198 residue along with the other hydrophobic interactions for the strong affinity of 1‒BACE1 complex. To sum up, our results demonstrated the importance of carbonyl moiety at 3 and 16 position of lupane-type triterpenoid over the hydroxyl group at the same position. Fil: Wagle, Aditi. Pukyong National University. Department of Food and Life Science; Corea del Sur Fil: Seong, Su Hui. Pukyong National University. Department of Food and Life Science; Corea del Sur Fil: Castro, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Faraoni, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Jung, Hyun Ah. Chonbuk National University. Department of Food Science and Human Nutrition; Corea del Sur Fil: Choi, Jae Sue. Chonbuk National University. Department of Food Science and Human Nutrition; Corea del Sur

BACKGROUND/AIM This study examined the potential role of natural triterpenoids lupeol, calenduladiol and heliantriol B2, and a set of 19 derivatives, as antiproliferative and antimetastatic agents against prostate cancer cells. MATERIALS AND METHODS Natural triterpenoids were isolated from Chuqiraga erinaceae. Analogs were obtained by transformations of lupeol and calenduladiol. The effects of compounds on PC-3 and LNCaP cells were determined using the MTT assay. Compounds with half-maximal inhibitory concentration

Tetrahydropyran derivative 1 was discovered in a high-throughput screening campaign to find new inhibitors of mycobacterial InhA. Following initial in-vitro profiling, a structure-activity relationship study was initiated and a focused library of analogs was synthesized and evaluated. This yielded compound 42 with improved antimycobacterial activity and low cytotoxicity. Additionally, the crystal structure of InhA in complex with inhibitor 1 was resolved, to reveal the binding mode and provide hints for further optimization.

Isoniazid (INH) remains one of the cornerstones of antitubercular chemotherapy for drug-sensitive strains of M. tuberculosis bacteria. However, the increasing prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains containing mutations in the KatG enzyme, which is responsible for the activation of INH into its antitubercular form, have rendered this drug of little or no use in many cases of drug-resistant tuberculosis. Presented herein is a novel family of antitubercular direct NADH-dependent 2-trans enoyl-acyl carrier protein reductase (InhA) inhibitors based on an N-benzyl-4-((heteroaryl)methyl)benzamide template; unlike INH, these do not require prior activation by KatG. Given their direct InhA target engagement, these compounds should be able to circumvent KatG-related resistance in the clinic. The lead molecules were shown to be potent inhibitors of InhA and showed activity against M. tuberculosis bacteria. This new family of inhibitors was found to be chemically tractable, as exemplified by the facile synthesis of analogues and the establishment of structure-activity relationships. Furthermore, a co-crystal structure of the initial hit with the enzyme is disclosed, providing valuable information toward the design of new InhA inhibitors for the treatment of MDR/XDR tuberculosis.

A set of triterpenoids with different grades of oxidation in the lupane skeleton were prepared and evaluated as cholinesterase inhibitors. Allylic oxidation with selenium oxide and Jones’s oxidation were employed to obtain mono-, di- and tri-oxolupanes, starting from calenduladiol (1) and lupeol (3). All the derivatives showed a selective inhibition of butyrylcholinesterase over acetylcholinesterase (BChE vs. AChE). A kinetic study proved that compounds 2 and 9, the more potent inhibitors of the series, act as competitive inhibitors. Molecular modeling was used to understand their interaction with BChE, the role of carbonyl at C-16 and the selectivity towards this enzyme over AChE. These results indicate that oxidation at C-16 of the lupane skeleton is a key transformation in order to improve the cholinesterase inhibition of these compounds. Fil: Castro, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Richmond, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Faraoni, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina

