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Chemistry informer libraries: a chemoinformatics enabled approach to evaluate and advance synthetic methods.

ABSTRACT: Major new advances in synthetic chemistry methods are typically reported using simple, non-standardized reaction substrates, and reaction failures are rarely documented. This makes the evaluation and choice of a synthetic method difficult. We report a standardized complex molecule diagnostic approach using collections of relevant drug-like molecules which we call chemistry informer libraries. With this approach, all chemistry results, successes and failures, can be documented to compare and evolve synthetic methods. To aid in the visualization of chemistry results in drug-like physicochemical space we have used an informatics methodology termed principal component analysis. We have validated this method using palladium- and copper-catalyzed reactions, including Suzuki-Miyaura, cyanation and Buchwald-Hartwig amination.

SUBMITTER: Kutchukian PS

PROVIDER: S-EPMC5477042 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Chemistry informer libraries: a chemoinformatics enabled approach to evaluate and advance synthetic methods.

Kutchukian Peter S PS Dropinski James F JF Dykstra Kevin D KD Li Bing B DiRocco Daniel A DA Streckfuss Eric C EC Campeau Louis-Charles LC Cernak Tim T Vachal Petr P Davies Ian W IW Krska Shane W SW Dreher Spencer D SD

Chemical science 20160126 4

Major new advances in synthetic chemistry methods are typically reported using simple, non-standardized reaction substrates, and reaction failures are rarely documented. This makes the evaluation and choice of a synthetic method difficult. We report a standardized complex molecule diagnostic approach using collections of relevant drug-like molecules which we call chemistry informer libraries. With this approach, all chemistry results, successes and failures, can be documented to compare and evol ...[more]

PMID: 28660032

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Project description:During traumatic joint injuries, impact overloading can cause mechanical damage to the cartilage. In the following inflammation phase, excessive inflammatory cytokines (e.g., interleukin-1β (IL-1β)) can act on chondrocytes, causing over-proliferation, apoptosis, and extracellular matrix (ECM) degradation that can lead to osteoarthritis. This study investigated the combined effects of traumatic overloading and IL-1β challenge on the metabolic activities of chondrocytes. Bovine cartilage explants underwent impact overloading followed by IL-1β exposure at a physiologically relevant dosage (1 ng/mL). New click chemistry-based methods were developed to visualize and quantify the proliferation of in situ chondrocytes in a nondestructive manner without the involvement of histological sectioning or antibodies. Click chemistry-based methods were also employed to measure the ECM synthesis and degradation in cartilage explants. As the click reactions are copper-free and bio-orthogonal, i.e., with negligible cellular toxicity, cartilage ECM was cultured and studied for 6 weeks. Traumatic overloading induced significant cell death, mainly in the superficial zone. The high number of dead cells reduced the overall proliferation of chondrocytes as well as the synthesis of glycosaminoglycan (GAG) and collagen contents, but overloading alone had no effects on ECM degradation. IL-1β challenge had little effect on cell viability, proliferation, or protein synthesis but induced over 40% GAG loss in 10 days and 61% collagen loss in 6 weeks. For the overloaded samples, IL-1β induced greater degrees of degradation, with 68% GAG loss in 10 days and 80% collagen loss in 6 weeks. The results imply a necessary immediate ease of inflammation after joint injuries when trauma damage on cartilage is present. The new click chemistry methods could benefit many cellular and tissue engineering studies, providing convenient and sensitive assays of metabolic activities of cells in native three-dimensional (3D) environments.

Dataset Information

Chemistry informer libraries: a chemoinformatics enabled approach to evaluate and advance synthetic methods.

Publications

Chemistry informer libraries: a chemoinformatics enabled approach to evaluate and advance synthetic methods.

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