Biomedical subjects

C Moog

Publications and source records attributed to C Moog.

31 records · Page 2Linked to original sources

PubMed1994

Bicyclic imidazo derivatives, a new class of highly selective inhibitors for the human immunodeficiency virus type 1.

In the search for new antiviral agents against human immunodeficiency virus, different members of two imidazoheterocycle families (imidazothiazoles, imidazopyridines) have been found to display potent inhibitory effects on the replication of HIV-1. Three of these derivatives, which show significant anti-HIV-1 activity, have been chosen for further studies. The analysis of these compounds and their comparison to AZT and TIBO revealed that these bicyclic imidazo derivatives represent a class of highly specific inhibitors of HIV-1, but not of HIV-2 or simian immunodeficiency virus (SIV). Their inhibition of HIV-1 is mediated through interaction with the reverse transcriptase (RT). The mechanism of action of these bicyclic imidazo derivatives may be similar to that of the other non-nucleoside RT inhibitors (NNRTIs).

Antiviral Agents↗

PubMed1992

Proline dithiocarbamate inhibits N-nitrosodiethylamine induced liver carcinogenesis.

A study was conducted to determine the toxicity of different dithiocarbamates and of disulfiram. In an experiment showing the cytotoxicity against murine spleen lymphocytes, proline dithiocarbamate (PDTC) and thioproline dithiocarbamate showed the lowest toxicity. Therefore one of them was selected and different doses of the hydrophilic PDTC were checked for their ability to affect the development of liver and oesophagus tumours induced in BD-6 rats by N-nitrosodiethylamine (NDEA). Rats were injected i.p. with 80 mg/kg NDEA once weekly for 10 weeks. Administration of PDTC, 1 h before and 24 h after the carcinogen, markedly decreased the number of rats developing NDEA-induced hepatocellular carcinoma and liver haemangioendothelioma. A 59%-77% reduction in the incidence of liver tumours was found in the different groups when the carcinogen was administered in combination with the inhibitor. For least 40 weeks after the start of the experiment PDTC protected the liver from NDEA carcinogenesis and did not shift the tumour development to any other organ. PDTC did not significantly affect the weight gain of the experimental animals. We conclude that parenteral administration of PDTC seems to represent a promising approach in chemoprevention of liver carcinogenesis.

Animals↗

PubMed1991

Oxysterols: biological activities and physicochemical studies.

To improve the understanding of the various biological activities of oxysterols (oxygenated derivatives of cholesterol), studies of their physicochemical properties have been undertaken. Oxysterols modify membrane dynamic properties which consequently trigger several biological effects. Despite the presence of at least one oxygenated group in addition to the C3 beta-hydroxyl, oxysterols insert perfectly into the lipidic bilayer of the membrane inducing a condensing effect similar to, but less potent than, that of cholesterol. In biological membranes oxysterols probably interact with membrane components as they are not easily exchanged after their incorporation into the cell membrane. These lipid-protein interactions are probably crucial for the expression of the biological activities of the oxysterols.

Cell Membrane↗

PubMed1991

Membrane-related oxysterol function: preliminary results on the modification of protein kinase C activity and substrate phosphorylation by 7 beta,25-dihydroxycholesterol.

Oxysterols exhibit a wide variety of biological activities, including potent immunosuppressive effects. 7 beta,25-Dihydroxycholesterol (7,25-OHC), a synthetic oxysterol, has been shown to strongly inhibit the lymphocyte response to different stimuli. This compound has been chosen as a model compound to investigate the mechanisms underlying the immunosuppressive effects of oxysterols. As protein kinase C (PKC) constitutes a key enzyme in the pathways leading to cell activation, we have studied the effect of 7,25-OHC on PKC activity in the cytosolic and particulate fractions of spleen cells. Lymphocytes treated with 7,25-OHC showed a decrease of the relative PKC activity in the particulate fractions compared to control cells. These results are confirmed by the observation that 7,25-OHC also reduces the phosphorylation of the endogenous PKC substrates. Thus oxysterols interfere with two membrane related phenomena, ie the modification of membrane PKC activity and the inhibition of the phosphorylation of the substrates of PKC located in the membrane. Previous results obtained by fluorescence polarisation revealed a modification of the membrane fluidity after oxysterol treatment. Furthermore, it has been demonstrated that oxysterols are incorporated into cell membranes. The alteration of the cell membrane could impair the signal transduction and may explain the immunosuppressive activity of oxysterol. Thus, along with other biological effects previously reported, oxysterols decrease membrane associated PKC activity in immune cells.

Animals↗

PubMed1990

Polyoxygenated sterols and triterpenes: chemical structures and biological activities.

