Repurposing consumer sunscreen habits and practices survey data to guide the development of UV filter environmental exposure models and risk assessments.

OBJECTIVE: A key factor that is deficient in most environmental emissions assessments for UV filters is a keen understanding of consumer habits and practices that can inform realistic exposure assessments. This study utilized a large volunteer survey (>11 000 persons) that captured many factors that affect consumer-based loadings to aquatic environments. The purpose of this study was to utilize this large survey to identify factors that affect the amount of sunscreen products used by consumers. METHODS: Correlations among more than 20 variables were used to provide an understanding of the overall dataset and identify factors that may be related to the amount of sunscreen product applied to the body (i.e., application thickness). Forward multiple linear regressions were used to identify the relative importance of each of these factors alone and in combination with others in predicting the amount of applied sunscreen. RESULTS: The proportion of body surface area (BSA) covered by sunscreen was the primary factor related to application thickness, followed by body surface area of the survey participant, seasonal usage, Fitzpatrick skin type and the sun protection factor, respectively. Each of the five regression models examined was statistically highly significant. CONCLUSIONS: Comparisons to recommendations from the National Academies of Science, Engineering and Medicine parameters illustrated sufficient differences so as to encourage the development of future consumer habits and practice surveys that include factors beyond the scope of this study (e.g., activities, time of day, year, location, etc.) that can lead to improved exposure and risk assessments.

OBJECTIF: Un facteur clé qui est insuffisant dans la plupart des évaluations des émissions environnementales pour les filtres UV est une bonne compréhension des habitudes et pratiques des consommateurs qui peuve informer sur les évaluations réalistes de l'exposition. Cette étude a utilisé une vaste enquête auprès de volontaires (> 11 000 personnes) qui a pris en compte de nombreux facteurs affectant les habitudes des consommateurs dans des environnements aquatiques. L'objectif de cette étude était d'utiliser cette vaste enquête pour identifier les facteurs qui affectent la quantité de produit d'écran solaire utilisée par les consommateurs. MÉTHODES: Des corrélations entre plus de vingt variables ont été utilisées pour fournir une compréhension de l'ensemble des données et identifier les facteurs qui peuvent être liés à la quantité de produit d'écran solaire appliqué sur le corps (c.-à-d., épaisseur d'application). Des régressions linéaires multiples ont été utilisées pour identifier l'importance relative de chacun de ces facteurs seuls et en association avec d'autres pour prédire la quantité d'écran solaire appliqué. RÉSULTATS: La proportion de la surface corporelle (SC) couverte par l'écran solaire était le facteur principal lié à l'épaisseur de l'application, suivie de la surface corporelle du participant à l'enquête, de l'utilisation saisonnière, du type de peau (Fitzpatrick) et du facteur de protection solaire, respectivement. Chacun des cinq modèles de régression examinés était hautement significatif statistiquement. CONCLUSIONS: Les comparaisons avec les recommandations des Académies nationales de la science, de l'ingénierie et de la médecine ont mis en évidence des différences suffisantes pour encourager le développement de futures enquêtes sur les habitudes et les pratiques des consommateurs qui incluent des facteurs dépassant le champ d'application de cette étude (ex., activités, moment de la journée, année, lieu, etc.) qui peuvent conduire à une amélioration de l'exposition et des évaluations des risques.

Aminobenzosuberone Scaffold as a Modular Chemical Tool for the Inhibition of Therapeutically Relevant M1 Aminopeptidases.

The synthesis of racemic substituted 7-amino-5,7,8,9-tetrahydrobenzocyclohepten-6-one hydrochlorides was optimized to enhance reproducibility and increase the overall yield. In order to investigate their specificity, series of enzyme inhibition assays were carried out against a diversity of proteases, covering representative members of aspartic, cysteine, metallo and serine endopeptidases and including eight members of the monometallic M1 family of aminopeptidases as well as two members of the bimetallic M17 and M28 aminopeptidase families. This aminobenzosuberone scaffold indeed demonstrated selective inhibition of M1 aminopeptidases to the exclusion of other tested protease families; it was particularly potent against mammalian APN and its bacterial/parasitic orthologues EcPepN and PfAM1.

Insight into the remarkable affinity and selectivity of the aminobenzosuberone scaffold for the M1 aminopeptidases family based on structure analysis.

