Cytotoxic withanolides from Datura innoxia.

Chemical investigation of the aerial parts (except fruits) of the medicinal, hallucinogen and toxic plant Datura innoxia Mill. [Solanaceae] led to the isolation of the new withanolide, dinnoxolide A (1), along with the known compounds 21,27-dihydroxy-1-oxowitha-2,5,24-trienolide (2), daturamalakin B (3) and withametelin (4). Their structures were established by analysis of their spectroscopic data, including 1D and 2D NMR experiments and MS. Compounds 2 and 3 were isolated as natural products for the first time and the name dinnoxolide B was given to compound 2. The four withanolides showed in vitro cytotoxic activity against U251 (glioblastoma) and SK-LU-1 (lung adenocarcinoma) human cancer cell lines, with IC50 values ranging from 1.2 to 19.6 µM, and also against the noncancerous monkey kidney cell line (COS-7), with IC50 values ranging from 5.0 to 19.7 µM. Compound 4 was two times more active than the reference compound, etoposide, against lung adenocarcinoma cells.

Structure, Absolute Configuration, and Antiproliferative Activity of Abietane and Icetexane Diterpenoids from Salvia ballotiflora.

From the aerial parts of Salvia ballotiflora, eleven diterpenoids were isolated; among them, four icetexanes and one abietane (1-5) are reported for the first time. Their structures were established by spectroscopic means, mainly ¹H- and 13C-NMR, including 1D and 2D homo- and hetero-nuclear experiments. Most of the isolated diterpenoids were tested for their antiproliferative, anti-inflammatory, and radical scavenging activities using the sulforhodamine B assay on six cancer cell lines, the TPA-induced ear edema test in mice, and the reduction of the DPPH assay, respectively. Some diterpenoids showed anti-proliferative activity, these being icetexanes 6 and 3, which were the most active with IC50 (µM) = 0.27 ± 0.08 and 1.40 ± 0.03, respectively, for U251 (human glioblastoma) and IC50 (µM) = 0.0.46 ± 0.05 and 0.82 ± 0.06 for SKLU-1 (human lung adenocarcinoma), when compared with adriamycin (IC50 (µM) = 0.08 ± 0.003 and 0.05 ± 0.003, as the positive control), respectively. Compounds 3 and 10 showed significant reduction of the induced ear edema of 37.4 ± 2.8 and 25.4 ± 3.0% (at 1.0 µmol/ear), respectively. Compound 4 was the sole active diterpenoid in the antioxidant assay (IC50 = 98. 4 ± 3.3), using α-tocopherol as the positive control (IC50 (µM) = 31.7 ± 1.04). The diterpenoid profile found is of chemotaxonomic relevance and reinforces the evolutionary link of S. ballotiflora with other members of the section Tomentellae.