Cholesterol and other sterols are precursors of many hormones of vertebrates (pregnane, androstane, estrane derivatives), invertebrates (ecdysteroids) and even of plants (brassinoids). The normal biosynthetic processes which begin by a series of oxidations lead to a family of compounds, some of which exhibit a wide variety of biological activities. Among the latter, those well-established are their inhibitory effect on the biosynthesis of cholesterol in mammalian cells, their toxic effect on tumor cells and their ability to modify some immunological responses. None of the members of this family has all of the activities just mentioned. The intensity of the effect depends markedly upon the specific structure of each compound.

Animals↗

PubMed1990

Monophosphoric acid diesters of 7 beta-hydroxycholesterol and of pyrimidine nucleosides as potential antitumor agents: synthesis and preliminary evaluation of antitumor activity.

7 beta-Hydroxycholesterol, which has been shown to be selectively cytotoxic toward tumor cells cultured in vitro, was converted into the corresponding water-soluble phosphoric acid ester and linked to a pyrimidine nucleoside such as 5-fluoro-2'-deoxyuridine or 2'-deoxyuridine. 2-Chlorophenyl phosphorodichloridate (3), without activation, was used directly to phosphorylate the protected oxygenated sterol. The intermediate phosphorylated the 5'-OH group of nucleoside selectively, leading to compounds 1a and 1b after deprotection. These compounds were screened for their antiproliferative activity toward EL-4 murine leukemia cells in vitro and for their antitumor activity against the mice bearing Krebs II ascitic carcinoma in vivo.

Animals↗

PubMed1990

Antiproliferative effects of two hydrosoluble derivatives of oxysterols on cultured lymphoma cells.

The antitumor effects of two new hydrosoluble derivatives of oxygenated sterols: JB69 and JC40 have been evaluated in vitro on a panel of lymphoma and leukemia cells from human and murine origins. These compounds result from the combination of a nucleotide with 7 beta-hydroxycholesterol (JB69) or 7 beta,25-dihydroxycholesterol (JC40). Both derivatives exhibit a significant cytotoxic activity against the different tumor cell lines tested, with some degree of difference between them. On the whole, the concentrations needed to inhibit the cell growth were found to be higher than those required for their parent compounds. However, two interesting features appeared in our experiments. (1) In a serum-free culture medium, cell lysis occurred within the first hours of incubation and seemed to result from the detergent-like properties possessed by this type of compounds. (2) In a culture medium supplemented with serum, we noted, that at high concentrations of JB69 (40 microM or 20 microM) and only with this oxysterol derivative, an important increase of incorporation of tritiated thymidine and uridine into DNA and RNA by viable cells. The origin of this effect is as yet unknown, but it strongly suggests a possible action on nucleic acids synthesis and metabolism. Taken together, these results emphasize the diversity and the complexity of the mechanisms involved in the cytotoxicity of these derivatives of oxysterols.

Animals↗

PubMed1990

Studies on the immunological properties of oxysterols: in vivo actions of 7,25-dihydroxycholesterol upon murine peritoneal cells.

Oxygenated derivatives of cholesterol are potent immunosuppressors. It has been reported previously that 7,25-dihydroxycholesterol (7,25-OHC), synthesized in the URA31, strongly inhibits the early steps of T-cell activation. So far, the mechanisms underlying this type of effect have been mainly investigated in vitro, and the activity of these substances on the immune system has been poorly studied. This study describes that a single i.p. injection of 7,25-OHC induces a strong inflammatory response, consisting of a massive influx of macrophages and neutrophils into the abdominal cavity. Macrophages harvested from 7,25-OHC-treated mice express class II antigen to a lesser extent. Moreover, the 7,25-OHC treatment abolishes the class II induction by bacillus Calmette-Guérin (BCG) or interferon-gamma (IFN-gamma). The inflammatory process triggered by the oxysterol is not the consequence of a non-specific effect due, for instance, to the presence of crystals in the abdominal cavity. Moreover, treatments by inhibitors of the acid arachidonic cascade do not affect the peritoneal exudate cell (PEC) influx induced by these substances. This study could be an important contribution to the mechanism determining the oxysterol-induced immunosuppression.

Animals↗

PubMed1989

In vitro modulation of leucocyte-function-associated antigen-1 expression on two leukemic cell lines.

Leukocyte-function-associated antigen-1 (LFA-1) expression on two widespread tumor cell lines: K562 (an erythroleukemia) and MOLT-4 (a T leukemia), was investigated using two monoclonal antibodies specific for the alpha chain of this surface antigen, and flow cytometry analysis. When K562 cells are in the exponential phase of growth, they display very low levels of LFA-1. By contrast, cells from the plateau phase exhibit a strong labelling, which disappears rapidly when they are allowed to resume division by changing the culture medium. Using the same experimental conditions, we failed to detect any LFA-1 expression on MOLT-4 cells. However, after stimulation of these cells by phorbol myristate acetate, we observed a significant labelling, which occurred within 2 days of treatment. The LFA-1 expression disappears progressively after removal of the phorbol ester. From these results it may be concluded that (a) LFA-1 expression can vary considerably according to the culture conditions, (b) the expression of this antigen on the surface of non-expressing variants can be induced by phorbol ester, and (c) in both cases, the change in expression can be reversed completely by replacing the culture medium or by removing phorbol myristate acetate from it.

