Academic literature on the topic 'Cyclophostines'

Cyclophostin, the cyclipostins and the salinipostins are structurally related cyclic enolphosphate natural products. This mini review describes their isolation, synthesis and biological activities. In addition, the synthesis and biological activities of monocyclic enolphosphate and mono and bicyclic enolphosphonate analogs are presented.

Mycobacterium abscessus est un pathogène opportuniste émergeant responsables d’infections pulmonaires chez les patients atteints de mucoviscidose, sa présence est une contre-indication aux greffes pulmonaires chez ces patients. La particularité de cette bactérie réside dans sa multirésistance naturelle aux antibiotiques, notamment aux antituberculeux de première et de seconde ligne. cette résistance rend le traitement actuellement lourd et contraignant, avec un faible taux de guérison. Ce projet de thèse, porte sur l’étude du potentiel thérapeutique de deux familles d’inhibiteurs d’enzymes à sérines et à cystéines actives vis-à-vis de cette bactérie : les analogues de Cyclipostins et de Cyclophostines (CyC) d’une part, et les dérivés d’Oxadiazolones (OX) d’autre part. Pour cela nous avons i) sélectionné les composés actifs in vitro et ex vivo, ii) déterminer leurs CMI, iii) déterminé la sélectivité des CyC vis-à-vis de plusieurs espèces bactériennes, iv) déterminer les cibles des composés les plus actifs en utilisant une approche ABPP (« activity based protein profiling »). Ainsi, mes travaux ont permis de montrer la spécificité de certaines molécules CyCs aux espèces mycobactériennes, mais aussi la capacité inhibitrice de plusieurs molécules CyCs et OXs vis-à-vis de M. abscessus in vitro et ex vivo sans présenter de cytotoxicité envers les macrophages murins. Nous avons montré que les deux meilleurs composés CyCs ainsi qu’un composé OX inhibent cette bactérie en ciblant une multitude d’enzymes à serine ou à cystéine active, majoritairement impliquées dans le métabolisme lipidique ou dans la biosynthèse de la membrane
Mycobacterium abscessus is an emerging opportunistic pathogen responsible for lung infections in patients with cystic fibrosis, its presence is a contraindication to lung transplants in these patients. The peculiarity of this bacterium lies in its natural multidrug resistance to antibiotics, especially first- and second-line anti-tuberculosis drugs. this resistance makes the treatment currently heavy and restrictive, with a low cure rate. This PhD thesis project deals with the study of the therapeutic potential of two families of inhibitors that target enzymes with an active serine or cysteine against this bacterium: Cyclipostins and Cyclophostins (CyC) analogues on the one hand and Oxadiazolone derivatives (OX) on the other hand. For this we have i) selected the active compounds in vitro and ex vivo, ii) determined their MICs, iii) determined the selectivity of CyCs with respect to several bacterial species, iv) determined the targets of the most active compounds in using an ABPP approach ("activity based protein profiling"). Thus, my work has shown the specificity of certain CyCs molecules to mycobacterial species, but also the inhibitory capacity of several CyCs and OXs molecules against M. abscessus in vitro and ex vivo without presenting cytotoxicity to murine macrophages. We have shown that the two best compounds CyCs and an OX compound inhibit this bacterium by targeting a multitude of active serine or cysteine ​​enzymes, mainly involved in lipid metabolism or in the biosynthesis of the membrane

Bactérias do gênero Streptomyces produzem diversos tipos de butirolactonas, cujos exemplos importantes são o cyclophostin, os compostos da família cyclipostin e as -butirolactonas autorreguladoras. O cyclophostin é um potente inibidor da enzima acetilcolinesterase, os compostos da família cyclipostin são inibidores de lipases, enquanto que as -butirolactonas autorreguladoras estimulam a produção de antibióticos em culturas de bactérias do gênero Streptomyces. Neste trabalho foram realizados estudos para a obtenção de derivados do cyclophostin e de derivados das -butirolactonas autorreguladoras. Para isso foram propostos dois planejamentos sintéticos mostrados nos esquemas 8 e 10 (Seção: III. Planejamento Sintético). Os estudos realizados de acordo com o planejamento sintético mostrado no esquema 8 tiveram como etapa chave uma reação de Barbier entre a butenolida 43, diversos aldeídos e um metal (zinco ou índio), em meio aquoso. Apesar dessa reação ser bem conhecida, em nenhum dos testes realizados foram obtidos os compostos de interesse, sendo que o principal produto obtido foi o composto 56, proveniente da redução da butenolida 43. Diante disso, foi proposta uma explicação para esses resultados com foco em possíveis mecanismos para a reação de Barbier, comparando com substratos similares a butenolida 43 que foram utilizados com sucesso na reação de Barbier. Os estudos realizados de acordo com o planejamento sintético mostrado no esquema 