A set of twenty one lupane derivatives (2–22) was prepared from the natural triterpenoid calenduladiol (1) by transformations on the hydroxyl groups at C-3 and C-16, and also on the isopropenyl moiety. The derivatives were tested for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and some structure–activity relationships were outlined with the aid of enzyme kinetic studies and docking modelization. The most active compound resulted to be 3,16,30-trioxolup-20(29)-ene (22), with an IC50 value of 21.5 μM for butyrylcholinesterase, which revealed a selective inhibitor profile towards this enzyme. Fil: Castro, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Richmond, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Romero, Carmen. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-Orgánica "Antonio González"; España Fil: Maier, Marta Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Unidad de Microanálisis y Métodos Físicos en Química Orgánica. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Unidad de Microanálisis y Métodos Físicos en Química Orgánica; Argentina Fil: Estevez Braun, Ana. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-Orgánica "Antonio González"; España Fil: Ravelo, Angel G.. Universidad de la Laguna. Departamento de Química Orgánica. Instituto Universitario de Bio-Orgánica "Antonio González"; España Fil: Faraoni, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina Fil: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina

As acetylcholinesterase (AChE) inhibitors are an important therapeutic strategy in Alzheimer's disease, efforts are being made in search of new molecules with anti-AChE activity. The fact that naturally-occurring compounds from plants are considered to be a potential source of new inhibitors has led to the discovery of an important number of secondary metabolites and plant extracts with the ability of inhibiting the enzyme AChE, which, according to the cholinergic hypothesis, increases the levels of the neurotransmitter acetylcholine in the brain, thus improving cholinergic functions in patients with Alzheimer's disease and alleviating the symptoms of this neurological disorder. This review summarizes a total of 128 studies which correspond to the most relevant research work published during 2006-2012 (1st semester) on plant-derived compounds, plant extracts and essential oils found to elicit AChE inhibition. Fil: Murray, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; Argentina Fil: Faraoni, María Belén. Universidad Nacional del Sur. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina Fil: Castro, Maria Julia. Universidad Nacional del Sur. Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina Fil: Alza, Natalia Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; Argentina Fil: Cavallaro, Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Instituto de Química del Sur; Argentina. Universidad Nacional del Sur; Argentina

Two new families of closely related selective, non-cytotoxic, and potent antitubercular agents were discovered: thioquinolines and thiazoloquinolines. The compounds were found to possess potent antitubercular properties in vitro, an activity that is dependent on experimental conditions of MIC determination (resazurin test and the presence or absence of Tween-80). To clarify the therapeutic potential of these compound families, a medicinal chemistry effort was undertaken to generate a lead-like structure that would enable murine efficacy studies and help elucidate the in vivo implications of the in vitro observations. Although the final compounds showed only limited levels of systemic exposure in mice, modest levels of efficacy in vivo at nontoxic doses were observed.

The announcement made by Swedish researches in April 2002 concerning the detection of acrylamide in many different foods, has generated a great deal of scientific publications coming from different parts of the world. The wide spectra of subjects studied includes: the kinetics of the formation and degradation of the acrylamide, the mechanisms proposed for its reduction; the analytical methods and techniques used for its determination and the experimental results obtained either with model systems or by industrial processing in the case of potato crisps and french fries.This review is focused on the state-of-the-art related to the occurrence of acrylamide in foods submitted to heat treatments in industrial operations such as frying, baking, toasting and extrusion. This review also considers the application of potato pre-treatments such as washing, blanching, and immersion in acid solutions. Special emphasis is placed on the differences between atmospheric frying and vacuum frying and on the health risks related to acrylamide intake through common foods. Con posterioridad al anuncio efectuado por investigadores suecos en Abril del año 2002 sobre la detección de acrilamida en un amplio grupo de alimentos, se han originado decenas de trabajos de investigación en diferentes partes del mundo, donde se estudian diversas temáticas de gran importancia, entre las que se pueden mencionar la cinética de la formación y degradación de la acrilamida; los mecanismos propuestos para su reducción; los métodos instrumentales empleados para su determinación y los resultados experimentales generados tanto en modelos experimentales, como en el procesamiento habitual de patatas crisps y french.En este trabajo se revisan los estudios relacionados con la formación de acrilamida en alimentos sometidos a tratamientos térmicos, en operaciones industriales básicas de fritura, horneo, tostado y extrusión. Esta revisión comprende además la aplicación de pretratamientos de lavado previo, escaldado e inmersión en soluciones ácidas de la patata y, finalmente, discute con especial énfasis la diferencia de los resultados obtenidos entre el proceso de fritura de patatas a presión atmosférica y a presión reducida así como la reciente información sobre probables riesgos para la salud humana.

