Richard A. Mueller

The antinociceptive effects of prostaglandin antagonists in the rat

This study examined the antinociceptive effects of two prostaglandin antagonists, SC-25469 and SC-19220 in the rat. SC-25469 and SC-19220 inhibited acetic acid-induced writhing with ED50 s of 6.9 and 6.8 mg/kg p.o., respectively. When compared to other analgesics, the rank order of potency in the writhing test was morphine greater than pentazocine = U-50,488 greater than SC-25469 = SC-19220 greater than ibuprofen greater than aspirin greater than acetaminophen. SC-25469 (150 and 300 mg/kg p.o.) and SC-19220 (50-300 mg/kg p.o.) also suppressed the behavioral response to s.c. injection of formalin, as did aspirin (50-150 mg/kg p.o.), ibuprofen (25-100 mg/kg p.o.) and acetaminophen (300 mg/kg p.o.). However, the suppression was not of the magnitude observed after administration of morphine (ED50: 0.9 mg/kg s.c.), pentazocine (ED50: 2.4 mg/kg s.c.) or U-50,488 (ED50: 0.8 mg/kg s.c.). This study demonstrates the antinociceptive properties of prostaglandin antagonists in two distinct tests of nociception.

A systematic evaluation of the inhibition of HIV-1 protease by its C- and N-terminal peptides

Abstract C- and N-terminal peptides of varying lengths corresponding to the dimerization interface of the retroviral protease of the human immunodeficiency virus-1 (HIV-1 protease) have been synthesized and evaluated as inhibitors of HIV-1 protease activity.

Short efficient synthesis of the α-L-fucosidase inhibitor, deoxyfuconojirimycin [1,5-dideoxy-1,5-imino-L-fucitol] from D-lyxonolactone

The only protection required in a five-step synthesis of the α-L-fucosidase inhibitor, deoxyfuconojirimycin [1,5-dideoxy-1,5-imino-L-fucitol] from D-lyxonolactone, a readily available chiral pool material, is a single isopropylidene group.

Nucleophilic Opening of N-Carboalkoxy-2,3-anhydro-1-deoxymannojirimycin. A Useful Method for the Syntheses of 2-, 3- and 2,3-Disubstituted 1-Deoxynojirimycin Analogs

Abstract A useful methodology for the synthesis of a number of 2-, 3- and 2,3-disubstituted deoxynojirimycin analogs is reported. It has been found that the epoxides in stereoselectively synthesized N-carboalkoxy-2,3-anhydro-1-deoxymannojirimycins (4 and 5) react with N-, S- and F- nucleophiles to give a mixture of gluco and altro products. The 3-azido altro compound (12b) yields the desired gluco derivative (40) by oxidation, in situ epimerization at C-3, followed by stereoselective reduction of the carbonyl group. The azido intermediate (12a) affords the 2,3-diazido gluco compound (51) by double inversion at C-3. Attempts have been made to understand the factors contributing to the opening of epoxides (4, 5 and 9) by different nucleophiles.

Contrasting effects of two arachidonate 5-lipoxygenase inhibitors on formyl-methionyl-leucyl-phenylalanine (fMLP) and complement fragment 5a induced human neutrophil superoxide generation

SC-45662 and SC-41661A, selective arachidonate 5-lipoxygenase (5-LO) inhibitors, had markedly different effects on formyl-methionyl-leucyl-phenylalanine (fMLP) and complement fragment 5a (C5a) induced superoxide release from human neutrophils (PMNs). SC-45662 inhibited superoxide generation induced by fMLP and C5a with IC50 values of 12 and 5 microM, respectively. Furthermore, SC-45662 was capable of inhibiting fMLP and C5a induced superoxide release in PMNs primed with bacterial lipopolysaccharide, tumor necrosis factor-alpha and other priming agents. SC-41661A, a compound from the same chemical series as SC-45662, did not inhibit or induce superoxide generation, but instead primed PMNs for fMLP and C5a induced superoxide generation. The induced superoxide release was concentration dependently enhanced 2 to 4-fold at 5-50 microM. Superoxide release induced by phorbol myristate acetate or serum-activated zymosan was unaffected by either SC-45662 or SC-41661A. The regulation of superoxide generation by these compounds, both of which have the identical oxidation-reduction pharmacophore, was clearly independent of their effects on 5-LO activity. Furthermore, the mechanism by which SC-45662 and SC-41661A alter superoxide generation did not appear to depend on inhibition of xanthine oxidase, catalase or superoxide dismutase. These new compounds provide effective tools for further investigation of the relationship of these two biochemical oxidative systems.

