Michael D. Lumsden

Preparation of a diphosphine with persistent phosphinyl radical character in solution: characterization, reactivity with O2, S8, Se, Te, and P4, and electronic structure calculations.

A new, easily synthesized diphosphine based on a heterocyclic 1,3,2-diazaphospholidine framework has been prepared. Due to the large, sterically encumbering Dipp groups (Dipp = 2,6-diisopropylphenyl) on the heterocyclic ring, the diphosphine undergoes homolytic cleavage of the P-P bond in solution to form two phosphinyl radicals. The diphosphine has been reacted with O(2), S(8), Se, Te, and P(4), giving products that involve insertion of elements between the P-P bond to yield the related phosphinic acid anhydride, sulfide/disulfide, selenide, telluride, and a butterfly-type perphospha-bicyclobutadiene structure with a trans,trans-geometry. All molecules have been characterized by multinuclear NMR spectroscopy, elemental analysis, and single-crystal X-ray crystallography. Variable-temperature EPR spectroscopy was utilized to study the nature of the phosphinyl radical in solution. Electronic structure calculations were performed on a number of systems from the parent diphosphine [H(2)P](2) to amino-substituted [(H(2)N)(2)P](2) and cyclic amino-substituted [(H(2)C)(2)(NH)(2)P](2); then, bulky substituents (Ph or Dipp) were attached to the cyclic amino systems. Calculations on the isolated diphosphine at the B3LYP/6-31+G* level show that the homolytic cleavage of the P-P bond to form two phosphinyl radicals is favored over the diphosphine by ~11 kJ/mol. Furthermore, there is a significant amount of relaxation energy stored in the ligands (52.3 kJ/mol), providing a major driving force behind the homolytic cleavage of the central P-P bond.

Comprehensive Chemical Characterization of Complexes Involving Lead-Amino Acid Interactions

Complexes of lead with L-phenylalanine, L-isoleucine, L-valine, or L-arginine have been isolated from reaction mixtures containing lead nitrate and the respective amino acid in acidic aqueous solution. The compounds have been comprehensively characterized using X-ray crystallography, solid state NMR spectroscopy and solution state NMR spectroscopy, IR and Raman spectroscopies, and electrospray ionization mass-spectrometry. The solid state structures of lead-phenylalanine, lead-valine, and lead-valine-isoleucine complexes show a lead center coordinated by two amino acid ligands, while the lead-arginine complex is a cluster involving two lead centers and three arginine molecules. The structural, spectroscopic, and spectrometric characterization of the complexes provides a basis to establish a fundamental understanding of heavy metal-amino acid interactions.

Glycosidase inhibition by macrolide antibiotics elucidated by STD-NMR spectroscopy.

A glycosynthase approach was attempted to glycodiversify macrolide antibiotics, using DesR, a family-3 retaining beta-glucosidase involved in the self-resistance mechanism of methymycin production. STD-NMR was used to probe enzyme-substrate interactions. Analysis of competitive STD-NMR experiments between erythromycin A and a chromogenic substrate (pNP-beta-d-glucose) with the hydrolytically inactive nucleophile mutants led us to discover a family of unprecedented glycosidase inhibitors. Analysis of kinetic data with wild-type DesR determined that erythromycin is a competitive inhibitor of the glucosidase (IC50 = 2.8 +/- 0.3 microM and Ki = 2 +/- 0.2 microM) with respect to the hydrolysis of pNP-beta-d-glucose. Comparable inhibitory data was obtained for clarithromycin; however, the inhibitory effect of azithromycin was weak and no significant inhibition was observed with methymycin or d-desosamine. This report documents significant inhibition of glycosidases by macrolide antibiotics and provides insight into the design of novel glycosidase inhibitors based on the macrolactone ring of macrolide antibiotics.