10 forneceram resultados satisfatórios. A reação entre o monóxido de butadieno e diferentes -cetoésteres possibilitou a obtenção de -butirolactonas 2,3-dissubstituídas na forma de um único diastereoisômero e -butirolactonas 2,4-dissubstituídas na forma de mistura de diastereoisômeros (mostradas na Tabela 7). Através das análises de NOEDiff-RMN, juntamente com dados da literatura e cálculos computacionais das constantes de acoplamento, foi possível determinar a configuração relativa dos grupos substituintes das -butirolactonas 2,3-dissubstituídas como sendo trans. Com três -butirolactonas 2,3-dissubstituídas foram realizadas reações de ozonólise, com clivagem redutiva do ozonídeo por boro-hidreto de sódio, fornecendo três compostos na forma de misturas de diastereoisômeros com estruturas análogas ao IM-2 e às virginiae butanolidas (mostrados na Tabela 8). Com a -butirolactona 54a foi realizada a formação do enol-fosfato 55a, utilizando dietil-clorofosfato como agente de fosforilação (reação mostrada no Esquema 23). Com este composto foram realizadas reações de ozonólise, utilizando boro-hidreto de sódio ou sulfeto de dimetila para a clivagem do ozonídeo, porém em nenhuma dessas tentativas foram obtidos resultados satisfatórios (reação mostrada no Esquema 24). Outras tentativas foram realizadas com intuito de obter derivados do cyclophostin utilizando outros materiais de partidas, porém todas as tentativas falharam, seja na etapa de ozonólise ou na etapa de ciclização para a formação do esqueleto de enol-fosfato cíclico presente no cyclophostin. Apesar dos resultados insatisfatórios descritos acima, alguns intermediários obtidos foram submetidos a um ensaio biológico em que foi monitorada a produção do antibiótico nigericina em culturas de actinobactérias do gênero Streptomyces. Nesse ensaio biológico foram obtidos resultados satisfatórios, sendo que alguns compostos estimularam a produção do antibiótico nigericina, outros inibiram e outros não mostraram efeitos significativos, indicando a existência de uma relação estrutura-atividade dos compostos testados.
Bacteria of the genus Streptomyces produce many kinds of butyrolactones; e.g., cyclophostin, compounds belonging to the cyclipostin family, and -butyrolactones autoregulators. Cyclophostin is a potent inhibitor of the enzyme acetylcholinesterase, the compounds of the cyclipostin family inhibit lipases, and -butyrolactones autoregulators stimulate antibiotics production in bacterial cultures of the genus Streptomyces. This work aimed to obtain cyclophostin derivatives and -butyrolactones autoregulators derivatives via two proposed synthesis designs as illustrated in schemes 8 and 10 (Section: III. Synthetic Planning). The key step in the design shown in scheme 8 consisted of a Barbier reaction between butenolide 43, several aldehydes, and a metal (zinc or indium), in aqueous medium. Although this reaction has long been known, the tests performed here did not afford any of the target compounds. The main product was compound 56, arising from the reduction of butenolide 43. An explanation for the results was proposed on the basis of possible mechanisms for the Barbier reaction and of comparison with similar compounds of butenolide 43, which have been successfully used in the Barbier reaction. Studies carried out according to the synthesis design presented in scheme 10 provided satisfactory results. The reaction between butadiene monoxide and various -ketoesters furnished 2,3-disubstituted--butyrolactones as a single diastereoisomer and 2,4-disubstituted--butyrolactones as a mixture of diastereoisomers (shown in Table 7). NOEDiff-NMR analysis together with literature data and computer calculations of coupling constants helped to determine the relative configuration of the 2,3-disubstituted--butyrolactones substituent groups as trans. Three 2,3-disubstituted--butyrolactones ozonolysis reactions were conducted by reductive cleavage of the ozonide with sodium borohydride, which afforded three compounds as diastereoisomers mixtures bearing structures analogous to those of IM-2 and virginiae butanolides (shown in Table 8). Reaction of -butyrolactone 54a with diethyl chlorophosphate as phosphorylating agent produced the enol-phosphate 55a (reaction shown in Scheme 23). Ozonolysis reactions of this compound using sodium borohydride or dimethyl sulfide to cleave the ozonide did not provide satisfactory results (reaction shown in Scheme 24). Other attempts to achieve cyclophostin derivatives using different starting materials failed during the ozonolysis step or the cyclization to form the cyclic enol-phosphate skeleton present in cyclophostin. Despite the poor results described above, some of the intermediates were submitted to a biological assay to monitor production of the antibiotic nigericin in Streptomyces actinomycetes cultures. Some of the tested compounds stimulated, others inhibited, and others did not affect nigericin production, indicating existence of a structure-activity relationship.

