Damian Grobelny

A Convenient Synthesis of Aminomethylphosphonous Acid

Abstract Aminomethylphosphonous acid has been prepared in exellent yield by alkylation of bis(trimethylsilyl) ethoxycarbonylphosphonite 2 with N-(bromomethyl)phthalimide 1, followed by acidic removal of protecting groups.

19F nuclear magnetic resonance spectroscopy study of the complex of 2-benzyl-4-oxo-5,5,5-trifluoropentanoic acid and carboxypeptidase A

(dl)-2-Benzyl-4-oxo-5,5,5-trifluoropentanoic acid is a strong transition state analog inhibitor of the zinc protease carboxypeptidase A. 19F NMR spectroscopy of the aqueous solution of this inhibitor shows the hydrate of the ketone carbonyl to be the major species, with a shift of -9.95 ppm. As the pH is varied from 4.9 to 13.1, a 1.53 ppm downfield shift occurs, giving a pK alpha of 11.10. When excess inhibitor is added to the enzyme, a new, bound peak appears at -8.84 ppm, in addition to the free hydrate peak. Spectra taken at pHs from 4.90 to 9.15 show no change in the position of the bound resonance; from 9.15 to 12.15, a 0.26 ppm upfield shift occurs. The interpretation is that the monoanion of the hydrate is the form that binds to the enzyme.

A metabolite of aspartame inhibits angiotensin converting enzyme

Aspartame (L-aspartyl-L-phenylalanine methyl ester, is a widely used artificIal sweetener. In humans and other animals aspartame is initially hydrolyzed to L-aspartyl-L-phenylalanine by intestinal esterases. L-Aspartyl-L-phenylalanine inhibits angiotensin converting enzyme purified from rabbit lungs with a Ki of 11 +/- 2 microM, equipotent to the IC50 of 12 microM for 2-D-methyl-succinyl-L-proline which has been reported to be an orally active antihypertensive agent in rats. Thus the possibility exists that L-aspartyl-L-phenylalanine inhibits angiotensin converting enzyme in humans consuming large quantities of aspartame. Both aspartame itself and the diketopiperazine formed from it, 3-carboxymethyl-6-benzyl-2,5-diketopiperazine, are weak inhibitors with Kis greater than 1 mM.

The ketone cinnamoyl-(1-13C-Phe)-CGly-Pro-Pro is a tetrahedral transition state analog inhibitor of C. histolyticum collagenase

The ketone cinnamoyl-(1-13C-Phe)-CGly-Pro-Pro [(4-13C-5-cinnamido-4-oxo-6-phenylhexanoyl)-Pro-Pro 2] competitively inhibits a mixture of collagenases from Clostridium histolyticum with a Ki of 40 +/- 6 nM. 13C-nmr spectroscopy of the ketone in the presence of this collagenase shows a bound 13C resonance at 102.6 ppm and the resonance of the free ketone at 212 ppm. Ketone alone shows no trace (less than 0.5%) of a resonance in the region around 100 ppm. The bound resonance is displaceable by another competitive inhibitor. This ketone is thus a transition state analog which is rehybridized from trigonal planar to tetrahedral upon binding to collagenase.