Phosphonium-mediated synthesis of a new class of indoloquinazoline derivatives bearing C-12 aryloxy ester and spiro-γ-lactone

Indoloquinazolines functionalized at C-12 which are structure analogs of the natural alkaloid cephalanthrin B were readily constructed via a Ph3P-I2 mediated one-pot reaction of isatins with aromatic alcohols. In the presence of excess phenols, the C-12 aryloxy ester products were afforded in moderate to good yields under mild conditions. Moreover, fused bicyclic hydroxyaryl derivatives such as 8-hydroxyquinoline gave rise to novel C-12 spiro-γ-lactone derivatives. Reactive iminium cation species derived from dehydration of the C-12 hydroxy ester precursor is proposed to be transient intermediates responsible for these unprecedented transformations.

Holistic evaluation of biodegradation pathway prediction: assessing multi-step reactions and intermediate products

The prediction of metabolism and biotransformation pathways of xenobiotics is a highly desired tool in environmental sciences, drug discovery, and (eco)toxicology. Several systems predict single transformation steps or complete pathways as series of parallel and subsequent steps. Their performance is commonly evaluated on the level of a single transformation step. Such an approach cannot account for some specific challenges that are caused by specific properties of biotransformation experiments. That is, missing transformation products in the reference data that occur only in low concentrations, e.g. transient intermediates or higher-generation metabolites. Furthermore, some rule-based prediction systems evaluate the performance only based on the defined set of transformation rules. Therefore, the performance of these models cannot be directly compared. In this paper, we introduce a new evaluation framework that extends the evaluation of biotransformation prediction from single transformations to whole pathways, taking into account multiple generations of metabolites. We introduce a procedure to address transient intermediates and propose a weighted scoring system that acknowledges the uncertainty of higher-generation metabolites. We implemented this framework in enviPath and demonstrate its strict performance metrics on predictions of in vitro biotransformation and degradation of xenobiotics in soil. Our approach is model-agnostic and can be transferred to other prediction systems. It is also capable of revealing knowledge gaps in terms of incompletely defined sets of transformation rules.

Elastic versus Brittle Mechanical Responses Predicted for Dimeric Cadherin Complexes

Cadherins are a superfamily of adhesion proteins involved in a variety of biological processes that include the formation of intercellular contacts, the maintenance of tissue integrity, and the development of neuronal circuits. These transmembrane proteins are characterized by ectodomains composed of a variable number of extracellular cadherin (EC) repeats that are similar but not identical in sequence and fold. E-cadherin, along with desmoglein and desmocollin proteins, are three classical-type cadherins that have slightly curved ectodomains and engage in homophilic and heterophilic interactions through an exchange of conserved tryptophan residues in their N-terminal EC1 repeat. In contrast, clustered protocadherins are straighter than classical cadherins and interact through an antiparallel homophilic binding interface that involves overlapped EC1 to EC4 repeats. Here we present molecular dynamics simulations that model the adhesive domains of these cadherins using available crystal structures, with systems encompassing up to 2.8 million atoms. Simulations of complete classical cadherin ectodomain dimers predict a two-phased elastic response to force in which these complexes first softly unbend and then stiffen to unbind without unfolding. Simulated α, β, and γ clustered protocadherin homodimers lack a two-phased elastic response, are brittle and stiffer than classical cadherins, and exhibit complex unbinding pathways that in some cases involve transient intermediates. We propose that these distinct mechanical responses are important for function, with classical cadherin ectodomains acting as molecular shock absorbers and with stiffer clustered protocadherin ectodomains facilitating overlap that favors binding specificity over mechanical resilience. Overall, our simulations provide insights into the molecular mechanics of single cadherin dimers relevant in the formation of cellular junctions essential for tissue function.

Holistic Evaluation of Biodegradation Pathway Prediction: Assessing Multi-Step Reactions and Intermediate Products

The prediction of metabolism and biotransformation pathways of xenobiotics is a highly desired tool in environmental and life sciences. There are several systems that currently predict single transformation steps or complete pathways as series of parallel and subsequent steps. Their accuracy is often evaluated on the level of a single transformation step. Such an approach cannot account for some specific challenges that are related to the nature of the biotransformation experiments. This is particularly true for missing transformation products in the reference data that occur only in low concentrations, e.g. transient intermediates or higher-generation metabolites. Furthermore, some rulebased prediction systems evaluate accuracy only based on the defined set of transformation rules. Therefore, the performance of different models cannot be directly compared.

Dissipation of Chlorpyrifos in the bottled tea beverages and the effects of EGCG

Bottled tea beverages (BTB) are popular for the benefits to human health and convenience. Because Chlorpyrifos (CP) is commonly used as a biomarker for exposure as well as a pesticide in the field, it is important to determine the dynamics of CP dissipation in BTB in order to better perform risk assessments. This study focused on the dynamic behavior of CP for 22 days by fortifying bottled green tea (GT), dark tea (DT), and Oolong tea (OT) beverages with the parent chemical and analyzing the degradation products. Photo-induction was used to generate the two transient intermediates, i.e. the reactive oxygen species (ROS) from H₂O₂ and the triplet state of CP ( 3 CP*) from the parental, in water was designed to observe the effects of (−)-Epigallocatechin-3-gallate (EGCG) on the dissipation and transformation of CP. The results indicated that the CP degraded in BTB and the main products were detected. The half-life values of CP illustrated that EGCG increased the dissipation of CP by combination with CP, and inhibited the generation of CP -oxon by scavenging the emerged oxidant ROS and interfering the transformation of 3 CP*. This work suggests EGCG could play the various roles on the dissipation and transformation of CP. Thus, a comprehensive identification of CP degradation should be performed when assessing the exposure risk in the drinking of bottled tea beverages.

Holistic Evaluation of Biodegradation Pathway Prediction: Assessing Multi-Step Reactions and Intermediate Products

The prediction of metabolism and biotransformation pathways of xenobiotics is a highly desired tool in environmental and life sciences. There are several systems that currently predict single transformation steps or complete pathways as series of parallel and subsequent steps. Their accuracy is often evaluated on the level of a single transformation step. Such an approach cannot account for some specific challenges that are related to the nature of the biotransformation experiments. This is particularly true for missing transformation products in the reference data that occur only in low concentrations, e.g. transient intermediates or higher-generation metabolites. Furthermore, some rulebased prediction systems evaluate accuracy only based on the defined set of transformation rules. Therefore, the performance of different models cannot be directly compared.

Holistic Evaluation of Biodegradation Pathway Prediction: Assessing Multi-Step Reactions and Intermediate Products

The prediction of metabolism and biotransformation pathways of xenobiotics is a highly desired tool in environmental and life sciences. There are several systems that currently predict single transformation steps or complete pathways as series of parallel and subsequent steps. Their accuracy is often evaluated on the level of a single transformation step. Such an approach cannot account for some specific challenges that are related to the nature of the biotransformation experiments. This is particularly true for missing transformation products in the reference data that occur only in low concentrations, e.g. transient intermediates or higher-generation metabolites. Furthermore, some rulebased prediction systems evaluate accuracy only based on the defined set of transformation rules. Therefore, the performance of different models cannot be directly compared.