ABSTRACT
Sesquiterpene lactones are found in plants of Asteraceae family, and endoperoxides are known for their antimalarial activity. Structural elucidation is a relevant aspect; however, it is not uncommon to find incorrect or incomplete structural assignments in the literature. Calculations based in quantum mechanics are frequently used to compute 1 H and 13 C NMR chemical shifts, and after comparing with the experimental data, the correct structure is established from diverse candidates. Targeting the synthesis of bioactive compounds, we envisaged the synthesis of a novel endoperoxide from the natural sesquiterpene lactone α-santonin (2). Photochemical transformation of α-santonin (2) to mazdasantonin (4) followed by photooxidation catalyzed by rose bengal afforded the novel endoperoxide 5. This new endoperoxide contains five stereogenic centers and is analogous to the antimalarial agent artemisinin (1). The relative configuration of the stereogenic centers of the endoperoxide were established by nuclear magnetic resonance (NMR) analyses and confirmed by theoretical calculations. All approaches were in complete agreement, and the structure of mazdasantonin endoperoxide was established as (3S,3aS,5aS,8R,9bS)-3,6,6-trimethyl-3,3a,4,5,8,9b-hexahydro-2H-5a,8-epidioxynaphtho[1,2-b]furan-2,7(6H)-dione.
ABSTRACT
The purpose of this study was to evaluate the impact of age on tetanus-specific immune response in successfully highly active antiretroviral therapy-treated AIDS patients, using healthy age-matched individuals as controls. Whole Peripheral blood mononuclear cells or CD8(+) cell-depleted peripheral blood mononuclear cells from previously tetanus toxoid (TT)-immunized individuals were activated with TT plus IL-2, and cell proliferation, cytokine production, and in vitro HIV-1 replication were measured. The in vivo magnitude of the humoral immune response was also assessed by antibody measurements. Our results showed that, compared with other groups, both in vitro TT-specific lymphoproliferation and serum antibody concentration were lower in older AIDS patients. Although the IL-1beta and tumour necrosis factor alpha (TNF-alpha) production were higher in cultures from aged HIV-1-infected patients, a dramatic damage on the interferon gamma (IFN-gamma) release was observed, when compared with younger patients. CD8(+) T lymphocytes depletion reduced IL-1beta and TNF-alpha release in the older groups, however, it did not significantly alter their IFN-gamma production. Furthermore, the neutralization of endogenous IL-10 did not change the IFN-gamma deficiency in older AIDS patients. Finally, the lower cellular immune response in this patient group was not related to in vitro HIV-1 replication. The results suggest that successfully highly active antiretroviral therapy-treated aged AIDS patients do not reconstitute the immune response to TT, making them probably more susceptible to tetanus even after vaccination.