Starting from a 3,5-dihydroxyheptanoic acid derivative, a new synthesis of pyrrole statins that contain a double bond on the dihydroxyacid chain has been developed. Key steps are N-acylamino acid enamide formation through enamine trapping with aromatic acyl chlorides and subsequent munchnone cycloaddition with activated acetylenes.

A number of novel 3'-O-acyl and alkyl sordarins were synthesised for structure-activity relationship studies. Many of these derivatives exhibit high activity against Candida albicans, Candida pseudotropicalis, Candida tropicalis and Cryptococcus neoformans.

Alzheimer´s disease (AD) is a progressive neurodegenerative disorder associated with memory impairment and cognitive deficit. It is characterized by low levels of the neurotransmitter acetylcholine (ACh) in the brain of AD patients. The inhibition of acetylcholinesterase (AChE), the enzyme that catalyzes ACh hydrolysis, is the main therapeutic strategy used to treat AD. In the healthy brain, another enzyme, namely butyrylcholinesterase (BChE), is involved in the metabolic degradation of ACh. BChE activity increases as AD progresses, which suggests that BChE may play an important role at the latter stages of AD. Therefore, selective BChE inhibitors attract interest nowadays. The chemistry of lupane-type triterpenoids has been actively explored due to their biological and pharmacological properties. Abundant in many plants, these metabolites are valuable natural raw materials to perform chemical modifications. In the present work, we aimed to evaluate of natural and semisynthetic lupanes as potential in vitro cholinesterase inhibitors. Lupeol (1) (lup-20(29)-en-3β-ol) and calenduladiol (2) (lup-20(29)-en-3β,16β-diol) have been isolated from Chuquiraga erinacea subsp. erinacea (Asteraceae), an endemic species growing wildly in our region. Semisynthetic lupanes 3-16 have been prepared from them. All of them failed to inhibit AChE, but we found that most of them exhibited BChE inhibition. The best BChE inhibitors were 16-oxolup-20(29)-en-3β-ol and 3,16,30-trioxolup-20(29)-ene with IC50 values of 28.9 and 21.5 µM respectively, an interesting result considering that the role of BChE is more relevant as the disease progresses.

Rapid triaging of three series of related hits selected from the Tres Cantos Anti-Malarial Set (TCAMS) are described. A triazolopyrimidine series was deprioritized due to delayed inhibition of parasite growth. A lactic acid series has derivatives with IC50 < 500 nM in a standard Plasmodium falciparumin vitro whole cell assay (Pf assay) but shows half-lives of < 30 min in both human and murine microsomes. Compound 19, from a series of cyclopropyl carboxamides, is a highly potent in vitro inhibitor of P. falciparum (IC50 = 3 nM) and has an oral bioavailability of 55% in CD-1 mice and an ED90 of 20 mg/kg after oral dosing in a nonmyelo-depleted P. falciparum murine model.

The synthesis of (6R,5S,2RS)-6-amino-5-hydroxy-2-isobutyl-4-oxo-7- phenylheptanoic acid (9), a carbaanalogue of the aminopeptidase (AP) inhibitor bestatin (1) is described. This synthesis was carried out by a malonic ester alkylation with the suitably protected halomethyl ketone of (2S,3R)-AHPBA*), followed by a second alkylation with isobutyl bromide of the resulting 4-ketodiester, and subsequent decarboxylation and deprotection. The inhibitory potencies of the 1:1 diastereomeric mixture 9 against AP-B, AP-M and Leu-AP were approximately 10-fold lower than those of bestatin.

