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Isatins are extensively researched compounds with diverse applications, particularly as synthetic precursors in pharmaceutical developments. However, their use as optical probes for enantioselective sensing of chiral amines has not been explored to date. Herein, we present a novel chiroptical assay with an optimized isatin that generates strong, red-shifted circular dichroism (CD) signals at approximately 380 nm upon ketimine formation with chiral amines. The intensity of the induced CD signal increases linearly with the enantiomeric excess of the analyte and thus allows quantitative chirality analysis. The general usefulness of this approach is demonstrated with a broad range of aliphatic and aromatic chiral amines, and by accurate determination of the enantiomeric composition of 10 samples., (© 2024 Wiley Periodicals LLC.)

Ewing Sarcoma (ES) is a cancer of bone and soft tissues affecting mostly children and young adults. Aggressive progression and poor prognosis of this malignancy call for novel and targeted treatments. CD99 is a transmembrane protein that is abundantly expressed on ES cells and is a diagnostic marker for the disease. ES cells are selectively sensitive to CD99 inhibition compared to most normal cells and other tumors. Therefore, CD99 is a good molecular target for ES treatment. Clofarabine and cladribine are two FDA approved drugs that are administered for their inhibitory acts on DNA synthesis to treat relapsed or refractory acute lymphoblastic and myeloid leukemia. They have also been shown to directly bind to CD99 and inhibit ES growth through a distinct mechanism. In the current study, we designed, synthesized and tested new ES specific derivatives of both drugs that would continue to target CD99 but with expected reduction in cellular membrane permeability and rendered unsuitable for inhibiting DNA synthesis. By using commercially available clofarabine and cladribine purine nucleoside analogs, we modified the primary alcohol moiety at the deoxyribose C-5' terminal site to suppress phosphorylation and thus inhibition of subsequent DNA synthesis pathways. In addition, we incorporated a variety of polar groups in the ribose and purine rings to reduce membrane permeability and investigated the effects of configurational changes in the sugar moiety. Among 26 new derivatives, we identified two compounds, BK50164 and BK60106, that cause cell death specifically in ES primarily due to inhibition of CD99 but not via inhibition of DNA synthesis. These findings provide a road map for the future development selective CD99 inhibitors for targeted treatment of ES., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Aykut Uren reports financial support was provided by Bone Cancer Research Trust, United Kingdom. Eryn Nelson reports financial support was provided by Henry Luce Foundation. Aykut Uren reports financial support was provided by National Institutes of Health. Christian Wolf reports financial support was provided by Bone Cancer Research Trust, United Kingdom., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

A novel approach to chiral recognition of small molecules using the classical ninhydrin agent is introduced. Well-defined dynamic covalent chemistry with amines and amino alcohols was developed and applied to quantitative ee sensing with good accuracy using a straightforward mixing protocol and subsequent circular dichroism measurements. This chiroptical assay is fast, broadly useful, practical and repurposes an inexpensive reagent known for more than 100 years in a new application.

Methods for the rapid determination of enantiomeric excess (ee) in asymmetric synthetic methodology development are increasingly in demand as high-throughput experimentation protocols in academia and industry are adopted. Optical approaches have been reported, many of which rely on the use of chemical derivatization or molecular assemblies, resulting in UV/vis, fluorescence, or circular dichroism (CD) signals that report the ee values. While UV/vis and fluorescence approaches benefit from readily available 96- and 384-well plate readers, until recently, no CD plate readers existed. Herein, we report the utility of using the EKKO CD plate reader to analyze a chlorocoumarin amine derivatization methodology for the ee determination of a diverse set of chiral amines with an error margin within ±7%. Linear calibration curves of ee versus CD responses for each amine were obtained, the minimum detectable and quantifiable ee values were calculated, the technique was applied to an asymmetric hydrogenation, and various interferents expected to be present in crude samples are explored. The technique described herein is found to be suitable for high-throughput experimentation that requires a parallel and rapid ee determination step.

Among the large number of chiroptical sensors that have been developed to date, few allow rational determination of the absolute configuration of chiral substrates together with quantitative ee analysis. We have prepared and tested stereodynamic N-aryl aminobenzaldehyde sensors that bind chiral amines via Schiff base formation. The covalent binding of the amine substrate generates a conformational bias in the chromophoric sensor moiety which results in characteristic CD signals. Computational analysis revealed that CD prediction of the sign of the Cotton effect and thus determination of the absolute configuration of the substrate becomes practical with a sterically crowded sensor design because the number of conformations to be considered is largely reduced and the chiroptical sensor response is less sensitive to conformational equilibria. The amplitude of the measured CD signal can be used for quantitative ee analysis of nonracemic amine samples with the help of a calibration curve.

This Perspective highlights the advances of optical methods for asymmetric reaction discovery. Optical analysis allows for the determination of absolute configuration, enantiomeric excess and reaction yield that is amenable to high-throughput experimentation. Thus, the synthetic organic community is encouraged to incorporate the methods discussed to expedite the development of high-yielding, enantioselective transformations.

Pyridoxal-5'-phosphate (PLP) is introduced to a biomimetic indicator displacement assay for simultaneous determination of the absolute configuration, enantiomeric composition and concentration of unprotected amino acids, amino alcohols and amines. The chiroptical assay is based on fast imine metathesis with a PLP aryl imine probe to capture the target compound for circular dichroism and fluorescence sensing analysis. The substrate binding yields characteristic Cotton effects that provide information about the target compound ee and the synchronous release of the indicator results in a nonenantioselective off-on fluorescence response that is independent of the enantiomeric sample composition and readily correlated to the total analyte concentration.