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Bioactive Rearrangement Products from Aqueous Photolysis of Pharmaceutical Steroids.

ABSTRACT: In an ongoing effort to study the environmental fate of endocrine-active steroid hormones, we report the formation of phenolic rearrangement products (3 and 4) with a novel 6,5,8,5-ring system following aqueous photolysis of dienogest (1) and methyldienolone (2). The structures were established by analysis of 2D NMR and HRMS data, and that of 3 was confirmed by X-ray diffraction analysis. These photoproducts exhibit progestogenic and androgenic activity, albeit with less potency than their parent compounds.

SUBMITTER: Pflug NC

PROVIDER: S-EPMC7059344 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Bioactive Rearrangement Products from Aqueous Photolysis of Pharmaceutical Steroids.

Pflug Nicholas C NC Knutson Christopher J CJ Martinović-Weigelt Dalma D Swenson Dale C DC Wammer Kristine H KH Cwiertny David M DM Gloer James B JB

Organic letters 20190425 10

In an ongoing effort to study the environmental fate of endocrine-active steroid hormones, we report the formation of phenolic rearrangement products (3 and 4) with a novel 6,5,8,5-ring system following aqueous photolysis of dienogest (1) and methyldienolone (2). The structures were established by analysis of 2D NMR and HRMS data, and that of 3 was confirmed by X-ray diffraction analysis. These photoproducts exhibit progestogenic and androgenic activity, albeit with less potency than their paren ...[more]

PMID: 31021644

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Project description:BackgroundCeliac disease (CD) is one of the most common gluten-related disorders. Although the only effective treatment is a strict gluten-free diet, doubts remain as to whether healthcare professionals take this restriction into consideration when prescribing and dispensing medicines to susceptible patients. This scoping review aimed to find out the current evidence for initiatives that either describe the gluten content of medicines or intend to raise awareness about the risk of prescribing and dispensing gluten-containing medicines in patients with CD and other gluten-related disorders.MethodsA scoping review was conducted using three search strategies in PubMed/MEDLINE, TripDatabase and Web of Science in April 2021, following the PRISMA extension for scoping reviews (PRISMA-ScR). References from included articles were also examined. Two researchers screened the articles and results were classified according to their main characteristics and outcomes, which were grouped according to the PCC (Population, Concept and Context) framework. The initiatives described were classified into three targeted processes related to gluten-containing medicines: prescription, dispensation and both prescription and dispensation.ResultsWe identified a total of 3146 records. After the elimination of duplicates, 3062 articles remained and ultimately 13 full texts were included in the narrative synthesis. Most studies were conducted in the US, followed by Canada and Australia, which each published one article. Most strategies were focused on increasing health professional's knowledge of gluten-containing/gluten-free medications (n = 8), which were basically based on database development from manufacturer data. A wide variability between countries on provided information and labelling of gluten-containing medicines was found.ConclusionInitiatives regarding the presence of gluten in medicines, including, among others, support for prescribers, the definition of the role of pharmacists, and patients' adherence problems due to incomplete labelling of the medicines, have been continuously developed and adapted to the different needs of patients. However, information is still scarce, and some aspects have not yet been considered, such as effectiveness for the practical use of solutions to support healthcare professionals.

Project description:In this work we report the effects of continuous UV-light (276 nm, ~2.20 W.m(-2)) excitation of human insulin on its absorption and fluorescence properties, structure and functionality. Continuous UV-excitation of the peptide hormone in solution leads to the progressive formation of tyrosine photo-product dityrosine, formed upon tyrosine radical cross-linkage. Absorbance, fluorescence emission and excitation data confirm dityrosine formation, leading to covalent insulin dimerization. Furthermore, UV-excitation of insulin induces disulphide bridge breakage. Near- and far-UV-CD spectroscopy shows that UV-excitation of insulin induces secondary and tertiary structure losses. In native insulin, the A and B chains are held together by two disulphide bridges. Disruption of either of these bonds is likely to affect insulin's structure. The UV-light induced structural changes impair its antibody binding capability and in vitro hormonal function. After 1.5 and 3.5 h of 276 nm excitation there is a 33.7% and 62.1% decrease in concentration of insulin recognized by guinea pig anti-insulin antibodies, respectively. Glucose uptake by human skeletal muscle cells decreases 61.7% when the cells are incubated with pre UV-illuminated insulin during 1.5 h. The observations presented in this work highlight the importance of protecting insulin and other drugs from UV-light exposure, which is of outmost relevance to the pharmaceutical industry. Several drug formulations containing insulin in hexameric, dimeric and monomeric forms can be exposed to natural and artificial UV-light during their production, packaging, storage or administration phases. We can estimate that direct long-term exposure of insulin to sunlight and common light sources for indoors lighting and UV-sterilization in industries can be sufficient to induce irreversible changes to human insulin structure. Routine fluorescence and absorption measurements in laboratory experiments may also induce changes in protein structure. Structural damage includes insulin dimerization via dityrosine cross-linking or disulphide bond disruption, which affects the hormone's structure and bioactivity.

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Bioactive Rearrangement Products from Aqueous Photolysis of Pharmaceutical Steroids.

Publications

Bioactive Rearrangement Products from Aqueous Photolysis of Pharmaceutical Steroids.

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