Analogues of the potent anti-influenza A and B compound, 4-guanidino-Neu5Ac2en, are described in which the stereochemically demanding C-6-glycerol side-chain is truncated. Syntheses of the one- and two-carbon side-chain analogues, of both 4-guanidino- and 4-amino-Neu5Ac2en, are presented, as well as the syntheses of analogues lacking any side-chain. Whilst complete removal of the C-6 side-chain abolishes activity, a stepwise increase in inhibition of influenza neuraminidase and influenza A and B in cell culture with increasing C-6 chain length is observed. The one-carbon, hydroxymethyl derivative retains significant activity to represent a suitable lead in the search for neuraminidase inhibitors of reduced stereochemical demand and synthetic complexity.

Starting from a 3,5-dihydroxyheptanoic acid derivative, a new synthesis of pyrrole statins that contain a double bond on the dihydroxyacid chain has been developed. Key steps are N-acylamino acid enamide formation through enamine trapping with aromatic acyl chlorides and subsequent munchnone cycloaddition with activated acetylenes.

The synthesis of aminodeoxybestatin and epi-aminodeoxybestatin [(2S,3R)- and (2R,3R)-2,3-di-amino-4-phenylbutanoyl-L-leucine; (2S,3R)- and (2R,3R)-DAPBA-L-Leu)], bestatin and epi-bestatin analogues, respectively, in which the hydroxy group has been replaced with an amino group, is described by two different methods. The first one involves the synthesis of bis-(N-Z)-DAPBA, by homologation of N-Z-phenylalanine, via a modified Strecker synthesis followed by subsequent coupling with the methyl ester of L-leucine and removal of the protecting groups. Following this procedure, 25% racemization at the C-3 centre of the DAPBA derivatives took place during the homologation reaction. The second method involves the stereospecific SN2 nucleophilic substitution of the 2-hydroxy group of (2R,3R)- and (2S,3R)-3-(benzyloxycarbonyl)amino-2-hydroxy-4-phenylbutanoyl-L-leucine methyl esters [(2R,3R)- and (2S,3R)-N-Z-AHPBA-L-Leu-OMe], and subsequent saponification, azido reduction and removal of the N-Z-protecting group. Replacement of the hydroxy group of bestatin and epi-bestatin with an amino group results in a decrease in their aminopeptidase (AP-B, AP-M and Leu-AP)-inhibitory potencies.

A bioactivity-guided approach was taken to identify the acetylcholinesterase (AChE) inhibitory agents in the ethanolic extract of CHUQUIRAGA ERINACEA D. Don. subsp. ERINACEA leaves using a bioautographic method. This permitted the isolation of the pentacyclic triterpenes calenduladiol ( 1), faradiol ( 2), heliantriol B2 ( 3), lupeol ( 4), and a mixture of α-and β-amyrin ( 5A and 5B) as active constituents. Pseudotaraxasterol ( 6) and taraxasterol ( 7) were also isolated from this extract and showed no activity at the same analytical conditions. Compound 1 showed the highest AChE inhibitory activity with 31.2 % of inhibition at 0.5 mM. Looking forward to improve the water solubility of the active compounds, the sodium sulfate ester of 1 was prepared by reaction with the (CH 3 ) 3 N.SO 3 complex. The semisynthetic derivative disodium calenduladiol disulfate ( 8) elicited higher AChE inhibition than 1 with 94.1 % of inhibition at 0.5 mM (IC 50 = 0.190 ± 0.003 mM). Compounds 1, 2, 3, 5, 6, and 7 are reported here for the first time in C. ERINACEA. This is the first report of AChE inhibition from calenduladiol ( 1) as well as from a sulfate derived from a natural product.

