Palladium-Catalyzed Cyclocarbonylation of Pyridinylated Vinylogous Amides and Ureas to Generate Ring-Fused Pyridopyrimidinones

As part of a program aimed at generating new heterocyclic frameworks for medicinal chemistry exploration, an efficient approach to the assembly of novel ring-fused pyridopyrimidinones was undertaken. Specifically, a collection of 11<i>H</i>-pyrido­[2,1-<i>b</i>]­quinazoline-1,11­(2<i>H</i>)-diones and 2,3-dihydropyrido­[1,2-<i>a</i>]­pyrrolo­[3,4-<i>d</i>]­pyrimidine-1,10-diones was generated via a palladium-catalyzed, pyridine-directed, cyclocarbonylation of 2-pyridyl-linked vinylogous amides and ureas in yields of up to 90%

Supplementary Information from Degree heterogeneity and stability of ecological networks

Technical details in obtaining the key results presented in the main text

Refine and Strengthen SAR-Based Read-Across by Considering Bioactivation and Modes of Action

Structure–activity relationship (SAR)-based read-across is an important and effective method to establish the safety of a data-poor target chemical (structure of interest (SOI)) using hazard data from structurally similar source chemicals (analogues). Many methods use quantitative similarity scores to evaluate the structural similarity for searching and selecting analogues as well as for evaluating analogue suitability. However, studies suggest that read-across based purely on structural similarity cannot accurately predict the toxicity of an SOI. As mechanistic data become available, we gain a greater understanding of the mode of action (MOA), the relationship between structures and metabolism/bioactivation pathways, and the existence of “activity cliffs” in chemical chain length, which can improve the analogue rating process. For this purpose, the current work identifies a series of classes of chemicals where a small change at a key position can result in a significant change in metabolism and bioactivation pathways and may eventually result in significant changes in chemical toxicity that have a big impact on the suitability of analogues for read-across. Additionally, a series of SAR-based read-across case studies are presented, which cover a variety of chemical classes that commonly link to different toxic endpoints. The case study results indicate that SAR-based read-across can be refined and strengthened by considering MOAs or proposed reactive metabolite formation pathways, which can improve the overall accuracy, consistency, transparency, and confidence in evaluating analogue suitability

Refine and Strengthen SAR-Based Read-Across by Considering Bioactivation and Modes of Action

Structure–activity relationship (SAR)-based read-across is an important and effective method to establish the safety of a data-poor target chemical (structure of interest (SOI)) using hazard data from structurally similar source chemicals (analogues). Many methods use quantitative similarity scores to evaluate the structural similarity for searching and selecting analogues as well as for evaluating analogue suitability. However, studies suggest that read-across based purely on structural similarity cannot accurately predict the toxicity of an SOI. As mechanistic data become available, we gain a greater understanding of the mode of action (MOA), the relationship between structures and metabolism/bioactivation pathways, and the existence of “activity cliffs” in chemical chain length, which can improve the analogue rating process. For this purpose, the current work identifies a series of classes of chemicals where a small change at a key position can result in a significant change in metabolism and bioactivation pathways and may eventually result in significant changes in chemical toxicity that have a big impact on the suitability of analogues for read-across. Additionally, a series of SAR-based read-across case studies are presented, which cover a variety of chemical classes that commonly link to different toxic endpoints. The case study results indicate that SAR-based read-across can be refined and strengthened by considering MOAs or proposed reactive metabolite formation pathways, which can improve the overall accuracy, consistency, transparency, and confidence in evaluating analogue suitability

Mock-ablation (PDB) sample video

Processed video showing mock-ablated animal (with segmentation) freely-moving on a bacterial lawn for 15 minutes

PDB ablations_1 feature files and segmented movies

Processed videos of mock- and PDB-ablated animals (with segmentation) freely-moving on a bacterial lawn for 15 minutes, and Matlab files containing data for features extracted from these videos, for replicate 1 of the PDB-ablation experiment

DD5-ablation sample video

Processed video showing DD5-ablated animal (with segmentation) freely-moving on a bacterial lawn for 15 minutes

Synthesis and Biological Activity Evaluation of Novel α‑Amino Phosphonate Derivatives Containing a Pyrimidinyl Moiety as Potential Herbicidal Agents

To find novel high-activity and low-toxicity herbicide lead compounds with novel herbicidal mode of action, series of novel α-amino phosphonate derivatives containing a pyrimidinyl moiety, <b>I</b>, <b>II</b>, <b>III</b>, and <b>IV</b>, were designed and synthesized by Lewis acid (magnesium perchlorate) catalyzed Mannich-type reaction of aldehydes, amines, and phosphites. Their structures were clearly identified by spectroscopy data (IR, ¹H NMR, ³¹P NMR, EI-MS) and elemental analyses. The bioassay [in vitro, in vivo (GH1 and GH2)] showed that most compounds <b>I</b> exhibited good herbicidal activities; for example, the activities of compounds <b>Ib</b>, <b>Ic</b>, <b>Ig</b>, <b>Ii</b>, <b>Ik</b>, and <b>Im</b> were as good as the positive control herbicides (acetochlor, atrazine, mesotrione, and glyphosate). However, their structural isomers <b>II</b> and <b>III</b> and analogues <b>IV</b> did not display any herbicidal activities in vivo, although some of them possessed selective inhibitory activity against Arabidopsis thaliana in vitro. Interestingly, it was found that compounds <b>IVs</b>, <b>IVt</b>, and <b>IVl</b> showed selective insecticidal activities against Aphis species or Plutella xylostella, respectively. Their preliminary herbicidal mode of action and structure–activity relationships were also studied

DD3 DD4 ablations raw videos (mock/DD3/DD4)

Raw videos of mock-, DD3- and DD4-ablated animals freely-moving on a bacterial lawn for 15 minutes, for the DD3/DD4-ablation experiment

PDB-ablation sample video 1

Processed video showing PDB-ablated animal (with segmentation) freely-moving on a bacterial lawn for 15 minutes