THE SYNTHESIS OF 1,5-DIDEOXY-1,5-(ALKYL)IMINO-2-C-METHYL-D-GLUCITOLS

The regio- and stereoselective synthesis of the title compounds 3 and 4 has been accomplished starting with deoxynojirimycin. The factors affecting the stereochemical outcome of Grignard addition to the key carbonyl intermediate are discussed.

HIV-1 protease inhibitors: Ketomethylene isosteres with unusually high affinity compared with hydroxyethylene isostere analogs

HIV protease is a member of the aspartic proteinase family of proteolytic enzymes which include pepsin and renin. In contrast to the enhanced affinity seen with renin and pepsin upon conversion of the transition-state isostere, ketomethylene, to the hydroxyethylene, a set of HIV protease inhibitors showed a reduction in affinity. This implies that interactions with the active site of other segments of the inhibitor than those of the transition-state analog must predominate in the case of HIV protease, and that observations made on mammalian aspartic proteinases do not necessarily apply to viral aspartic proteinases.

Virucidal effect of murine duodenal extracts: studies with lactate dehydrogenase-elevating virus

Abstract Mucosal resistance to infection with lactate dehydrogenase-elevating virus (LDV) has been previously demonstrated, and the LDV system presents an important murine model for the study of mucosal barriers to viral infection. In the present study, duodenal molecules were isolated from normal mice which had potent virucidal activity, when tested against LDV as well as canine herpes, canine hepatitis, Semliki forest, and visna viruses. The virucidal activity was demonstrated to be non-immune in nature, and was present in apparently non-enzymatic protein molecules, having a molecular mass of between 10–100 kDa by membrane filtration and 10–17 kDa by gel filtration. The anti-LDV activity of these molecules was suppressed by anti-duodenum antibodies in vitro, and in vivo studies suggested a possible protective role for the anti-viral molecules. We conclude that the normal mouse duodenum contains potent virucidal molecules, which are of interest to the study of biological and molecular mechanisms of viral resistance.

Role of Arachidonic Acid in Collagenase IV Production and Malignant Behavior of Tumor Cells

The spread of cancer from the original lesion is a critical event in cancer etiology, placing the tumor beyond conventional modes of treatment. Indeed, metastasis is the major cause of death in cancer (1). The actual success of a given tumor cell to metastasize depends on numerous factors including the invasiveness of the tumor cell, the host’s immune system and local factors which support the growth of the tumor at different sites (2–4). During metastasis the cells must breach numerous barriers to their invasion and dissemination. These barriers include stromal matrix, basement membranes and cellular layers. Because of the diversity of these barriers, the penetration of the cells must involve proteolytic enzymes.

Chapter 18. Prostaglandins and Related Compounds

Publisher Summary This chapter elaborates studies that focus on prostaglandins and related compounds. A novel direct synthesis of PGA 2 was achieved. The first step involved cyclization of the anion of the enamine of a specific compound. The relative stereochemistry at positions 12 and 15 was controlled by proper choice of a cis double bond and trans epoxide. The synthesis of ent-11,15-bis-epi-PGE 2 , was reported. A group at Alza reported the synthesis of 11-epi-PGE 2 and 11-epi-PGF2α. The cardiovascular effects of the prostaglandins were reviewed and a hypothesis on their involvement in the maintenance of normal blood pressures via the renal system was reported. A report on clinical trials of PGA 1 with sixty hypertensive patients with no untoward effects was disclosed. Structure–activity relationships with respect to pressure responses in the dog and isolated perfused pancreas preparation were reported on a number of natural prostaglandins and their analogs. Three independent reports on the beneficial effects of PGE l on stored platelets were discussed. They suggested that separation of platelets from whole blood is facilitated and they showed no side effects when administered to humans.