Nucleoamino acids, wherein D- and L-penicillamine and D-and L-cysteine are attached to uridine or thymidine through a carboxylic ester linkage, have been synthesized and evaluated as antivirals and aminopeptidase B (AP-B) inhibitors. The coupling of the α-amino-β-mercapto acids, N,S-protected as N-formylthiazolidines, to 2′,3′-O-isopropylideneuridine, 3′-O-acetylthymidine, 5′-O-tritylthymidine, and thymidine was achieved via the mixed anhydride formed from N,N-bis-(2-oxooxazolidin-3-yl)phosphorodiamidic chloride and the corresponding protected amino acid in the presence of 4-(dimethylamino)pyridine. Treatment of the protected compounds with 1 mol dm–3-HCl in refluxing MeOH, under argon, afforded the corresponding deprotected nucleoamino acids free of racemization. Neither the compounds herein described nor D-penicillamine showed anti-HIV-1 activity in MT-4 cells or antiviral activity against some other viruses at concentrations below the cytotoxicity threshold. Penicillamine and cysteine monoesters were equipotent with the corresponding free amino acid in inhibiting AP-B with an IC50 in the 10–4 mol dm–3 range, while the bis-(α-amino-β-mercaptoacyl)thymidine derivatives were approximately twice as potent as the monoesters.

5′-O-[N-(Aminoacyl)sulfamoyl]-uridines and -thymidines 4a-12a and 4b-12b have been synthesized and tested against Herpes Simplex virus type 2 (HSV-2) and as cytostatics. Condensation of 2′,3′-O-isopropylidene-5′-O-sulfamoyluridine and 3′-O-acetyl-5′-O-sulfamoylthymidine with the N-hydroxysuccinimide esters of Boc-L-Ser(Bzl), (2R, 3S)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbuta-noic acid [(2R, 3S-N-Z-AHPBA], (2R, 3S) and (2S, 3R)-N-Boc-AHPBA gave 4a,b-7a,b, which after removal of the protecting groups provided 1Oa,b-12a,b. A study of the selective removal of the O-Bzl protecting group from the L-Ser derivatives 4a,b, without hydrogenation of the pyrimidine ring, has been carried out. Only the fully protected uridine derivatives 4a-7a did exhibit high anti-HSV-2 activity, and none of the synthesized compounds showed significant cytostatic activity against HeLa cells cultures.

A number of new 2′,3′-fused oxirane derivatives were synthesized for structure–activity relationship study. Many of these derivatives exhibit high potency against Candida spp. In addition, sordarin manno epoxide derivative 6 presents in vivo therapeutic effect in mice and is considered a promising antifungal lead within this series.

4 pages, 1 figure, 1 table, 2 schemes.-- Printed version published Sep 17, 2001., The use of polymer-bound guanidine 6b or polymer-bound phosphazene 6c significantly improve the yield of the Hofmann elimination step in the preparation of tertiary amines using REM resin, providing products with superior purities and free from contamination with trialkylammonium salts.

La synthese d'acides [β-amino α-hydroxy] benzenebutyrique et [amino-3 hydroxy-2 methyl-5] caproique a partir des α-aminoaldehydes correspondants est etudiee

Synthese par addition chimique de cyano stannane de tributyle avec des phenylalaninal ou leucinal N proteges

Analogues of the potent anti-influenza A and B compound, 4-guanidino-Neu5Ac2en, are described in which the stereochemically demanding C-6-glycerol side-chain is truncated. Syntheses of the one- and two-carbon side-chain analogues, of both 4-guanidino- and 4-amino-Neu5Ac2en, are presented, as well as the syntheses of analogues lacking any side-chain. Whilst complete removal of the C-6 side-chain abolishes activity, a stepwise increase in inhibition of influenza neuraminidase and influenza A and B in cell culture with increasing C-6 chain length is observed. The one-carbon, hydroxymethyl derivative retains significant activity to represent a suitable lead in the search for neuraminidase inhibitors of reduced stereochemical demand and synthetic complexity.

