Synthesis of novel O-acylated-D-ribono-1,5-lactones and structural assignment supported by conventional NOESY-NMR and x-ray analysis

A practical method for the structural assignment of 3,4-O-benzylidene-D-ribono-1,5-lactones and analogues using conventional NMR techniques and NOESY measurements in solution is described. 2-O-Acyl-3,4-O-benzylidene-D-ribono-1,5-lactones were prepared in good yields by acylation of Zinner’s lactone with acyl chlorides under mildly basic conditions. Structural determination of 2-O-(4-nitrobenzoyl)-3,4-O-benzylidene-D-ribono-1,5-lactone was achieved by single crystal x-ray diffraction, which supports the results based on spectroscopic data.

Synthesis of benzophenones from geminal biaryl ethenes using m-chloroperbenzoic acid

The oxidation of geminal biaryl ethenes 3 and 1,3-enynes 5 using m-chloroperbenzoic acid in dichloromethane at room temperature presents a catalyst-free approach for the synthesis of functionalized benzophenones 4 and ynones 6, respectively. (C) 2009 Elsevier Ltd. All rights reserved.

Síntese de moléculas contendo a unidade de piperazina como potenciais agentes antipsicóticos

Tese de Doutoramente em Ciências (área de especialização em Química).

Síntese de 1-indanonas através da reação de acilação de Friedel-Crafts intramolecular utilizando NbCl5 como ácido de Lewis

The intramolecular Friedel-Crafts acylation reaction of 3-arylpropanoic acids to give 1-indanones can be effected in good yields under mild conditions (room temperature) by using niobium pentachloride. Our results indicate that NbCl5 acts both as reagent (to transform carboxylic acids into acyl chlorides) and as catalyst in the Friedel-Crafts cyclization.

Sintesi di PNA a libertà conformazionale ridotta

The present work started a research project aimed at the synthesis of conformationally “locked” PNA (Peptide Nucleic Acids) monomers. Compared to classic aeg-PNA, this structural modification would result in an improvement in the pairing properties with natural nucleic acids, due to entropic variations in the process. Specifically, an attempt was made to build a PNA monomer around a β-lactam ring. That ring could be imagined as obtained by linking the methylene groups in α position of both the nucleobase and the carboxyl function. These structural properties would imply pre-organization of the final oligomer, improving the pairing process in biological systems. The first step of this work was the investigation of the Staudinger reaction for the ciclization of the lactam ring, and in particular the activation method of the carboxylic group of the nucleobase derivatives. Use of triazine chloride led to the synthesis of the adenine-based β-lactam-PNA. Attempts to synthesize the same monomer based on cytosine, guanine and thymine were unsuccessful, so alternative methods for carboxylic group activation were investigated. Conversion of carboxylic acids to acyl chlorides led to a partial result: despite the method worked well with analogues of the final reactants, it didn’t worked with substrates needed for lactam based PNAs. Search for a valid activation process continued involving carbonyl diimidazole, Mukayama reagent, and LDA (with methylester derivative of nucelobase) without good results. Last, it was investigated a different synthetic approach by first synthesizing a proper backbone with a chlorine in the β- lactam ring. This chlorine ring should undergo substitution by a nucleobase anion to give the desired PNA monomer. Unluckily also this synthetic route didn’t lead to the desired monomers.

(E)-2-[2-(2-Aminofenil)vinil]-1-metilquinolin-4(1H)-ona como precursor de novos compostos heterociclicos