Toxicological evaluation of the natural products and some semisynthetic derivatives of Heterotheca inuloides Cass (Asteraceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Heterotheca ineuloides Cass (Asteraceae), popularly known as árnica mexicana, is widely used in Mexican traditional medicine to treat bruises, dermatological problems, rheumatic pains, and other disorders as cancer. The major constituents in H. inuloides are cadinane type sesquiterpenes, flavonoids and phytosterols. Compounds with a cadinane skeleton have been proved to possess cytotoxic activity against human-tumor cell lines and brine shrimp, and display toxic effects in different animal species. Although this plant has been widely used, there is little available information on the safety and toxicity especially of pure compounds. AIM OF THIS STUDY: Evaluate the potential toxicity of the natural products isolated from H. inuloides and some semisynthetic derivatives. MATERIALS AND METHODS: The toxic aspects of the following natural products isolated from dried flowers of H. inuloides: 7-hydroxy-3,4-dihydrocadalene (1), 7-hydroxycadalene (2), 3,7-dihydroxy-3(4H)-isocadalen-4-one (3), (1R,4R)-1-hydroxy-4H-1,2,3,4- tetrahydrocadalen-15-oic acid (4), D-chiro-inositol (5), quercetin (6), quercetin-3,7,3'-trimethyl ether (7), quercetin-3,7,3',4'-tetramethyl ether (8), eriodictyol-7,4'-dimethyl ether (9), α-spinasterol (10), caryolan-1,9ß-diol (11) and 7-(3,3-dimethylallyloxy)-coumarin (12) as well as the toxic aspects of the semisynthetic compounds 7-acetoxy-3,4-dihydrocadalene (13), 7-benzoxy-3,4-dihydrocadalene (14), 7-acetoxycadalene (15), 7-benzoxycadalene (16), quercetin pentaacetate (17), 7-hydroxycalamenene (18), 3,8-dimethyl-5-(1-methylethyl)-1,2-naphthoquinone (19), and 4-isopropyl-1,6-dimethylbenzo[c]oxepine-7,9-dione (20). Toxic activities of compounds were determined by sulforhodamine B (SRB) assay, Artemia salina assay, RAW264.7 macrophage cells. Additionally, the acute toxicity in mouse of compound 1, the major natural sesquiterpene isolated from the acetone extract, was evaluated. RESULTS: The best cytotoxicity activity was observed for mansonone C (19) on K562 cell line with IC50 1.45 ± 0.14 µM, for 7-hydroxycadalene (2) on HCT-15 cell line with IC50 18.89 ± 1.2 µM, and for quercetin pentaacetate (17) on MCF-7 cell line with IC50 22.57 ± 2.4 µM. Sesquiterpenes mansonone C (19) and 7-hydroxy-3,4-dihydrocadalene (1) caused the strongest deleterious effects against A. salina with IC50 39.4 ± 1.07, and 45.47 ± 1.74 µM, respectively. The number of viable RAW 264.7 cells was reduced with sesquiterpenes 1 and 2 by more than 90%. In addition, the acute study of 1 revealed no lethal effects at 300 mg/kg body weight, however, a reduction in the body weight of mice, morphological changes in the tissues of the liver and kidney and toxic signs were observed at very high doses (2000 mg/kg). CONCLUSION: The results provided evidence for the cytotoxicity of Mexican arnica (H. inuloides) metabolites and may be correlated with one of the popular uses of this plant, in traditional Mexican medicine, as anticancer remedy. Among the active compounds contained in the acetone extract, the cytotoxic activity is mainly ascribable to cadinene type sesquiterpenes. In addition, evidence of acute toxicity suggests that 7-hydroxy-3,4-dihydrocadalene (1) may lead to toxicity at very high doses.

Bio-guided isolation of the cytotoxic corytenchine and isocoreximine from roots of Annona cherimolia.

The roots of Annona cherimolia have been shown to contain the known tetrahydroprotoberberine alkaloids corytenchine (1) and isocoreximine (2), investigated for their cytotoxic properties.

Evaluation of the cytotoxicity, cytostaticity and genotoxicity of argentatins A and B from Parthenium argentatum (Gray).

Argentatins A and B are abundant triterpenes present in Parthenium argentatum. Both compounds have shown cytotoxic properties on K562, MCF-7, PC-3, HCT-15 and U251 human cancer cell lines. Furthermore the cytotoxic, cytostatic and genotoxic effects of the argentatins on proliferating lymphocytes were evaluated using cytokinesis-block micronucleus test. Argentatin A had no cytostatic properties, but it was cytotoxic for proliferating lymphocytes at a concentration of 25 microM (P < 0.005). On the other hand, argentatin B showed significant cytostatic effects (P < 0.001) at concentrations of 5 to 25 microM and it did not show cytotoxic effects at the same concentrations. Neither argentatin showed genotoxic effects in terms of micronucleus frequency in human lymphocytes. According to these results the argentatins are not able to cause injury on DNA by clastogenic or aneugenic mechanisms.