La tuberculose (TB) reste la maladie infectieuse la plus meurtrière au monde. L’absence de développement de médicaments accompagnée de l'émergence de la résistance aux molécules existantes se traduit principalement par l'échec du traitement et la mort. M. tb infecte l'homme par l'inhalation. Le patient peut rester en bonne santé sans aucun symptôme, on parle alors de tuberculose latente. Dans ce cas, la bactérie résider dans le macrophage. La principale caractéristique de M. tb est de rester cacher à l'intérieur de ces cellules, puis se réactiver lorsque le système immunitaire s’affaibli.Mon travail a été consacrée à l'étude de nouveaux analogues de Cyclophostin / Cyclipostins (CyCs) et Oxadiazolone. Nombreuses molécules présentaient des activités antibactériennes lorsque la bactérie était cultivée dans le milieu liquide ou à l'intérieur du macrophage sans aucun effet toxique sur les macrophages.En utilisant le meilleur inhibiteur de CyC17, nous avons identifié 23 protéines cibles potentielles, étant impliquées dans le métabolisme des lipides de M. tb et / ou dans la biosynthèse des lipides de la paroi cellulaire. Parmi ces cibles, Ag85C et TesA, ont été caractérisées biochimiquement et structurallemnent.De plus, nous avons établi que les CyC sont des inhibiteurs puissants et sélectifs de la croissance des mycobactéries. De manière intéressante, ces composés étaient également actifs contre de nombreuses souches cliniques de M. abscessus, un pathogène opportuniste également appelés « cauchemars pour les antibiotiques », ouvrant ainsi la voie à la recherche de solutions alternatives pour lutter contre les souches mycobactériennes résistantes
Tuberculosis (TB) is one of the deadliest infectious diseases worldwide. The stagnation in drug development accompanied with the emergence of drug resistance mainly results in treatment failure and death. M. tb infect human through inhalation. Patient can remains healthy without any symptom in which case it is known as latent TB. In latent TB, the bacteria is known to be reside in the macrophage - a type of white blood cell of the immune system, that engulfs and digests infected microorganisms. The famous characteristic of M. tb is the ability to stay inside and avoid to be killed by these cells, then reactivate when the immune system is weak.My work was devoted to the study of two series of new compounds, namely analogs of Cyclophostin/Cyclipostins (CyCs) and Oxadiazolone (OXs). Many molecules exhibited antibacterial activities when the bacteria was grown in the liquid medium or inside the macrophage without any toxic effect to the macrophages.Using the best CyC17 inhibitor, we identified 23 potential candidate target proteins, being involved in M. tb lipid metabolism and/or in cell wall lipid biosynthesis. Among these targets, two important protein, i.e. Ag85C and TesA, were biochemically and structurally characterized.Moreover, we clearly established that the CyCs are powerful and selective growth inhibitors of mycobacteria, with no effect on Gram-negative or Gram-positive bacteria. Interestingly, these compounds were also active against numerous M. abscessus clinical strains, an opportunistic pathogens also called “nightmare for antibiotic”, thus opening the way to find alternative solutions to fight against resistant mycobacterial strains