Antigens, Differentiation↗

PubMed1989

Studies on the immunosuppressive properties of 7,25 dihydroxycholesterol--II. Effects on early steps of T-cell activation.

The effects of an oxysterol, 7,25-dihydroxycholesterol (7,25-OHC), cyclosporin A (CsA) and dexamethasone (Dex) on the blastogenic response of murine lymphocytes to various stimuli were investigated. 7,25-OHC markedly depressed the response to Con A, anti-T3 monoclonal antibodies and to the combination phorbol myristate acetate (PMA) + IL-2 and PMA + ionomycin. Dexamethasone was also active within the same range of concentrations. However, it did not inhibit the stimulation induced by PMA + ionomycin. On the other hand, Cs A failed to depress the lymphocyte response to IL-2 + PMA. Therefore, the mechanisms of action involved in the blockage of lymphocyte activation are different for these three compounds. Moreover, we noted that 7,25-OHC was less active upon purified T-cells. Taken together, these results suggest that 7,25-OHC may act at the level of signal transduction across the membrane.

Animals↗

PubMed1988

Studies on the immunosuppressive properties of 7,25-dihydroxycholesterol--I. Reduction of interleukin production by treated lymphocytes.

Several oxysterols are powerful immunosuppressors. Among them 7,25-dihydroxycholesterol (7,25-OHC) seems to be particularly interesting. The effect of this synthetic sterol on murine lymphocytes, stimulated by Con A, or by allogeneic or TNP-modified syngeneic lymphocytes, was investigated. The results showed that the induction of cytotoxic T-lymphocytes (CTL) was strongly inhibited by a treatment with non-toxic concentrations of this sterol. A marked reduction of interleukin 2 (IL-2) production by alloantigen stimulated lymphocytes occurred at the same concentrations. We also showed that receptors to IL-2 did not appear on lymphocytes stimulated by Con A, when 7,25-OHC was added at the beginning of the culture. The addition of exogenous IL-2 to the culture was found to only slightly reverse the inhibition caused by 7,25-OHC. Taken together, these results indicate that an impairment at the early steps of lymphocyte activation, involving IL-2 secretion, could be responsible, at least in part for the various immunosuppressive effects of 7,25-OHC.

Animals↗

PubMedDate not supplied

Antitumor activity of oxysterols. Effect of two water-soluble monophosphoric acid diesters of 7 beta-hydroxycholesterol on mastocytoma P815 in vivo.

Oxysterols, a family of naturally occurring products, have been shown to possess several biological activities. In particular, they are more toxic towards tumor cells than towards normal cells. In addition, they markedly modify immune cell responses. To carry out in vivo studies, we have synthesized phosphodiesters of 7 beta-hydroxycholesterol (JB69 and XA29). These water-soluble prodrugs have a similar toxicity to their parent compound under in vitro conditions. When administered intraperitoneally to mice bearing the P815 mastocytoma, they induced significant increases in life span. The results depend on the administration protocol. Under appropriate conditions, 20 to 40% of treated mice recover completely. This, together with their immunological effect, suggests that these oxysterols should be considered to be agents for immunochemotherapeutic investigations. By their ability to inhibit HMG CoA reductase, they may prevent the biosynthesis of prenyl groups whose coupling to oncogenes is responsible for the biological activity expression of the latter. Several indications are compatible with an effect on the cell membrane. Our recent studies have shown Protein Kinase C to be a target of oxysterols. On the basis of results obtained by our group and by others, we believe that oxysterols may form a new class of antitumor agents.

Animals↗

PubMedDate not supplied

Metabolism of new anticancer oxysterol derivatives in rats.

New water soluble derivatives of oxysterols--the phosphodiesters of oxysterols and of nucleosides--have been synthesized. In vitro, these compounds share the biological properties of their parent oxysterols. Furthermore, they display anticancer activity when injected i.p. in mice bearing experimental tumors. The pharmacokinetic study described here proved that the water-soluble derivatives of oxysterols act as prodrugs releasing free oxysterol in the blood, the liver and the kidney after i.p. or i.v. injection in rats. The hydro-solubility of such compounds as well as their slow metabolism into the active principle could account for their biological activity and make them suitable as new therapeutic agents.

Animals↗