A methodology to determine the enantiomeric excess and the absolute configuration (AC) of natural epoxythymols was developed and tested using five constituents of Ageratina glabrata. The methodology is based on enantiomeric purity determination employing 1,1'-bi-2-naphthol (BINOL) as a chiral solvating agent combined with vibrational circular dichroism (VCD) measurements and calculations. The conformational searching included an extensive Monte Carlo protocol that considered the rotational barriers to cover the whole conformational spaces. (+)-(8S)-10-Benzoyloxy-6-hydroxy-8,9-epoxythymol isobutyrate (1), (+)-(8S)-10-acetoxy-6-methoxy-8,9-epoxythymol isobutyrate (4), and (+)-(8S)-10-benzoyloxy-6-methoxy-8,9-epoxythymol isobutyrate (5) were isolated as enantiomerically pure constituents, while 10-isobutyryloxy-8,9-epoxythymol isobutyrate (2) was obtained as a 75:25 (8S)/(8R) scalemic mixture. In the case of 10-benzoyloxy-8,9-epoxythymol isobutyrate (3), the BINOL methodology revealed a 56:44 scalemic mixture and the VCD measurement was beyond the limit of sensitivity since the enantiomeric excess is only 12%. The racemization process of epoxythymol derivatives was studied using compound 1 and allowed the clarification of some stereochemical aspects of epoxythymol derivatives since their ACs have been scarcely analyzed and a particular behavior in their specific rotations was detected. In more than 30 oxygenated thymol derivatives, including some epoxythymols, the reported specific rotation values fluctuate from -1.6 to +1.4 passing through zero, suggesting the presence of scalemic and close to racemic mixtures, since enantiomerically pure natural constituents showed positive or negative specific rotations greater than 10 units.

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Chemical investigations of Acacia schaffneri led to the isolation of the new diterpenoid (5S,7R,8R,9R,10S)-(-)-7,8-seco-7,8-oxacassa-13,15-diene-7,17-diol (1), together with the known (5S,7R,8R,9R,10S)-(-)-7,8-seco-7,8-oxacassa-13,15-dien-7-ol-17-al (2) and (5S,7R,8R,9R,10S)-(-)-7,8-seco-7,8-oxacassa-13,15-dien-7-ol (3). Compounds 2 and 3 were analyzed by single-crystal X-ray diffraction, while the structure of 1 was determined by 1D and 2D NMR experiments and by chemical correlation with 2. Oxidation of 3 afforded conformationally restricted (5S,8R,9R,10S)-(-)-8-hydroxy-7,8-seco-cassa-13,15-dien-7-oic acid ε-lactone (4), which was studied by vibrational circular dichroism spectroscopy. Comparison of the experimental VCD spectrum of 4 with the DFT//B3PW91/DGDZVP2 calculated spectrum assigned for the first time the absolute configuration of these seco-oxacassane diterpenes.

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An unprecedented macrocyclic dimeric diterpene containing a C2 symmetry axis was isolated from Acacia schaffneri . This compound, named schaffnerine, was characterized as (5S,7S,8R,9R,10S,17S,5'S,7'S,8'R,9'R,10'S,17'S)-7,8:7,17':16,17:17,7':7',8':16',17'-hexaepoxy-7,8-seco-7',8'-seco-dicassa-13,13'-diene (1) from its spectroscopic data. Comparison of its experimental vibrational circular dichroism spectrum with that calculated using density functional theory, at the B3LYP/DGDZVP level, assigned its preferred conformation and absolute configuration. The latter was confirmed by evaluation of the Flack and Hooft parameters obtained after single-crystal X-ray diffraction analysis.

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This work reports the antiproliferative activity of seco-oxacassanes 1-3, isolated from Acacia schaffneri, against human colon (HT-29), lung (A-549), and melanoma (UACC-62) cancer cell lines, as well as against their non-malignant counterparts CCD-841 CoN, MRC-5, and VH-10, respectively, using the sulforhodamine B test. While compounds 1 and 3 were inactive, 2 presented strong activity with IC 50 values between 0.12 and 0.92 µg mL-1. The cytotoxicity mechanisms of 2 were investigated by cell cycle analysis and through DNA repair pathways, indicating that the compound is capable of arresting the cell cycle in the G0/G1 phase. This effect might be generated through damage to DNA by alkylation. In addition, compound 2 was able to decrease HT-29 migration.

Undernutrition induces an increase of the oxidative stress that can predispose offspring to various diseases in adulthood through epigenetic reprogramming. The aim of this study was to evaluate the effects of intergenerational undernutrition on protein oxidation and antioxidant defence response on liver, heart and brain of the second-generation neonates (F ) of undernourished rats. For this purpose, both parents in parental (F ) and first generation (F ) were fed with a low-nutrient diet. Body mass and length decreased (p < 0.05) in F , F and F being the F males who exhibited a greater mass loss. A decrease in plasma albumin concentration was observed in F neonates (p < 0.05) and also a mass loss of liver, heart and brain (p < 0.05), although proportionally to body length reduction. Undernutrition increased levels of protein oxidation in liver and heart (p < 0.05) but not in brain (p > 0.05) while catalase activity increased only in brain (p < 0.05). In summary, intergenerational undernutrition modifies the antioxidant status through an organ-specific response, on F neonate rats, where the brain increased catalase activity to prevent a severe oxidative damage and support the vital functions of this key organ to maintain vital functions.