The cytochrome P45O activities of the naturally occurring Amaryllidaceae alkaloid narciclasine (3), isolated from Narcissus pseudonarcissus, and synthetic derivative trans-dihydronarciclasine (5) are reported. While narciclasine was found to possess potent inhibitory activity to human CYP3A4, its dihydro analogue was inactive. This study revealed that the C1-C10b double bond is required for inhibition of this crucial metabolizing enzyme. Compound 5 also demonstrated no inhibition of the related human cytochromes CYP19 and CYP1A1. This study elevates the status of trans-dihydronarciclasine (5) as a highly privileged, readily available molecule, with potent and selective anticancer activity.
The fluorescence enhancement (“turn‐on”) response of the amyloid‐sensing dye thioflavin T (ThT) is examined in vacuo, where solvent interactions are absent. Upon the complexation of ThT with a derivatized β‐cyclodextrin, heptakis‐[6‐deoxy‐6‐(3‐sulfanylpropanoic acid)]‐β‐cyclodextrin, turn‐on responses in both the gas phase and solution phase were observed. In contrast, turn‐on response was not detected when ThT was bound to gaseous cucurbit[7]uril or human telomeric DNA 22AG, whereas clear turn‐on response occurs in solution. The observed difference in turn‐on response in the gas phase emphasizes the key interplay between chromophore, host and solvent and demonstrates the utility of gas‐phase spectroscopy to tease out the balance among intermolecular forces driving the behavior of important chromophores in solution.
Mass cytometry (MC) and imagingm ass cytometry (IMC TM ) have emergeda si mportant tools for the study of biological heterogeneity.W er ecently demonstrated the use of l-2-tellurienylalanine (TePhe),amimic of phenylalanine (Phe), as an MCand IMC-compatible protein synthesis reporter.I nt his work, the biochemical similarity of TePhe and its cognate analogue, Phe, are examined in the contexto ft he RNase Sc omplex. Isothermalt itration calorimetry studies show that incorporation of TePhe preserves the interaction of S-peptide with S-protein, and the dissociation constants for the interaction of the Phe and Te Phep eptides are within af actor of two. The resulting RNase Sc omplex is catalytically active without significant alterations in the enzyme'skinetic parameters. Furthermore, circular dichroism spectroscopy does not reveal any changes to the secondary structure of Te Phe-substituted RNase S. These findings provide strong evidence that Te Phe functions as aPhe isostere in the context of afolded protein. It is anticipated that incorporation of Te Phe into peptides or peptidomimetic scaffolds will enablefacile generation of MC and IMC TM probes.[a] Dr.
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