Matcher: An Open-Source Application for Translating Large Structure/Property Data Sets into Insights for Drug Design.

To solve recurring problems in drug discovery, matched molecular pair (MMP) analysis is used to understand relationships between chemical structure and function. For the MMP analysis of large data sets (>10,000 compounds), available tools lack flexible search and visualization functionality and require computational expertise. Here, we present Matcher, an open-source application for MMP analysis, with novel search algorithms and fully automated querying-to-visualization that requires no programming expertise.

S: A New Opportunity for the Efficient Synthesis of Stable Isotope Labeled Compounds.

The synthesis of stable isotope labeled (SIL) complex drug molecules with a ≥3 mass unit increase from the parent compound is essential for drug discovery and development. Typical approaches that rely on H, C, and N isotopes can be very challenging or even intractable, and can delay the drug development process. This work introduces a new concept for the synthesis of labeled compounds that relies on the use of S.

Palladium(II)-Mediated C-H Tritiation of Complex Pharmaceuticals.

Tritium-labeled molecules are critical tools for elucidating the binding and metabolic properties of bioactive compounds, particularly during pharmaceutical discovery. Direct tritiation of inert C-H bonds with T gas is an ideal approach for tritium labeling, but significant gaps remain for direct tritiation of structurally complex molecules with diverse functional groups. Here we report the first application of palladium(II) C-H activation chemistry for tritiation with T gas.

Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds.

Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at α-amino sp carbon-hydrogen bonds in a single step, using isotopically labeled water (DO or TO) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of TO from T, providing access to high-specific-activity TO.

Noninvasive Assessment of Losartan-Induced Increase in Functional Microvasculature and Drug Delivery in Pancreatic Ductal Adenocarcinoma.

Purpose: Losartan, an angiotensin II receptor blocker, can reduce desmoplasia and enhance drug delivery and efficacy through improving interstitial transport and vascular perfusion in pancreatic ductal adenocarcinoma (PDAC) models in mice. The purpose of this study was to determine whether magnetic resonance imaging (MRI) of magnetic iron oxide nanoparticles (MNPs) and micro-positron emission tomography (PET) measurements could respectively detect improvements in tumor vascular parameters and drug uptake in orthotopic PDAC in mice treated with losartan.

Method And Materials: All experiments were approved by the local Institutional Animal Care and Use Committee.

A Transmetalation Reaction Enables the Synthesis of [F]5-Fluorouracil from [F]Fluoride for Human PET Imaging.

Translation of new F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [F]fluoride of human doses of [F]5-fluorouracil, a PET tracer for cancer imaging in humans.

On the absolute configurational stability of bromonium and chloronium ions.

Halonium ions have long been established as the critical intermediates in halogenation and halofunctionalization of alkenes. Although these workhorse reactions have been extensively studied mechanistically and employed synthetically, the paucity of enantioselective variants is striking. A central problem in the development of catalytic enantioselective halofunctionalizations is the reversible formation of halonium ions and the facile olefin-to-olefin transfer.