Development of Decarboxylative Cyanation Reactions for C‑13/C-14 Carboxylic Acid Labeling Using an Electrophilic Cyanating Reagent

Degradation-reconstruction approaches for isotope labeling synthesis have been known for their remarkable efficiency, but applications are scarce due to some fundamental limitations of the chemistries developed to date. The decarboxylative cyanation reaction, as a degradation-reconstruction approach, is especially useful in rapid carboxylic acid carbon isotope labeling, however development toward its application as a widespread technique has stalled at the early stages due to numerous limitations which include somewhat narrow applicability. Employing the electrophilic cyanating reagent <i>N</i>-cyano-<i>N</i>-phenyl-<i>p</i>-toluenesulfonamide (NCTS) as the cyano source, efficient decarboxylative cyanation chemistry has been developed for aryl and alkyl carboxylic acids respectively with two rationally designed reaction pathways. The reactions provided good yields of nitrile products from carboxylic acids, with complete retention of isotopic purity from the [¹³CN]-NCTS used. The reaction conditions are relatively mild requiring no oxidant and no excess toxic heavy metal and the reagent [^13/14CN]-NCTS is a stable, easy-to-handle crystalline solid that can be prepared quickly and effectively from the readily available [^13/14C]-KCN. The following work describes this novel and efficient method for alkyl and aryl carboxylic acid isotopic labeling using a single reagent

Hydroxylation of Substituted Anilides with Metallaphotocatalysis

We report the combination of organo-photocatalysis with transition metal (TM) catalysis for directed ortho-hydroxylation of substituted anilides for the synthesis of α-aminophenol derivatives under mild conditions. The developed metallaphotocatalysis utilizes N-pivaloyl as a directing group and phenyl iodine(III) bis(trifluoroacetate) (PIFA) in the combination of the 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) photocatalyst and [RuCl2(p-cymene)]2 TM catalyst under visible-light irradiation at room temperature. The hydroxylation reaction works well for a wide range of substrates containing electron-withdrawing substituents and could be applied to late-stage functionalization and ortho-hydroxyl metabolite generation for drug compounds-containing anilides with electron-withdrawing substituents in a single mild reaction

Standard-Free Bioanalytical Approach for Absolute Quantitation of Drug Metabolites Utilizing Biosynthesis of Reciprocal Radio and Stable Isotopologues and Its Application

The following work describes a combined enzymatic and bioanalytical method that permits absolute quantitation of metabolites in biological samples without the requirement for reference metabolite standards. This technique was exemplified using a radio (¹⁴C) isotopologue and a stable (¹³C₆) isotopologue of acetaminophen as substrates for <i>in vitro</i> biosynthesis of the corresponding radio and stable isotope labeled metabolites, namely, ¹⁴C- and ¹³C₆-glucuronides and sulfates. By supplanting the use of authentic metabolite standards, traditionally used to calibrate ¹³C₆-metabolites via liquid chromatography-tandem mass spectrometry (LC-MS/MS), ¹³C₆-metabolites were radiocalibrated by their ¹⁴C-isotopologues via liquid chromatography coupled with radioactivity detection and mass spectrometry (LC-RAD/MS). The radiocalibrated ¹³C₆-isotopologues were in turn used to quantitate acetaminophen and its corresponding metabolites in rat plasma samples by LC-MS/MS. Variation between this and a conventional LC-MS/MS method using authentic standards for calibration was within ±17%, permitting its use in preclinical and clinical applications. Since authentic metabolite standards are not required under the concept of radio and stable isotopologues using adapted LC-RAD/MS protocols, significantly fewer resources are required to support accurate metabolite quantitation which in turn enables efficient analysis of simple and complex metabolite profiles

Discovery of <i>N</i>‑(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimer’s Disease

A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified <i>N</i>-(6-methylpyridin-2-yl)­quinolin-2-amine <b>10</b> as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated β-amyloid (Aβ). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with suboptimal physicochemical properties. Further optimization toward a more optimal pharmacokinetic profile led to the discovery of 1,5-naphthyridine <b>75</b>, a potent and selective tau aggregate binder with potential as a tau PET tracer