Ronald G. Almquist

Synthesis of ketomethylene analogs of dipeptides

Abstract A convenient method of synthesizing ketomethylene dipeptides by using homoallylic Grignard reagents as amino acid analog synthons is described.

Isolation and characterization of a new atrial peptide-degrading enzyme from bovine kidney

An endopeptidase isolated from bovine kidney displays high affinity and selectivity for the Ser-Phe bond located in the C-terminal region of atrial peptides. Enzymatic activity converts APIII and APII to the less active peptide API. This peptidase is inhibited by both metal chelators and sulfhydryl-reactive agents, suggesting both a tightly bound metal and a cysteine residue are important for enzymatic activity. This enzyme may be important for the processing and/or degradation of atrial peptides.

Synthesis of 6,6′-disubstituted sucrose derivatives from 1′,6,6′-tri-O-tripsylsucrose

Abstract An improved synthesis of 6,6′-disubstituted derivatives of sucrose is described that uses 1′,6,6′-tri- O -tripsylsucrose as the starting material. The 6- and 6′-tripsyloxy groups have been selectively displaced, leaving the (more sterically hindered) 1′-tripsyloxy group untouched. Subsequent displacement of the 1′-tripsyloxy group by sodium benzoate, under forcing conditions, effected sulfonate displacement and gave sucrose derivatives substituted at C-6 and C-6′.

Inhibition of [3H]captopril binding by peptide analog angiotensin converting enzyme inhibitors

Ketomethylene containing peptide analogs, modeled after a snake venom pentapeptide, have been shown to be potent angiotensin converting enzyme inhibitors. Although the most potent compounds are up to five times more potent than captopril in inhibiting angiotensin converting enzyme activity, they are relatively weak inhibitors of [3H]captopril binding to membrane bound angiotensin converting enzyme. This indicates that inhibition of [3H]captopril binding and enzymatic activity is due to binding to distinct sites. These results suggest that the inhibitors bind to an additional site on the enzyme distinct from the captopril binding site.

Absorption, metabolism, and excretion studies of carbon 14- and tritium-labeled derivatives of a ketomethylene containing tripeptide.

Tritium and Carbon 14 analogs of the angiotensin converting enzyme inhibitor ketoACE were synthesized and their oral absorption, metabolism and excretion in rats were investigated. KetoACE, a ketomethylene analog of the tripeptide Bz-Phe-Gly-Pro, was slowly absorbed at a 35% level upon oral administration. It is rapidly eliminated from the blood with a half-life of about 10 minutes. Its excretion is primarily via the bile duct and it is excreted as 80% unchanged drug. The only identified metabolite consisting of 5-10% of the excreted radioactivity was determined to be the reduced ketoACE in which the ketone group was reduced to a hydroxyl.