On the Mode of Action of the Immunosuppressive Sesquiterpene Ovalicin

Abstract

When the potent immunosuppressive sesquiterpene ovalicin is added to lymphocyte cultures one first observes a preferential inhibition of uridine incorporation into rRNA. The uptake of the nucleoside, its conversion into the triphosphate or the polymerizing activity itself are not affected. A longer period of incubation with the drug results in a marked decrease in the number of ribosomes, with a concomitant reduction of the rate of leucine incorporation into all cellular proteins. After extended periods of time, the incorporation of thymidine into DNA in stimulated lymphocytes as well as in S 49.1 lymphoma cells is inhibited by 1 nM ovalicin or less, although part of the incorporation seems to be resistant to the drug even at much higher concentrations. A similar effect is observed with 3T6 mouse fibroblasts or HeLa cells. Here, however, a much longer incubation with the drug is required. This observation explains the selective effect of ovalicin on lymphocytes observed in vivo.The sesquitcrpene ovalicin [I -31 has been shown to be one of the most potent immunosuppressive drugs in cell culture. A drug concentration of 1-0.01 nmol/l is sufficient to inhibit significantly the antigen-induced formation of antibodies as well as the mixed lymphocyte reaction and the proliferation of murine or human lymphocytes following stimulation with various mitogens [4]. The addition of ovalicin to cell cultures several hours after the mitogen does not result in a reduction of the inhibitory effect. Therefore the very early events in the cell cycle of lymphocytes cannot be the target of the drug [4]. On the other hand, ovalicin does not reduce the incorporation of radioactive thymidine into DNA when added during the S-phase or shortly before it. Concequently DNA synthesis itself and reactions closely connected with it in time are also excluded as the targets of this inhibitor [4]. These and other observations [4] suggest that ovalicin primarily affects some reactions which occur in lymphocytes after the early phase of induction and prior to the S-phase. One of the crucial reactions in the sequence of events required for the proliferation of lymphocytes is the biosynthesis of rRNA [5] which is necessary for the formation of ribosomes. The number of active ribosmes present in resting lymphocytes is too low for cell proliferation. Mitogenic stimulation causes a 3 -4-fold increase followed by attainment of a high level of protein synthesis which in turn is a prerequisite for DNA synthesis [6-91. It therefore appeared of interest to investigate the effect of ovalicin on the synthesis of rRNA tration of 2 x 106/ml. After a 12-14-h preincubation the experiments were started by addition of 1 pg concanavalin A (Pharmacia, Freiburg) per ml, 10 pM 2-mercaptoethanol and, if indicated, ovalicin (Sandoz SA, Basel, Switzerland). All added compounds were dissolved in Hank's solution. At the time indicated 0.9-ml aliquots (in duplicate) of the suspended cells were transferred into small plastic tubes. The medium was replaced with leucine-free m...

Stereoselective Total Synthesis of (-)-Ovalicin

“…2 It also exhibits antibiotic, antitumor and immunosuppressive properties. 3,4 TNP-470, a semi-synthetic derivative of fumagillin, has also been shown to inhibit angiogenesis and reduce the proliferation of endothelial cells 5 (Figure 1). This wide range of activities of ovalicin has attracted several research groups to accomplish its synthesis using different chemical approaches.…”

Ovalicin Ameliorates Compound 48/80-Induced Atopic Dermatitis-Related Symptoms

“…anisopliae. [17][18][19][20] The compound consisted of C 16 H 24 O 5 with a molecular weight of 296.359, and showed anti-cancer, antifungal, anti-microsporidal, and anti-trypanosomal activities, [21][22][23] indicating that it has great potential for pharmaceutical application to various clinical fields. In initial purpose, we screened the isolate for an anti-inflammatory agent and purified it to identify the active compound as ovalicin.…”