quinolinylmethybamine, 99071-54-2; methyl 4,7,8,9-tetra-Oacetyl-JV-acetyl-2-chloro-2-deoxy-/3-D-neuraminate, 67670-69-3.

7967mL of 4 M HCI was added, followed by 1.0 mL of 0.37 M FeCI, solution.The absorbance of the resulting solution was then measured.(c) Ester Assay. A 1.0-mL volume of NaOH solution was placed in a 15" test tube to which 1.0 mL of 28% N H 2 0 H solution was also added. The absorbance of the resulting solution was then measured.(d) Amide Assay. A 0.5-mL volume of NaOH solution was placed in a 15-mL test tube to which 1.0 mL of reaction mixture was added. After 20 min, 1 .O mL of 40% NH20H.HC1 solution was added. This mixture was heated for 90 min at 90 OC and then allowed to cool to room temperature, after which 1.0 mL of 4 M HCI, 1.0 mL of 0.37 M FeCI,, and 0.5 mL of water were added. The absorbance of the resulting solution was then measured.Kinetic Measurements. Solutions for kinetic studies were prepared immediately before use. A 25-mL solution containing all the ingredients except acetyl phosphate was equilibrated at 40 OC in a water-jacketed beaker. The pH of the solution was monitored continuously with a pH meter standardized at 40 OC. The pH of the solution was adjusted to the desired level by adding a few drops of 1.0 N NaOH (for pH 9-11) or 0.1 N N a O H (for pH 7-9). An accurately weighed sample (ca. 2.3 mg) of dilithium acetyl phosphate was added to the solution, and aliquots were taken at 30-s to 3-min intervals, depending on the anticipated rate of the reaction. The course of the reaction was followed by means of the acetyl phosphate assay. Ester assays were performed whenever the possibility of ester formation existed, and amide assays were carried out when amines were present. The reactions were followed for a period of 10 min to 6 h. T, aliquots were taken at 6-24 h, depending on the reaction rate. In all cases, the plot of the log values of the concentrations vs. time yielded a straight line. Rate constants were determined graphically and by a least-squares computer program. The rate constants for each reaction were determined 3 times from three separte runs, and a 5-7% range in the rate constant was generally observed.Abstract: A convergent synthesis of the novel, potent antiulcer agent U-68,215 (3), a benzindene prostacyclin analogue, is described. U-68,215 is prepared via a cyclopentane annulation sequence in optically pure form in 14 steps and 12% yield from 5-methoxy-2-tetralone (Sa). The key step in the synthesis involves the coupling of the phosphonate reagent 6 (the chirality of which was derived from a Sharpless resolution of a n allylic alcohol precursor) with the enol lactone 7a (prepared in 50% overall yield from Sa) to produce enone 5 via a modified intramolecular Wadsworth-Emmons-Wittig reaction. Hydrogenation of 5 followed by an unusual one-pot equilibration-reduction sequence generates the four centers around the cyclopentane ring with complete stereocontrol.Several years ago, w e first reported t h e synthesis a n d initial biological evaluation of t h e benzindene prostaglandins, chemically stable potent prostacyclin (PGI,, la) mimics.' T h e parent 6 H iiH ijH Research"; Samuel...

To evaluate the bile acid transporter as a means of enhancing the ability of renin-inhibitory peptides (RIPs) to penetrate the intestinal mucosa, two RIP-cholic acid conjugates and an RIP-taurocholic acid conjugate were synthesized. Conjugation was through the N-terminus of an RIP and the 3-position of the bile acid, via a six-carbon spacer. An RIP derivative containing the spacer without the bile acid moiety was also synthesized. The bile acid-RIP conjugates and the RIP derivative were shown to be potent inhibitors of human renin in vivo and to have in vivo hypotensive activity equivalent to that of the parent RIP (ditekiren) in a human renin-infused rat model. The ability of these RIP derivatives to bind to the bile acid transporter and be transported across an epithelial cell monolayer was evaluated in an in vitro model of the intestinal mucosa consisting of Caco-2 cell monolayers grown on microporous membranes. One of the RIP-cholic acid conjugate (KI = 60 +/- 10 microM) and the RIP-taurocholic acid conjugate (KI = 19 +/- 5 microM), but not the RIP derivative, were shown to be potent inhibitors of the apical (AP) to basolateral (BL) transport of [14C]-taurocholic acid ([14C]-TA). At concentrations up to 250 microM these RIP-bile acid conjugates had no effect on the diffusion of [3H]-PEG (800-1000), which is a marker of the paracellular pathway. The permeability coefficients of the RIP-bile acid conjugates, determined using Caco-2 cell monolayers, were shown to be six times less than that of [3H]-PEG (800-1000). In addition, the transport of one of the RIP-cholic acid conjugates was investigated in perfused rat ileum in which the mesenteric vein was cannulated. The conjugate was not detected in blood samples taken from the mesenteric vein, while its concentration in intestinal perfusate remained almost constant during the perfusion experiment. These results suggest that while the peptide-bile acid conjugates retain binding affinity for the intestinal bile acid transporter, the molecules are not themselves transported.

No abstract

hydroxymethylene)cyclohexanone, 823-45-0; (Z)-&(hydroxymethylene)-a-tetralone, 87937-55-1; a-tetralone, 529-34-0.Supplementary Material Available: 13C NMR spectral data for 5b,c, 6a,b, and lla-e (4 pages). Ordering information is given on any current masthead The synthesis of a series of 9-substituted carbacyclin analogues with potent platelet antiaggregatory activity is described. The key step for the formation of 9-acetylene compounds (e.g., 8d) utilized a modification of the Schwartz procedure involving the nickel-catalyzed conjugate addition of the appropriate alkynyl aluminate to bicyclo[3.3.0]oct-l-en-3-one (2). It was found that 9-methylcarbacyclin (8b) could be prepared by a s i m i i procedure. In addition, a novel alternative to the Wittig reaction for introducing the carbacyclin upper side chain in base-sensitive substrates was developed which involves the addition of the dianion of 6-((tert-butyldimethylsily1)oxy)hexanoic acid to the appropriate ketone (e.g., 6f or 2) followed by decarboxylative dehydration of the resulting @-hydroxy acid.