Novel platensimycin derivatives with herbicidal activity.

BACKGROUND: Faced with the need to develop herbicides with different modes of action on account of weed resistance to existing herbicides, the sesquiterpene lactones can be the starting point in the search for new bioactive compounds. Lumisantonin and five novel amides have been evaluated against two monocotyledons and three dicotyledons. RESULTS: An efficient and versatile synthesis of lumisantonin and the five novel amides has been accomplished from readily available α-santonin. These compounds were subjected to evaluation for their biological activity against Sorghum bicolor (sorghum), Allium cepa (onion), Cucumis sativus (cucumber), Solanum lycopersicum (tomato) and Bidens pilosa (beggartick). Lumisantonin has inhibited the development of the aerial parts of sorghum and onion by 76 and 67% at 1000 µM respectively. One of the novel amides has prevented the growth of shoots and radicles of sorghum by 80 and 71% at 1000 µM respectively. CONCLUSION: All of the tested compounds have been found to exhibit promising seed germination inhibition. We can conclude that lumisantonin was on average the most lethal against all plant species evaluated; however, two of the novel amides have exhibited inhibition selectivity against monocotyledons when compared with dicotyledons. © 2015 Society of Chemical Industry.

Induction of G2/M arrest, caspase activation and apoptosis by α-santonin derivatives in HL-60 cells.

Sesquiterpene lactones (SLs) are natural products with a variety of biological activities. Previously, we demonstrated the cytotoxic effects of three new α-santonin derivatives on different tumor cell lines with low toxic effects upon peripheral human leukocytes. Here, we evaluated the mechanism of action triggered by these derivatives. HL-60 cell cycle determined after 24h treatment revealed a significant inhibition on cell-cycle progression and leading to an increasing of cells in G2/M [7.6% and 9.0% for compound 3% and 9.0% and 8.6% for compound 4 (1 and 2 µM, respectively)]. However, after 48 h exposure, all compounds caused G2/M reduction and a significant DNA fragmentation. Compounds 2, 3 and 4 were able to induce apoptosis on leukemia cells, which was corroborated by phosphatidyserine externalization and activation of caspases-3 and -7 after 24h exposure. None of the derivatives analyzed caused depolarization of mitochondrial membrane within 24h of incubation, suggesting the involvement of the extrinsic apoptotic pathway in the death process. The antiproliferative action of these compounds is related to the DNA synthesis inhibition and cell cycle arrest, which probably lead to apoptosis activation. Therefore, these santonin derivatives are promising lead candidates for development of new cytotoxic agents.

Synthesis of novel α-santonin derivatives as potential cytotoxic agents.

Ten novel α-santonin derivatives have been synthesized as cytotoxic agents. The in vitro antitumor activity of these compounds has been evaluated against cancer cells lines. Structure-activity relationships indicate that α-methylene-γ-lactone and endoperoxide functionalities play important roles in conferring cytotoxicity. The compounds 2-4, possessing the α-methylene-γ-lactone group showed IC50 values between 5.70 and 16.40 µM. Mixture of isomers 5 and 6, with the α-methylene-γ-lactone and endoperoxide functionalities, displayed the greatest activity, with IC50 values between 1.45 and 4.35 µM. The biological assays conducted with normal cells revealed that the compounds 2, 5 and 6 are selective against cancer cells lines tested. Bioactive lactones described herein and in our previous report did not cause disruption of the cell membrane in mouse erythrocytes.

Synthesis and cytotoxic activity of alpha-santonin derivatives.

Ten alpha-santonin derivatives were synthesized in moderate to high yields. Four derivatives namely 10alpha-acetoxy-3-oxo-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (2), isofotosantonic acid (3), 10alpha-hydroxy-3-oxo-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (4), and lumisantonin (5), were prepared by different photochemical reactions using alpha-santonin (1) as starting material. These transformations were carried out in either anhydrous acetic acid, acetic acid/water (1:1 v/v) or acetonitrile, using different types of reactors and ultraviolet light sources. Treatment of alpha-santonin (1) with lithium diisopropyl amide (LDA) followed by capture of the organolithium with phenyl selenium chloride produced the compound 3-oxo-7alphaH,6betaH,11-(phenylselenyl)-eudesma-1,4-dien-6,12-olide (6). Subsequent treatment of compound 6 with hydrogen peroxide gave 3-oxo-7alphaH,6betaH-eudesma-1,4,11-trien-6,12-olide (7). Photochemical reaction of compound 7 led to the formation of 11,13-dehydrolumisantonin (8) and 10alpha-acetoxy-3-oxo-1,7alphaH,6betaH-guai-4,11-dien-6,12-olide (9). Sodium borohydride reduction of compounds 2 and 4 afforded the derivatives 10alpha-acetoxy-3beta-hydroxy-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (10) and 3beta,10alpha-hydroxy-1,7alphaH,6,11betaH-guai-4-en-6,12-olide (11). The cytotoxicity of the synthesized compounds were evaluated against the cancer cell lines HL-60 (leukemia), SF-295 (central nervous system), HCT-8 (colon), MDA-MB-435 (melanoma), UACC-257 (melanoma), A549 (lung), OVACAR-8 (ovarian), A704 (renal), and PC3 (prostate). The compounds with higher activity, possessing IC(50) values in the range of 0.36-14.5 microM, showed as common structural feature the presence of an alpha-methylidene-gamma-butyrolactone moiety in their structures. The biological assays conducted with normal cells (PBMC) revealed that the compounds are selective against cancer cell lines. The modified lactones seem to be interesting lead structures towards anticancer drug development.