Joel Oiry

The increase in intra-macrophage thiols induced by new pro-GSH molecules directs the Th1 skewing in ovalbumin immunized mice

In the present work, the capacity of new pro-GSH molecules to increase the intra-macrophage thiol content in vitro and in vivo as well as to shift the immune response to Th1 in ovalbumin (Ova)-sensitized mice were examined. The molecules were the N-butanoyl GSH derivative, GSH-C4, and a pro-drug of N-acetylcysteine (NAC) and beta-mercaptoethylamine (MEA), I-152. In vitro, 2h-incubation with both molecules was found to increase intra-macrophage thiol content; in vivo, Ova-sensitized mice pre-treated by intraperitoneal administration of the pro-GSH molecules showed an increase in plasma anti-Ova IgG2a and IgG2b, characterizing Th1 immune response, and a decrease in IgG1, typical of the Th2 response. Such findings were connected to a shift to a Th1 response also involving splenocyte IFN-γ production as revealed by ELISPOT assay and higher levels of IL-12 in circulation. Although immune responses are in vivo mediated both by dendritic cells and macrophages, the data reported in this paper corroborate the suggestion that the pro-GSH molecules, increasing the intra-cellular thiol pool, modulate the Th1/Th2 balance favouring Th1-type responses and may be employed as Th1-directing adjuvants in new vaccination protocols and as immunomodulators in those diseases where Th1 response patterns are compromised in favour of Th2.

Synthesis of new N-isobutyryl-L-cysteine/MEA conjugates: evaluation of their free radical-scavenging activities and anti-HIV properties in human macrophages.

Four novel N-isobutyryl-L-cysteine/2-mercaptoethylamine (MEA, cysteamine) conjugates have been designed and synthesized. The antioxidant activities of these new series were evaluated by three different free radical scavenging methods (DPPH test, ABTS test, and deoxyribose assay) and their metal binding capacity was evaluated by the ethidium bromide fluorescence binding assay. These results were compared with those obtained with their pro-GSH acetyl analogues recently developed in our laboratory. We observed that most of these compounds exhibit free radical-scavenging activities similar to those of Trolox, but always superior than NAC. While none of these new derivatives had pro-GSH activities, they displayed anti-HIV properties in human monocyte-derived macrophages infected in vitro. The present study demonstrates that these new N-isobutyryl derivatives, which are expected to have a greater bioavailability than their acetyl analogues, may have useful applications in HIV infection in respect to their antioxidant and anti-HIV activities.

NAC/MEA conjugate: a new potent antioxidant which increases the GSH level in various cell lines.

I-152 is a prodrug of NAC and MEA with potent pro-GSH effects in human macrophages, astrocytes and lymphocytes. This molecule could be of interest in HIV infection in respect to its antioxidant and anti-HIV activities, but also in other diseases to counteract oxidative stress, that is, inflammation, cardiovascular diseases, and neurodegenerative diseases.

Synthesis of New Lipoic Acid Conjugates and Evaluation of Their Free Radical Scavenging and Neuroprotective Activities

A series of new lipoic acid derivatives were designed and synthesized as multitarget ligands against Alzheimers disease. In particular, analogues combining both lipoic acid and cysteine core structures were synthesized. The antioxidant properties of these compounds were evaluated by 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH), 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid (ABTS•+) radical cation scavenging assays and ferrous ion chelation. The antioxidant potential of the synthesized compounds was also evaluated in a cellular context and compared to α‐lipoic acid and its reduced form, dihydrolipoic acid. The antioxidant effects observed for these compounds in vitro confirmed the importance of free thiol functions for effective antioxidant capacities. However, these promising in vitro results were not mirrored by the antioxidant activity in T67 cell line. This suggests that multiple factors are at stake and warrant further investigations.

Synthesis and radioprotective activity of new N-(amino acid)-S-acetylcysteamine and cystamine derivatives

Abstract In order to evaluate the influence of an amino acid conjugation (Sar, Ser, Phe, Pro, Thz) on S -acetylcysteamine, cystamine, N -(amino acid)- S -acetylcysteamine ( 14–18 ) and N,N ′-bis (amino acid) cystamine ( 24–28 ) derivatives have been synthesized and evaluated as potential radioprotectors. Their toxicity and radioprotective activity, as the dose reduction factor (DRF) have been determined ( in vivo ; ip) and compared with cysteamine and cystamine parent compounds; N -glycyl- S -acetylcysteamine trifluoroacetate 1 and N,N ′-bis (glycyl)cystamine bis (trifluoroacetate) 2 . Among these compounds, 14 (Sar), 15 (Ser), 15a [Ser (Ac)], 16 [Phe], 24 (Sar) had significant radioprotective activity.

Synthesis and radioprotective activity of WR-1065 derivatives: N-(2-acetylthioethyl)-1,3-propanediamine and N,N′-bis(2-acetylthioethyl)-1,3-propanediamine

Summary N -(2-Acetylthioethyl)-1,3-propanediamine ( 13a , as its 2HBr salt, or 13b , as its 2CF 3 CO 2 H salt) and N,N′ -bis(2-acetylthioethyl)-1,3-propanediamine ( 16 , as its 2CF 3 CO 3 H salt) have been prepared and evaluated as potential radioprotectors in mice. Their toxicity and radioprotective activity (survival rate) have been determined and compared with that of WR-2721. Intermediate N -(2-acetylthioethyl)- N,N′ -bis(Z or Boc)-1,3-propanediamines were prepared in two ways from the corresponding alcohols. The most convenient method (the Mitsunobu procedure) was used to obtain the N,N′ -bis(2-acetylthioethylated) derivative from the corresponding diol. Surprisingly, none of these compounds possesses radioprotective activity.