Karst Hoogsteen

N-Bromosuccinimide/Dibromodimethylhydantoin in aqueous base: A practical method for the bromination of activated benzoic acids

A new bromination method employing NBS or dibromodimethylhydantoin in aqueous base is described for the synthesis of 3-bromo-2,6-dimethoxybenzoic acid (1) and other monobrominated alkoxybenzoic acids.

Isolation and structure determination of pycnidione, A novel bistropolone stromelysin inhibitor from a Phoma sp.

Abstract A novel bistropolone, pycnidione (1), was isolated by bioassay guided fractionation from fermentations of a Phoma sp.. The structure was determined by spectroscopic methods and single crystal X-ray diffraction.

Renin cleavage of a human kidney renin substrate analogous to human angiotensinogen, H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Ser-OH, that is human renin specific and is resistant to cathepsin D

A synthetic tetradecapeptide, H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Ser-OH, which corresponds to the 13 amino terminal residues of human angiotensinogen plus a carboxy terminal serine to replace a suggested site of carbohydrate attachment, has been shown to be a good substrate for human kidney renin. At pH 7.2 and 37 degrees C the KM or Michaelis constant was 8.4 +/- 2.9 microM, and the VM or velocity at infinite tetradecapeptide concentration was 11.3 +/- 2.4 mumol angiotensin I made per hour per milligram renin. The tetradecapeptide was highly resistant to cleavage by mouse submaxillary renin. The tetradecapeptide was also slowly cleaved by human liver cathepsin D, by rabbit lung angiotensin-converting enzyme, and by reconstituted human serum, but did not yield angiotensin I. Thus, this synthetic renin substrate should permit more specific measurement of human kidney renin activity.

Synthesis of 2-amino C-glucosides and 2-amino C-glucosides spiroketals

Abstract Bis(2,2,2-trichloroethyl) azodicarboxylate adds on 1-alkylglucal to provide [4+2] cycloadducts which in turn can be converted to 2-amino C-glucosides. This method was also applied to the synthesis of 2-amino C-glucoside spiroketals.

Metabolic studies on diphenylsulfone derivatives in chick macrophages

Abstract The activity of 1-[4-(4-sulfanilyl)phenyl]urea, a compound previously found to decrease visceral lesions and mortality in chickens infected with Mareks disease virus, was investigated using chick peritoneal macrophages. The material showed no effect on the biosynthesis of DNA, RNA or protein but markedly inhibited the synthesis of phosphatidylcholine. The site of action in this pathway was determined to be subsequent to the formation of phosphorylcholine, and on the steps involving the synthesis of either cytidinediphosphate choline or phosphatidyl choline. Several derivatives of diphenylsulfone were also examined for their effects on choline incorporation. The analogues that were found to be active in the macrophage system in vitro closely paralleled those that were found to be active in the Mareks disease assay in vivo .

Synthetic studies on the immunosuppressive agent FK-506: Enantioselective synthesis of a C22C34 fragment

Abstract The C28C32 cyclohexyl group of the natural product, FK-506, was prepared enantioselectively from the iodolactone by replacement of iodide with retention of configuration . The C27C28 trisubstituted olefin was introduced stereoselectively via a classical aldol/elimination sequence employing titanium enolate methodology. Elaboration of this chemistry has led to a synthesis of a C22C34 fragment of the natural product.

Dihydrofolate reductase from a methotrexate-resistant Escherichia coli: proton magnetic resonance studies of complexes with folate and methotrexate.

Abstract Proton magnetic resonance studies of 1:1 complexes of E. coli dihydrofolate reductase with folate and methotrexate were performed. A resonance at 1850 Hz in 1:1 enzyme-folate was assigned as the C-7 proton of bound folate by comparison with the spectra of enzyme complexed with folate specifically deuterated at C-7. The first order rate constant for folate dissociation was calculated to be less than 110 sec −1 . Four of the five histidine residues exhibited the same pKs and chemical shifts in the two complexes with pK values of 8.0, 7.3, 6.5 and ∼5. However, one histidine increased its pK by 0.7 units (6.25→6.95) and its C-2 proton resonance shifted upfield 50 Hz when folate was substituted for methotrexate. Comparison of these results with those of chemical modification and ultraviolet difference spectroscopy experiments suggests that this histidine may be in the folate binding site — possibly near the pteridine portion of that site.

A synthesis of 1-azabicyclo[2.2.1]heptane-3-carboxylic acid esters in enantiomerically pure form

A novel synthesis of ethyl 1-azabicyclo[2.2.1]heptane-3-carboxylate via 1-benzylperhydropyrano[3,4-c]pyrrol-4-one and 1-benzyl-3-(2-bromoethyl)-4-ethoxycarbonylpyrrolidinium bromide is described. Modification of the method, by incorporation of a chiral substituted benzyl group on the nitrogen atom, has led to the first reported process for the preparation of these esters in enantiomerically pure form. The absolute configuration of the bicyclic esters was deduced by X-ray crystallography of an intermediate, 2-[(S)-1-phenylethyl]perhydropyrano[3,4-c]pyrrole-4-one.

Cyclization and cycloaddition of 1-cinnamylidene-5-phenyl-3-oxopyrazolidinium ylide

Abstract Thermal cyclization of 1-cinnamylidene-5-phenyl-3-oxopyrazolidinium ylide( 1b ) led to a product 4 which is formally derived for further cycloaddition of 1b to the anticipated bicyclic [3.3.0]pyrazolidinone 3 .

Design of Renin Inhibitors Containing Conformationally Restricted Mimetics of the P1-P1′ and P1 through P2′ Sites

The clinical efficacy of converting enzyme inhibitors1 for reducing blood pressure in a large percentage of hypertensive patients has aroused considerable interest in developing agents that interrupt the renin-angiotensin system at other points, for example by blockade of the angiotensin II receptor2 or by inhibition of the aspartic proteinase, renin. Substrate based design of renin inhibitors in which the scissile P1-P1′ dipeptide is replaced with a non-hydrolyzable group, often a mimetic of a tetrahedral transition state for amide bond hydrolysis, has provided a useful approach for obtaining a variety of inhibitor structure types,3 many with Ki’s of better than 10−9 M. A clinically useful renin inhibitor, however, has not yet emerged due to poor pharmacokinetics (i.e., metabolism or rapid clearance) or poor oral absorption, problems often encountered with peptidic drug targets. An example of this is seen with 1, a “tetrapeptide” inhibitor4 that spans the P4 through P3′ sites of the renin substrate and which utilizes the statine analog, ACHPA5, as a P1-P1′ dipeptide replacement (Figure 1). Although 1 is quite potent in vitro, very low levels of drug are found in the blood after oral administration to the rhesus monkey at 50 mg/kg, and the half life after intravenous administration is short (< 1 h). Rapid biliary excretion of intact drug has been demonstrated for a number of other renin inhibitors.6