NMR assignment and characterization of proton exchange of the ellagitannin granatin B.

Granatin B, a complex ellagitannin extracted from pomegranate fruit, has two equilibrating isomers, form a and form b. A full ensemble of proton and carbon-13 NMR methods over a wide range of temperature enabled a complete assignment of the more abundant isomer and showed it to be form b. This result is based on the NMR data for granatin alone and agrees with the previous determinations which were based on a combination of chemical methods and a partial assignment of the NMR spectra. The new NMR spectra also yield exchange rates for the hydroxyl protons as a function of temperature. A molecular model involving hydrogen bonding provides an explanation for the exchange data.

Synthesis of a molecular charm bracelet via click cyclization and olefin metathesis clipping.

We describe the synthesis of a polycatenated cyclic polymer, a structure that resembles a molecular charm bracelet. Ruthenium-catalyzed ring-opening metathesis polymerization of an amino-containing cyclic olefin monomer in the presence of a chain transfer agent generated an alpha,omega-diazide functionalized polyamine. Cyclization of the resulting linear polyamine using pseudo-high-dilution copper-catalyzed click cyclization produced a cyclic polymer in 19% yield. The click reaction was then further employed to remove linear contaminants from the cyclic polymer using azide- and alkyne-functionalized scavenging resins, and the purified cyclic polymer product was characterized by gel permeation chromatography, (1)H NMR spectroscopy, and IR spectroscopy. Polymer hydrogenation and conversion to the corresponding polyammonium species enabled coordination and interlocking of diolefin polyether fragments around the cyclic polymer backbone using ruthenium-catalyzed ring-closing olefin metathesis to afford a molecular charm bracelet structure. This charm bracelet complex was characterized by (1)H NMR spectroscopy, and the catenated nature of the small rings was confirmed using two-dimensional diffusion-ordered NMR spectroscopy.

NMR studies of the conformation of the natural sweetener rebaudioside A.

Rebaudioside A is a natural sweetener from Stevia rebaudiana in which four beta-D-glucopyranose units are attached to the aglycone steviol. Its (1)H and (13)C NMR spectra in pyridine-d(5) were assigned using 1D and 2D methods. Constrained molecular dynamics of solvated rebaudioside using NMR constraints derived from ROESY cross peaks yielded the orientation of the beta-D-glucopyranose units. Hydrogen bonding was examined using the temperature coefficients of the hydroxyl chemical shifts, ROESY and long-range COSY spectra, and proton-proton coupling constants.

3D QSAR study of the toxicity of trichothecene mycotoxins.

Trichothecene mycotoxins, toxic natural products of fungi from the family Hypocreaceae, are potent inhibitors of protein synthesis. The application of 3D QSAR to these toxins explored the structural basis for their biological activities. A CoMFA (Q(2)=0.619, R(2)=0.921) model was developed for a set of 15 toxins with the trichothecene nucleus; CoMFA (Q(2)=0.518, R(2)=0.855) and CoMSIA (Q(2)=0.695, R(2)=0.960) models were developed for 31 toxins with the nucleus and a macrolide ring. The results show the role of electrostatics and steric factors in the activity of the toxins and indicate that the conformation of the macrolide ring influences the toxicity of the macrolide toxins.

Structure and conformational dynamics of trichothecene mycotoxins.

A combination of NMR spectroscopy and molecular modeling has been employed to characterize the conformation and dynamics of the macrolide ring in verrucarin A and roridin A, two closely related toxins in the trichothecene mycotoxin family. Longitudinal carbon-13 relaxation times demonstrate the relative flexibility of the macrolide ring. The calculations, NOEs, and scalar vicinal coupling constants show that verrucarin A in CDCl 3 and CD 2Cl 2 predominantly adopts a single, well-defined conformation that matches the crystal structure. In contrast, roridin A is present as a mixture of two conformers.

Determination of the three-dimensional, solution-phase structure of the macrolide antibiotic oxolide in CD2Cl2 and D2O from NMR constraints.

The three-dimensional structure of the antibiotic oxolide, (9S,11S)-11-amino-9-deoxo-11,12-deoxy-9,12-epoxyerythromycin, was determined in CD2Cl2 through constrained molecular mechanics with constraints derived from proton NMR. The calculations yielded a well-defined global minimum. Data acquired for oxolide in D2O, although not as complete, indicate that the antibiotic adopts the same conformation in water.

Structure-selectivity relationships and structure for a peptide-based enantioselective acylation catalyst.

Studies of analogues of a recently discovered enantioselective peptide-based catalyst for enantioselective acylation reactions have led to mechanistic insight and improved catalysts. Systematic replacement of each residue within the parent peptide with alanine of the appropriate stereochemistry allows for an unambiguous evaluation of the kinetic role of each amino acid side chain in the catalyst. The results of the alanine scan support a bifunctional catalysis mechanism at the heart of the origin of enantioselectivity. In addition, an experimentally derived solution structure of the peptide-based catalyst is presented that supports a key role for each residue within the peptide chain.

On the role of polarizability in chemical-biological interactions.

This report considers the importance of electronic effects in their role in the QSAR of chemical-biological interactions. The problem of accounting for polarizability effects in ligand-substrate interactions is discussed in terms of molecular polarizability (MR) and NVE (number of valence electrons) using additive values for valence electrons. The two approaches give essentially the same result in examples of frog nerve toxicity and examples of nerve toxicity with rabbits and cockroaches. The point is made that no matter how one approaches QSAR, electronic interactions must be considered if we are to begin to develop a science of chemical-biological interactions.

The structure of erythromycin enol ether as a model for its activity as a motilide.

Erythromycin enol ether is a potent mimic of the peptide hormone motilin. To understand its biological activity, its three-dimensional structure in CD(2)Cl(2) was determined from constrained molecular mechanics using constraints derived from NMR spectra. The structure of the enol ether is well defined by 10 structures that minimize the energy and satisfy the NMR data. We infer the molecular basis for its activity as a motilide from a comparison of its structure with that of motilin. The macrolide ring of the enol ether is a beta-turn mimic of the peptide. Furthermore, a superposition of the structures of the enol ether and motilin shows a striking overlap of the sugar rings attached to the macrolide ring with essential aromatic side chains in the peptide.