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Targeted protein degradation via the ubiquitin-proteasome system has emerged as one of the most promising drug discovery modalities. Autophagy, another intracellular degradation system, can target a wide range of nonproteinous substrates as well as proteins, but its application to targeted degradation is still in its infancy. Our previous work revealed a relationship between guanine modification of cysteine residues on intracellular proteins and selective autophagy, resulting in the first autophagy-based degraders, autophagy-targeted chimeras (AUTACs). Based on the research background, all the reported AUTACs compounds contain cysteine as a substructure. Here, we examine the importance of this substructure by conducting SAR studies and report significant improvements in the degrader's activity by replacing cysteine with other moieties. Several derivatives showed sub-μM range degrading activity, demonstrating the increased practical value of AUTACs.

This Article describes the simultaneous imaging of chiral nitroxyl radicals using electron paramagnetic resonance (EPR). Chiral nitroxyl radicals could be simultaneously visualized with the labeling of isotopic nitrogen. Chiral nitroxyl radicals, hydroxylmethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl, were visualized using the method of simultaneous EPR imaging, which refers to the visualization of two kinds of molecules with unpaired electrons in a single image scan. EPR spectra of a racemic mixture of chiral nitroxyl radicals and those of the respective R and S configurations confirmed labeling by isotopic nitrogen. (1)H nuclear magnetic resonance (NMR) imaging and simultaneous imaging of solutions of chiral nitroxyl radicals were performed. The advantages and limitations of simultaneous imaging using EPR are also discussed. Simultaneous imaging with chiral-labeled nitroxyl radicals is a new application of EPR imaging and may be useful for biological studies involving biologically active chiral molecules.

Nitric oxide (NO), a gaseous free radical that is biologically synthesized by nitric oxide synthases, participates in a critical fashion in the regulation of diverse physiological functions including vascular and neuronal signal transduction, host defense, and cell death regulation. This article reviews the chemical and biochemical mechanisms of protein thiol modifications caused by NO and by electrophiles derived from NO metabolism. The classical NO signaling pathway involves formation of the second messenger guanosine 3',5'-cyclic monophosphate (cGMP). Post-translational modifications of redox-sensitive protein thiols have also been shown to be important in this signaling pathway. For instance, redox-sensitive thiols are targets for NO conjugation and formation of S-nitrosothiols. Electrophiles generated by reactions of NO or reactive nitrogen oxide species and biomolecules (i.e., fatty acids) effect thiol conjugations through S-alkylation. Among this class of reactions, S-guanylation is particularly emphasized. S-Guanylation is a novel type of S-alkylation with nitrated cGMP that contributes to the cytoprotective effects of NO. Post-translational modifications of thiols affect protein structures and functions: allosteric effects may alter protein structure, modification of active centers of enzymes may suppress enzyme actions, and modifications may modulate protein-protein interactions. Better understanding of protein modification by NO-derived electrophiles and the molecular basis of NO signaling would be useful in the development of new diagnostic methods and treatment of diseases related to NO metabolism.

Novel semisynthetic vancomycin derivatives with antibacterial activity against vancomycin-resistant S. aureus (VRSA) were prepared. Replacement of Cl groups of vancomycin by Suzuki-Miyaura cross-coupling reaction, which gave the title compounds, is described for the first time. Introduction of a carbon substituent at the amino acid residue 2 of vancomycin led to an enhancement of antibacterial activity against vancomycin-resistant strains, whereas the additional introduction at the amino acid residue 6 resulted in a reduction in activity even against vancomycin-susceptible strains.

A plant growth regulator, theobroxide, which produces potato tubers under noninduced long-day conditions, was synthesized in four steps from dihydrotoluene.

To evaluate the protective activity of fruits against liver injury, 22 different fruits were fed to rats with liver damage caused by D-galactosamine, a powerful liver toxin. As measured by changes in the levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), avocado showed extraordinarily potent liver injury suppressing activity. Five active compounds were isolated and their structures determined. These were all fatty acid derivatives, of which three, namely, (2E,5E,12Z,15Z)-1-hydroxyheneicosa-2,5,12,15-tetraen-4-one, (2E,12Z,15Z)-1-hydroxyheneicosa-2,12,15-trien-4-one, and (5E,12Z)-2-hydroxy-4-oxoheneicosa-5,12-dien-1-yl acetate, were novel.

[formula: see text] A triply convergent, highly efficient second-generation synthesis of the potent antimitotic agent (+)-discodermolide (1) has been achieved on a 1-g scale.

Surface ionization organic mass spectrometry (SIOMS) has been performed on some clinically important drugs (imipramine, desipramine, clomipramine, lidocaine) by using quadrupole mass spectroscopy in which the thermal ion source has a rhenium oxide emitter. The mass spectra were presented, interpreted in a purely empirical way, by means of evidence from previous investigations, and then compared to conventional EI techniques. Sensitivity and selectivity have also been studied, demonstrating that (a) these drug compounds are efficiently surface-ionized, (b) experimental results rationalize the high sensitivity of the surface ionization detector (SID) of gas chromatography (GC) for the examined drugs, and (c) the GC/SIOMS coupling can be used for sensitive and selective detection of the drugs in the serum. An approach to detection of these drugs in serum by GC/SIOMS and GC with SID is described. The characteristics of both methods provide a reliable, sensitive, and selective method, which is needed for low concentration level measurements in complex mixtures.