Although much attention has been devoted to resveratrol, a unique polyphenol produced by plants throughout the world and credited as potentially being responsible for the so-called “French paradox” given its broad spectrum activity, the hundreds of oligomeric materials derived from it have been largely ignored despite their similarly high biochemical potential. Challenges in achieving their isolation in quantity from natural sources, coupled with an inability to rationally prepare them in the laboratory, are the main culprits. Here we show that a programmable, controlled, and potentially scaleable synthesis of the resveratrol family is possible through a unique three-stage design. These efforts required novel tactics coupled with strategy- and reagent-guided functionalizations to differentiate two distinct cores possessing multiple sites with the same and/or similar reactivity, ultimately leading to five higher-order natural products. We anticipate that this work 1) demonstrates that challenging, positionally-selective functionalizations of complex materials are possible where biosynthetic studies have indicated otherwise, 2) provides materials and tools to finally unlock the full biochemical potential of the family, particularly from the standpoint of activity and drug-property optimization, and 3) affords an intellectual framework to potentially access other oligomeric families controllably.

This paper reports the solution conformation and calmodulin binding of a 43-residue peptide from the calmodulin-binding domain of Bordetella pertussis adenylate cyclase. The peptide (P225-267) was synthesized and 15N-labeled at specific amino acids. It binds calmodulin with an equilibrium dissociation constant of 25 nM. Assignment of the NMR spectrum of the free peptide and analysis of the NOE connectivities and secondary shifts of C alpha protons allowed us to identify a 10-amino acid fragment (Arg237 to Arg246) which is in rapid equilibrium between alpha-helical and irregular structures. Titration experiments showed that at substoichiometric molar ratios the two molecules are in intermediate exchange between free and bound conformations. Using 15N-edited methods we assigned a large part of resonances of the labeled residues in the bound peptide. Analysis of the chemical shift differences between free and bound states shows that the fragment Leu240-Ala257 is the most affected by the interaction. The proton spectra of the calmodulin, in the free and complexed states were extensively assigned using homonuclear experiments. Medium- and long-range NOE patterns are consistent with a largely conserved secondary and tertiary structure. The main changes in chemical shift of calmodulin resonances are grouped in six structural regions both in NH2- and COOH-terminal domains. Intermolecular NOE connectivities indicate that the NH2-terminal of the bound peptide fragment is engulfed in the COOH-terminal domain of calmodulin. The interaction geometry appears to be similar to those previously described for myosin light chain kinase or calmodulin kinase II fragments.

Biosynthesis of bacterial natural-product virulence factors is emerging as a promising antibiotic target. Many such natural products are produced by nonribosomal peptide synthetases (NRPS) from amino acid precursors. To develop selective inhibitors of these pathways, we have previously described aminoacyl-AMS (sulfamoyladenosine) macrocycles that inhibit NRPS amino acid adenylation domains but not mechanistically-related aminoacyl-tRNA synthetases. To improve the cell permeability of these inhibitors, we explore herein replacement of the α-amino group with an α-hydroxy group. In both macrocycles and corresponding linear congeners, this leads to decreased biochemical inhibition of the cysteine adenylation domain of the Yersina pestis siderophore synthetase HMWP2, which we attribute to loss of an electrostatic interaction with a conserved active-site aspartate. However, inhibitory activity can be regained by installing a cognate β-thiol moiety in the linear series. This provides a path forward to develop selective, cell-penetrant inhibitors of the biosynthesis of virulence factors to probe their biological functions and potential as therapeutic targets.

Sulfonyl fluorides are highly versatile molecules for click chemistry that have found applications in many areas of chemistry and biology. Recent chemical approaches have focused on the synthesis of alkyl sulfonyl fluorides from readily available starting materials. Here, we report a photocatalytic synthesis of alkyl sulfonyl fluorides from organotrifluoroborates and boronic acid pinacol esters, which are building blocks commonly employed by medicinal chemists in the synthesis of bioactive molecules. Steady-state and time-resolved spectroscopy have confirmed that the absorption of photons by the acridinium catalysts leads to the oxidation of the organotrifluoroborate substrates. The reaction exhibits broad functional group tolerance, which can be attributed to the mild activation with visible light. Importantly, this general approach provides easy access to primary, secondary, and tertiary alkyl sulfonyl fluorides.

This paper presents low and high resolution mass spectra as well as fragmentation processes under electron impact for methyl, ethyl and propyl-pivaloyl acetate. The fragmentation patterns have been established using elemental compositions of ions detemhed by high resolution, metastable hutsitions and deuterium labelling.