Esta dissertação reporta a síntese de novos derivados de 4-quinolonas com potencial atividade biológica e está dividida em 3 capítulos. No primeiro capítulo é feita uma breve introdução aos compostos do tipo 4quinolona, azepina e indol, focando a nomenclatura, atividade biológica e métodos de síntese mais comuns deste tipo de compostos, e é apresentada a nomenclatura dos compostos sintetizados ao longo deste trabalho. No segundo capítulo são descritas as metodologias desenvolvidas para obtenção dos compostos pretendidos. Foram sintetizados novos derivados de 4-quinolonas via reações de N-metilação seguida de ciclização in situ da (E)-N(2-acetilfenil)-3-(2-nitrofenil)acrilamida, via reações de redução da 1-metil-2-[2(2-nitrofenil)vinil]quinolin-4(1H)-ona e reações de halogenação da 1-metil-2-[2(2-nitrofenil)vinil]quinolin-4(1H)-ona e da 2-[2-(2-aminofenil)vinil]-1metilquinolin-4(1H)-ona. Posteriormente, fizeram-se estudos de reatividade da 1-metil-2-[2-(2-nitrofenil)vinil]quinolin-4(1H)-ona e da 2-[2-(2-aminofenil)vinil]-3bromo-1-metilquinolin-4(1H)-ona. Na reação de redução in situ seguida de ciclização intramolecular da 1-metil-2-[2-(2-nitrofenil)vinil]quinolin-4(1H)-ona obteve-se a 2-(1H-indol-2-il)-1-metilquinolin-4(1H)-ona. Partindo da 2-[2-(2aminofenil)vinil]-3-bromo-1-metilquinolin-4(1H)-ona via reações de BuchwaldHartwig obteve-se a 11-metil-5H-benzo[6,7]azepino[3,2-b]quinolin-6(11H)-ona. Novas N-[2-(2-(3-bromo-1-metil-4-oxo-1,4-di-hidroquinolin-2il)vinil)fenil]alquilamidas foram obtidas via reações de acilação da 2-[2-(2aminofenil)vinil]-3-bromo-1-metilquinolin-4(1H)-ona em piridina seca usando diferentes cloretos de acilo. Numa tentativa de ciclização intramolecular da N[2-(2-(3-bromo-1-metil-4-oxo-1,4-di-hidroquinolin-2-il)vinil)fenil]-hexanamida via reação de Ullmann intramolecular foi obtida a 2-(1-hexanoil-1H-indol-2-il)-1metilquinolin-4(1H)-ona. Após a descrição detalhada das metodologias de síntese são apresentadas as principais conclusões deste trabalho e perspectivas futuras. Por último, no terceiro capítulo, são apresentados os procedimentos experimentais usados para obtenção dos compostos sintetizados e os dados relativos à sua caracterização estrutural, que foi sendo discutida ao longo do segundo capítulo. Os compostos sintetizados foram caracterizados por espetroscopia de ressonância magnética nuclear monodimensional (1H e 13C) e bidimensional (HSQC, HMBC) e por espetrometria de massa e sempre que possível por espetrometria de massa de alta resolução.

Síntese de amidas graxas: uma nova família de lipídios biologicamente ativos

Amidas graxas são compostos orgânicos nitrogenados derivados de ácidos carboxílicos, as quais contém em sua estrutura uma longa cadeia carbônica (C16- C24), possuindo ou não insaturações. Estes compostos podem ser encontrados em vegetais terrestres ou aquáticos, microorganismos e animais. Já em meados do século passado, a identificação de duas amidas graxas: a N-araquidonoiletanolamina (AEA, 5) e a cis-oleamida (cOA, 6), membros mais conhecidos e estudados desta família, devido as suas propriedades como indutora do sono fisiológico e canabinomimética respectivamente; levantou o interesse para a investigação das propriedades, identificação, síntese e isolamento de novas amidas graxas. Atualmente as pesquisas acerca das amidas graxas se devem as suas atividades biológicas tais como: aumento da libido sexual, analgesia, inseticida ou agente redutor da fome. Neste contexto, objetivo desse trabalho foi desenvolver metodologias para a síntese de novas amidas graxas. As amidas foram produzidas a partir de ácidos graxos, via cloreto de ácido ou via ésteres metílicos graxos, em rendimentos compreendidos entre 44% e 88%. Todos os compostos sintetizados foram caracterizados por espectroscopia de Infravermelho e RMN de 1H e 13C. Ensaios citotóxicos em células eritroleucêmicas K562 para a série das pirrolidil amidas demonstraram atividade citotóxica e capacidade de inibir proliferação celular em menos de 72 horas na concentração máxima de 1000µg/mL.

Efficient synthesis of selenol esters from acid chlorides mediated by indium metal

This article describes an efficient and easy one-pot route for the synthesis of a wide range of selenol esters from acyl chloride with diselenides in the presence of indium metal. A variety of functional groups can be tolerated within the diorgano diselenide and the acyl chloride coupling partner. (C) 2009 Elsevier Ltd. All rights reserved.

