Anti-Inflammatory and Cytotoxic Activities of Clerodane-Type Diterpenes.

The secondary metabolites of clerodane diterpenoids have been found in several plant species from various families and in other organisms. In this review, we included articles on clerodanes and neo-clerodanes with cytotoxic or anti-inflammatory activity from 2015 to February 2023. A search was conducted in the following databases: PubMed, Google Scholar and Science Direct, using the keywords clerodanes or neo-clerodanes with cytotoxicity or anti-inflammatory activity. In this work, we present studies on these diterpenes with anti-inflammatory effects from 18 species belonging to 7 families and those with cytotoxic activity from 25 species belonging to 9 families. These plants are mostly from the Lamiaceae, Salicaceae, Menispermaceae and Euphorbiaceae families. In summary, clerodane diterpenes have activity against different cell cancer lines. Specific antiproliferative mechanisms related to the wide range of clerodanes known today have been described, since many of these compounds have been identified, some of which we barely know their properties. It is very possible that there are even more compounds than those described today, in such a way that makes it an open field to discover. Furthermore, some diterpenes presented in this review have already-known therapeutic targets, and therefore, their potential adverse effects can be predicted in some way.

Anti-Inflammatory Activity of 3, 5-Diprenyl-4-hydroxyacetophenone Isolated from Ageratina pazcuarensis.

Inflammation is implicated in a wide variety of physiological and pathological processes. Plants are an important source of active anti-inflammatory compounds. The compound 3, 5-diprenyl-4-hydroxyacetophenone (DHAP) was isolated from the dichloromethane extract of the aerial parts of Ageratina pazcuarensis by chromatography and identified by spectroscopic (IR, NMR) and spectrometric (GC-MS) methods. Anti-inflammatory activity was evaluated on ear edema mouse induced with 12-O-tetradecanoylphorbol 13-acetate (TPA) at 2 mg/ear. The antioxidant activity of DHAP was determined using DPPH assay. Cell viability was tested in J774A.1 macrophages, the levels of NO, TNF-α, IL-1ß, IL-6, and IL-10 production in macrophages stimulated with lipopolysaccharide (LPS), and membrane lysis induced by hypotonic solution in erythrocytes were evaluated. DHAP diminished the ear edema mouse in 70.10%, and it had scavenger effect against the radical with IC50 of 26.00 ± 0.37 µg/mL. Likewise, 91.78 µM of this compound inhibited the production of NO (38.96%), IL-1ß (55.56%), IL-6 (51.62%), and TNF-α (59.14%) in macrophages and increased the levels of IL-10 (61.20%). Finally, 25 and 50 µg/mL DHAP provided the greatest protection against erythrocyte membrane lysis. These results demonstrate that DHAP has anti-inflammatory activity.

Understanding the Antilymphoma Activity of Annona macroprophyllata Donn and Its Acyclic Terpenoids: In Vivo, In Vitro, and In Silico Studies.

Annona macroprophyllata Donn (A. macroprophyllata) is used in traditional Mexican medicine for the treatment of cancer, diabetes, inflammation, and pain. In this work, we evaluated the antitumor activity of three acyclic terpenoids obtained from A. macroprophyllata to assess their potential as antilymphoma agents. We identified the terpenoids farnesyl acetate (FA), phytol (PT) and geranylgeraniol (Gg) using gas chromatography-mass spectroscopy (GC-MS) and spectroscopic (1H, and 13C NMR) methods applied to petroleum ether extract of leaves from A. macroprophyllata (PEAm). We investigated antitumor potential in Balb/c mice inoculated with U-937 cells by assessing brine shrimp lethality (BSL), and cytotoxic activity in these cells. In addition, to assess the potential toxicity of PEAm, FA, PT and Gg in humans, we tested their acute oral toxicity in mice. Our results showed that the three terpenoids exhibited considerable antilymphoma and cytotoxic activity. In terms of lethality, we determined a median lethal dose (LD50) for thirteen isolated products of PEAm. Gg, PT and AF all exhibited a higher lethality with values of 1.41 ± 0.42, 3.03 ± 0.33 and 5.82 ± 0.58 µg mL-1, respectively. To assess cytotoxic activity against U-937 cells, we calculated the mean cytotoxic concentration (CC50) and found that FA and PT were closer in respect to the control drug methotrexate (MTX, 0.243 ± 0.007 µM). In terms of antilymphoma activity, we found that FA, PT and Gg considerably inhibited lymph node growth, with median effective doses (ED50) of 5.89 ± 0.39, 6.71 ± 0.31 and 7.22 ± 0.51 mg kg-1 in females and 5.09 ± 0.66, 5.83 ± 0.50 and 6.98 ± 0.57mg kg -1 in males, respectively. Regarding acute oral toxicity, we classified all three terpenoids as category IV, indicating a high safety margin for human administration. Finally, in a molecular docking study of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, we found binding of terpenoids to some amino acids of the catalytic site, suggesting an effect upon activity with a resulting decrease in the synthesis of intermediates involved in the prenylation of proteins involved in cancer progression. Our findings suggest that the acyclic terpenoids FA, PT, and Gg may serve as scaffolds for the development of new treatments for non-Hodgkin's lymphoma.

Anti-Inflammatory Activity of Piquerol Isolated from Piqueria trinervia Cav.

BACKGROUND: Inflammation is a complex process as a response to several stimuli, such as infection, a chemical irritant, and the attack of a foreign body. Piquerol was isolated from Piqueria trinervia, and its anti-inflammatory activity was evaluated using in vivo and in vitro models. METHODS: Piquerol is a monoterpene that was identified using NMR, FT-IR spectroscopy, and mass spectrometry analysis. The anti-inflammatory activity was tested in vivo in ear edema induced with TPA in mice. Piquerol was also tested on J774A.1 macrophages stimulated with lipopolysaccharide (LPS), and the levels of NO, NF-κB, TNF-α, IL-1ß, IL-6, and IL-10 were determined using ELISA. RESULTS: The results show that piquerol diminished ear edema (66.19%). At 150.51 µM, it also inhibited the levels of NO (31.7%), TNF-α (49.8%), IL-1ß (69.9%), IL-6 (47.5%), and NF-κB (26.7%), and increased the production of IL-10 (62.3%). Piquerol has a membrane stabilization property in erythrocyte, and at 100 µg/mL, the membrane protection was of 86.17%. CONCLUSIONS: Piquerol has anti-inflammatory activity, and its possible mechanism of action is through the inhibition of pro-inflammatory mediators. This compound could be a candidate in the development of new drugs to treat inflammatory problems.

Comparison of the diastereoisomeric excess of uridine, inosine and adenosine cyanohydrins determined by HPLC-DAD and 1H NMR.

The separation of the diastereoisomers of the nucleoside derivatives of uridine, inosine and adenosine was performed by HPLC using chiral and no chiral columns, it was observed with the no chiral columns the resolution was good enough to determine diastereoisomeric excess. These methods were compared with 1H NMR, and no significant differences were observed between the three techniques. Diastereoisomeric uridine (3a), inosine (3b) and adenosine (4c) cyanohydrins were resolved by 1H nuclear magnetic resonance (1H NMR), chiral normal phase-high-performance liquid chromatography-diode array detector (NP-HPLC-DAD) and reversed phase (RP-HPLC-DAD); these methods allowed the assesment of the percent diastereoisomeric excess (% de) of the nucleosidic cyanohydrins of 3a (4, 6 and 4), 3b (10, 8 and 6) and 4c (4, 4 and 4). To the best of our knowledge, there are no reports using analytical techniques for the separation of the epimers of 3a, 3b and 4c.