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A mechanochemical approach to access the proline-proline diketopiperazine framework.

ABSTRACT: Ball milling was exploited to prepare a substituted proline building block by mechanochemical nucleophilic substitution. Subsequently, the mechanocoupling of hindered proline amino acid derivatives was developed to provide proline-proline dipeptides under solvent-free conditions. A deprotection-cyclization sequence yielded the corresponding diketopiperazines that were obtained with a high stereoselectivity which could be explained by DFT calculations. Using this method, an enantiopure disubstituted Pro-Pro diketopiperazine was synthesized in 4 steps, making 5 new bonds using a ball mill.

SUBMITTER: Petry N

PROVIDER: S-EPMC5669228 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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A mechanochemical approach to access the proline-proline diketopiperazine framework.

Pétry Nicolas N Benakki Hafid H Clot Eric E Retailleau Pascal P Guenoun Farhate F Asserar Fatima F Sekkat Chakib C Métro Thomas-Xavier TX Martinez Jean J Lamaty Frédéric F

Beilstein journal of organic chemistry 20171019

Ball milling was exploited to prepare a substituted proline building block by mechanochemical nucleophilic substitution. Subsequently, the mechanocoupling of hindered proline amino acid derivatives was developed to provide proline-proline dipeptides under solvent-free conditions. A deprotection-cyclization sequence yielded the corresponding diketopiperazines that were obtained with a high stereoselectivity which could be explained by DFT calculations. Using this method, an enantiopure disubstitu ...[more]

PMID: 29114324

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Project description:Cyclic dipeptides administered by both parenteral and oral routes are suggested as promising candidates for the treatment of neurodegeneration-related pathologies. In this study, we tested Cyclo (His-Pro) isomers (cHP1-4) for their anti-Alzheimer potential using a differentiated human neuroblastoma cell line (SH-SY5Y) as an Alzheimer's disease (AD) experimental model. The SH-SY5Y cell line was differentiated by the application of all-trans retinoic acid (RA) to obtain mature neuron-like cells. Amyloid-beta 1-42 (A?1-42) peptides, the main effector in AD, were administered to the differentiated cell cultures to constitute the in vitro disease model. Next, we performed cell viability analyses 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays) to investigate the neuroprotective concentrations of cyclodipeptides using the in vitro AD model. We evaluated acetylcholinesterase (AChE), ?- and ?-secretase activities (TACE and BACE1), antioxidant potency, and apoptotic/necrotic properties and performed global gene expression analysis to understand the main mechanism behind the neuroprotective features of cHP1-4. Moreover, we conducted sister chromatid exchange (SCE), micronucleus (MN), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) analyses to evaluate the genotoxic damage potential after applications with cHP1-4 on cultured human lymphocytes. Our results revealed that cHP1-4 isomers provide a different degree of neuroprotection against A?1-42-induced cell death on the in vitro AD model. The applications with cHP1-4 isomers altered the activity of AChE but not the activity of TACE and BACE1. Our analysis indicated that the cHP1-4 increased the total antioxidant capacity without altering total oxidative status levels in the cellular AD model and that cHP1-4 modulated the alterations of gene expressions by A?1-42 exposure. We also observed that cHP1-4 exhibited noncytotoxic and non-genotoxic features in cultured human whole blood cells. In conclusion, cHP1-4 isomers, especially cHP4, have been explored as novel promising therapeutics against AD.

Project description:It is widely accepted that healthcare-seeking behaviour is neither limited to nor terminated by access to one single healthcare provider. Yet the sequential conceptualisation of healthcare-seeking processes has not diffused into quantitative research, which continues to analyse healthcare access as a "one-off" event. The ensuing lack of understanding healthcare behaviour is problematic in light of the immense burden of premature death especially in low- and middle-income countries. This paper presents an alternative approach. Based on a novel survey instrument, we analyse original survey data from rural India and China that contain 119 unique healthcare pathways among 637 respondents. We offer three applications of how such sequential data can be analysed to enhance our understanding of people's health behaviour. First, descriptive analysis of sequential data enables more a comprehensive representation of people's health behaviours, for example the time spent in various healthcare activities, common healthcare pathways across different groups, or shifts in healthcare provider access during a typical illness. Second, by analysing the effect of mobile technology on healthcare-seeking process characteristics, we demonstrate that conventional, sequence-insensitive indicators are potentially inconsistent and misleading approximations when compared to a more precise, sequence-sensitive measure. Third, we describe how sequential data enable transparent and flexible evaluations of people's healthcare behaviour. The example of a sequence-insensitive evaluation suggests that household wealth has no statistical link to an illustrative "ideal" form of public healthcare utilisation. In contrast, sequence-sensitive evaluations demonstrate that household wealth is associated with an increased likelihood of bypassing referral processes and approaching unregulated and costly informal and private practitioners before accessing a public clinic. Sequential data therefore do not only reveal otherwise neglected locational idiosyncrasies, but they also yield deeper insights into the drivers of people's health behaviours compared to a conventional approach to "access to healthcare."

Project description:OBJECTIVE:Improving access to effective and safe medicines is one of the major goals of all health systems. To achieve this goal, assessment is a fundamental phase of national medicine programs for access improvement. Collecting and compiling applicable indicators and impart a comprehensive framework for assessing access to medicine, are the aims of this study. METHODS:To investigate the published materials on access to medicines framework or indicators, a literature review with a systematic search was conducted using PubMed/ Medline, Scopus, and Google Scholar databases. The results were completed with a general search of documents in Iran Food and Drug Administration (IRFDA). Two independent researchers reviewed all the articles and documents. Thereafter the related indicators were extracted. In focused group discussion of academics and IRFDA experts, duplicate entries or ineffectual concepts were cleaned from the preliminary indicators. In the next step, Delphi questionnaire was sent to the 17 experts that work in academia, Social Security Insurance, IRFDA, Ministry of Health and Iran Pharmacist Association. The results of Delphi technique were finalized in an expert panel. RESULTS:One hundred and thirty one indicators were found in systematic search. After primary extraction of related indicators, 77 indicators were sent to the 17 experts in a Delphi form. The results of Delphi were finalized in a specialized-working group and 67 indicators were accepted in 5 categories including physical availability and geographical accessibility (19 indicators), affordability (23 indicators), human resources (4 indicators), quality and safety (5 indicators), information and rational use (16 indicators). CONCLUSION:The indicators that inclusively assess the full access to medicine in the concept of rational use have been categorized into five categories in this study. To determine the access to medicine status in each country further local surveys are necessary for all several indicators in each category. Graphical abstract The graphical abstract of accomplished steps.

Dataset Information

A mechanochemical approach to access the proline-proline diketopiperazine framework.

Publications

A mechanochemical approach to access the proline-proline diketopiperazine framework.

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