The Penicillium chrysogenum aclA gene encodes a broad-substrate-specificity acyl-coenzyme A ligase involved in activation of adipic acid, a side-chain precursor for cephem antibiotics

Activation of the cephalosporin side-chain precursor to the corresponding CoA-thioester is an essential step for its incorporation into the P-lactam backbone. To identify an acyl-CoA ligase involved in activation of adipate, we searched in the genome database of Penicillium chrysogenum for putative structural genes encoding acyl-CoA ligases. Chemostat-based transcriptome analysis was used to identify the one presenting the highest expression level when cells were grown in the presence of adipate. Deletion of the gene renamed aclA, led to a 32% decreased specific rate of adipate consumption and a threefold reduction of adipoyl-6-aminopenicillanic acid levels, but did not affect penicillin V production. After overexpression in Escherichia coli, the purified protein was shown to have a broad substrate range including adipate. Finally, protein-fusion with cyan-fluorescent protein showed co-localization with microbody-borne acyl-transferase. Identification and functional characterization of aclA may aid in developing future metabolic engineering strategies for improving the production of different cephalosporins. (C) 2009 Elsevier Inc. All rights reserved.

Long-Chain Acyl-Homoserine Lactones from Methylobacterium mesophilicum: Synthesis and Absolute Configuration

The acyl-homoserine lactones (acyl-HSLs) produced by Methylobacterium mesophilicum isolated from orange trees infected with the citrus variegated chlorosis (CVC) disease have been studied, revealing the occurrence of six long-chain acyl-HSLs, i.e., the saturated homologues (S)-N-dodecanoyl (1) and (S)-N-tetradecanoyl-HSL (5), the uncommon odd-chain N-tridecanoyl-HSL (3), the new natural product (S)-N-(2E)-dodecenoyl-HSL (2), and the rare unsaturated homologues (S)-N-(7Z)-tetradecenoyl (4) and (S)-N-(2E,7Z)-tetradecadienyl-HSL (6). The absolute configurations of all HSLs were determined as 3S. Compounds 2 and 6 were synthesized for the first time. Antimicrobial assays with synthetic acyl-HSLs against Gram-positive bacterial endophytes co-isolated with M. mesophilicum from CVC-infected trees revealed low or no antibacterial activity.

The effect of protein binding on the hepatic first pass of O-acyl salicylate derivatives in the rat

In this work the in-situ perfused rat liver has been used to examine the effect of changing the protein content of the perfusate on the hepatic extraction of O-acyl esters of salicylic acid. The hepatic availability (F) of these solutes was studied at a flow-rate of 30 mt min(-1) with perfusate albumin concentrations of 0, 2, and 4% w/v. The hepatic availability of the esters was shown to decrease with increasing carbon-chain length in the O-acyl group; for all the esters the hepatic availability increased with increasing albumin concentration in the perfusate. The dispersion-model-derived efficiency number (R-N) Of the esters was shown to increase with increasing lipophilicity and decrease with increasing albumin concentration in the perfusate. The unbound fraction (f(u),) of the esters decreased with lipophilicity. R-N/f(u), for acetylsalicylic acid remained relatively constant as the albumin concentration was increased. However, R-N/f(u), for n-pentanoyl- and n-hexanoylsalicylic acids increased significantly as albumin concentration increased from 0% to 4%. Thus, for the more lipophilic solutes (n-pentanoyl- and n-hexanoylsalicylic acids) the presence of albumin apparently facilitates the uptake of unbound solute relative to acetylsalicylic acid.

Hepatic structure-pharmacokinetic relationships: The hepatic disposition and metabolite kinetics of a homologous series of O-acyl derivatives of salicylic acid

1 The hepatic disposition and metabolite kinetics of a homologous series of O-acyl (acetyl, propionyl, butanoyl, pentanoyl, hexanoyl and octanoyl) esters of salicylic acid (C2SA, C3SA, C4SA, C5SA, C6SA and C8SA, respectively) was determined using a single-pass, in-sills rat liver preparation. 2 The hepatic venous outflow profiles for the parent esters and the generated metabolite, salicylic acid (SA) were analysed by HPLC. Non-parametric moments analysis was used to determine the area under the curve (AUC'), mean transit time (MTT) and normalized variance (CV2) for the parent esters and generated SA. 3 Pregenerated SA ([C-14]-salicylic acid) was injected into each liver with the parent ester to determine its distribution characteristics. 4 The overall recovery of ester plus metabolite was 89% of the ester dose injected and independent of the ester carbon number, suggesting that ester extraction was due to hepatic metabolism to salicylic acid. 5 The metabolite AUC' value increased directly with the lipophilicity of the parent ester (from 0.12 for C2SA to 0.95 for C8SA). By contrast, the parent AUC' decreased with the lipophilicity (from 0.85 for C2SA to zero for C8SA). The metabolite MTT value also showed a trend to increase with the lipophilicity of the parent ester (from 15.72 s for C3SA to 61.97 s for C8SA). However, the parent MTT value shows no significant change across the series. 6 The two-compartment dispersion model was used to derive the kinetic parameters for parent ester, pregenerated SA and generated SA. Consequently, these parameters were used to estimate the values of AUG', MITT and CV2 for the parent ester and metabolite. The moments values obtained using the two-compartment dispersion model show similar trends to the corresponding moments values obtained from the outflow profiles using a non-parametric approach. 7 The more lipophilic aspirin analogues are more confined to the portal circulation after oral administration than aspirin due to their more extensive hepatic elimination avoiding systemic prostacyclin inhibition. Given that aspirin's selectivity as an anti-thrombotic agent has been postulated to be due to selective anti-platelet effects in the portal circulation, the more lipophilic and highly extracted analogues are potentially more selective anti-thrombotic agents than aspirin.