Synthese par addition chimique de cyano stannane de tributyle avec des phenylalaninal ou leucinal N proteges

Four analogues of ascamycin 〈5′-O-[N-(L-alanyl)sulfamoyl]-2-chloroadenosine〉 (1) in which the 2-chloroadenosine moiety has been replaced by uridine, thymidine, cytidine, and 2′-deoxy-5-methylcytidine have been synthesized by selective aminoacylation of the 5′-O-sulfamoyl derivatives 2, 9, 14, and 21 of 2′,3′-di-O-acetyluridine, 3′-O-acetylthymidine, 2′,3′-O-isopropylidenecytidine, and 3′-O-acetyl-2′-deoxy-5-methylcytidine, respectively, with Boc-L-Ala-OSu in DMF and in the presence of DBU, followed by removal of the protecting groups. Similarly, 5′-O-[N-(D-alanyl)sulfamoyl]uridine (8) has been prepared from Boc-D-Ala-OSu and 2. Compounds 14 and 21 were directly prepared by sulfamoylation of the 4-N-(dimethylamino)methylene derivatives 13 and 20 of 2′,3′-O-isopropylidenecytidine and 3′-O-acetyl-2′-deoxy-5-methylcytidine, respectively, via the intermediate 5′-O-tributyltin derivatives. Compound 20 was obtained from 5′-O-(tert-butyldimethylsilyl)thymidine (17) by a route involving acetylation, conversion of the thymidine moiety into 5-methylcytosine through the corresponding triazolylpyrimidinone, and amidine protection. Synthese von Pyrimidin-Analoga des Nucleosid-Antibiotikums Ascamycin Vier Analoga des Ascamycins 〈5′-O′-O-[N-(L-alanyl)sulfamoyl]-2-chloradenosin〉(1), bei welchen der 2-Chloradenosinrest durch Uridin, Thymidin, Cytidin und 2′-Deoxy-5-methylcytidin ersetzt wurde, sind durch selektive Aminoacylierung der 5′-O-Sulfamoyl-Derivate 2, 9, 14 und 21 des 2′,3′-Di-O-acetyluridins, 3′-O-Acetylthymidins, 2′,3′-O-Isopropylidencytidins, bzw. des 3′-O-Acetyl-2′-deoxy-5-methylcytidins mit Boc-L-Ala-OSu in DMF und in Anwesenheit von DBU, mit nachfolgender Abspaltung der Schutzgruppen, erhalten worden. Ahnlich wurde 5′-O-[N-(D-Alanyl)sulfamoyl]uridin (8) ausgehend von Boc-D-Ala-OSu und 2 hergestellt. Die Verbindungen 14 und 21 wurden direkt durch Sulfamoylierung der 4-N-(Dimethylamino)methylen-Derivate 13 und 20 von 2′,3′-O-Isopropylidencytidin bzw. 3′-O-Acetyl-2′-deoxy-5-methylcytidin uber die 5′-O-Tributylzinn-Zwischenverbindungen dargestellt. Verbindung 20 wurde aus 5′-O-Isopropylidencytidin bzw. 3′-O-Acetyl-2′-deoxy-5-methylcytidin uber die 5′-O-Tributylzinn-Zwischenverbindungen dargestellt. Verbindung 20 wurde aus 5′-O-(tert-Bu-tyldimethylsilyl)thymidin (17) mittels Acetylierung und nachfolgende Uberfuhrung des Thymidinrestes in 5-Methylcytosin uber das entsprechende Triazolylpyrimidinon unter Schutz der Amidingruppe erhalten.

Boron trifluoride-diethyl ether mediated addition of trimethylsilylcyanide (TMSCN) to the chiral acetals derived from Z-L- and Z-D-phenyl alaninal, (Z=N-benzyloxycarbonyl), and (+)-(2S,4S)- and (–)-(2R,4R)-2,4-pentanediol stereoselectively gave the four stereoisomers of the 3-amino-2-hydroxy-4-phenylbutanoic acid, key intermediates for bestatin and bestatin analogues.