Aminopeptidases are ubiquitous hydrolases that cleave the N-terminal residues of proteins and oligopeptides. They are broadly distributed throughout all kingdoms of life and have been implicated in a wide variety of physiological processes, including viral infection, parasite metabolism, protein processing, regulation of peptide hormones, and cancer cell proliferation. Members of the M1 family, also termed gluzincins, are defined by two highly conserved motifs in the catalytic domain: a zinc-binding motif, HEXXH-(X18)-E; and an exopeptidase motif, GXMEN. We report the high-resolution X-ray structures of E. coli aminopeptidase N (PepN) in complex with three aminobenzosuberone scaffolds that display various Ki values (50, 0.33, and 0.034 µM) and provide a compelling view of the outstanding selectivity of these chemical entities for the M1 aminopeptidases. This series of inhibitors interacts as transition state mimics with highly conserved residues of the catalytic machinery and substrate recognition sites. Structural comparisons and model-building studies allowed a deep interpretation of the SAR observed for bacterial, as well as mammalian enzymes. Proteins 2017; 85:1413-1421. © 2017 Wiley Periodicals, Inc.

Exploring S1 plasticity and probing S1' subsite of mammalian aminopeptidase N/CD13 with highly potent and selective aminobenzosuberone inhibitors.

In order to probe the S1 and S1' mammalian aminopeptidase N subsites, racemic 1- or 4-substituted 7-aminobenzocyclohepten-6-one derivatives were synthesized and evaluated for their ability to inhibit mammalian aminopeptidase N. We focused on improving the physicochemical and ADME properties of this series by targeting lipophilicity and LELP score. Some 4-heteroaryl substituted analogues displayed reduced lipophilicity and enhanced inhibition potency with Ki values in the nanomolar range.

Selective aminopeptidase-N (CD13) inhibitors with relevance to cancer chemotherapy.

Aminopeptidase-N (APN/CD13) is highly expressed on the surface of numerous types of cancer cells and particularly on the endothelial cells of neoangiogenic vessels during tumourigenesis. This metallo-aminopeptidase has been identified as a potential target for cancer chemotherapy. In this work, we evaluated the efficacy of a novel series of benzosuberone analogues, which were previously reported to be highly potent, selective APN inhibitors with Ki values in the micromolar to sub-nanomolar range. Endothelial cell morphogenesis as well as cell motility were inhibited in vitro in a dose-dependent manner at concentrations that correlated with the potency of the compounds, thus confirming the key role of APN in these established models of angiogenesis. We report toxicity studies in mice showing that these compounds are well tolerated. We report the effects of the compounds, used alone or in combination with rapamycin, on the growth of a select panel of tumours that were subcutaneously xenografted onto Swiss nude mice. Our data indicate that the in vivo efficacy of these new APN inhibitors during the initial phase of tumour growth can be ascribed to their anti-angiogenic activities. However, we also provide evidence that these compounds are effective against established solid tumours. For colonic tumours, the anti-tumour effect depends on the level of APN expression in epithelial cells, and APN expression is associated with down-regulation of the transcription factor HIF-1α. These effects seem to be distinct from those of rapamycin. Our finding that the anti-tumour effect of the inhibitors in the colon requires APN expression strongly suggests that APN plays a crucial function in tumour cells that is distinct from its known role in neovascularisation.

A novel amino-benzosuberone derivative is a picomolar inhibitor of mammalian aminopeptidase N/CD13.

A new class of low molecular weight, highly potent and selective non peptidic inhibitors of aminopeptidase N (APN/CD13) is described. We report the synthesis and in vitro evaluation of racemic substituted analogues of 7-amino-benzocyclohepten-6-one 1a. We investigated various substitutions on the aromatic ring with phenyl and halogen groups. In vitro kinetic studies revealed that these compounds are among the most effective APN/CD13 inhibitors found so far. Hydrophobic substituents placed at position 1 or 4 on the cycloheptenone 1a led to the potent compounds 1c-h,b'-c',f',h' with K(i) in the nanomolar range. The key finding of the present work was the observed additive effect of 1,4-disubstitutions which led to the discovery of the picomolar inhibitor 1d' (K(i)=60 pM). The designed inhibitors retain the selectivity of our lead structure 1a towards selected members of the aminopeptidase family, combined with an impressive increase in inhibitory potency and a conserved stability.