An Activated O N Acyl Transfer Auxiliary: Efficient Amide-Backbone Substitution of Hindered "Difficult" Peptides

Overcoming the phenomenon known as difficult synthetic sequences has been a major goal in solid-phase peptide synthesis for over 30 years. In this work the advantages of amide backbone-substitution in the solid-phase synthesis of difficult peptides are augmented by developing an activated N-alpha-acyl transfer auxiliary. Apart from disrupting troublesome intermolecular hydrogen-bonding networks, the primary function of the activated N-alpha-auxiliary was to facilitate clean and efficient acyl capture of large or beta-branched amino acids and improve acyl transfer yields to the secondary N-alpha-amine. We found o-hydroxyl-substituted nitrobenzyl (Hnb) groups were suitable N-alpha-auxiliaries for this purpose. The relative acyl transfer efficiency of the Hnb auxiliary was superior to the 2-hydroxy-4-methoxybenzyl (Hmb) auxiliary with protected amino acids of varying size. Significantly, this difference in efficiency was more pronounced between more sterically demanding amino acids. The Hnb auxiliary is readily incorporated at the N-alpha-amine during SPPS by reductive alkylation of its corresponding benzaldehyde derivative and conveniently removed by mild photolysis at 366 nm. The usefulness of the Hnb auxiliary for the improvement of coupling efficiencies in the chain-assembly of difficult peptides was demonstrated by the efficient Hnb-assisted Fmoc solid-phase synthesis of a known hindered difficult peptide sequence, STAT-91. This work suggests the Hnb auxiliary will significantly enhance our ability to synthesize difficult polypeptides and increases the applicability of amide-backbone substitution.

Characterization of the acyl carrier protein gene and the fab gene locus in Xanthomonas albilineans

A genomic region containing the fatty acid biosynthetic (fab) genes was isolated from the sugarcane leaf-scald pathogen Xanthomonasalbilineans. The order and predicted products of fabG (beta -ketoacyl reductase), acpP (acyl carrier protein), fabF(ketoacyl synthase II) and downstream genes in X. albilineans are very similar to those in Escherichia coli, with one exception. Sequence analysis, confirmed by insertional knockout and specific substrate feeding experiments, shows that the position occupied by pabC (encoding aminodeoxychorismate lyase) in other bacteria is occupied instead by pabB (encoding aminodeoxychorismate synthase component I) in X. albilineans. Downstream of pabB, X. albilineans resumes the arrangement common to characterized Gram-negative bacteria, with three transcriptionally coupled genes, encoding an ORF340 protein of undefined function, thymidylate kinase and delta' subunit of DNA polymerase III holoenzyme (HolB). Different species may obtain a common advantage from coordinated regulation of the same biosynthetic pathways using different genes in this region. (C) 2000 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.

Chemistry of 5-oxodihydroisoxazoles .18. Synthesis of oxazoles by the photolysis and pyrolysis of 2-acyl-5-oxo-2,5-dihydroisoxazoles

N-Acylisoxazol-5-ones lose carbon dioxide under photochemical and thermal conditions affording iminocarbenes which undergo intramolecular cyclisation through the oxygen of the acyl group to give oxazoles. Under photochemical conditions those acylisoxazolones with electron withdrawing groups at C-4 usually give high yields of oxazoles, while those with electron donating groups at C-4 give only poor yields: the reverse is observed under thermal conditions.