596-85-0Relevant articles and documents
Antischistosomal Properties of Sclareol and Its Heck-Coupled Derivatives: Design, Synthesis, Biological Evaluation, and Untargeted Metabolomics
Crusco, Alessandra,Whiteland, Helen,Baptista, Rafael,Forde-Thomas, Josephine E.,Beckmann, Manfred,Mur, Luis A. J.,Nash, Robert J.,Westwell, Andrew D.,Hoffmann, Karl F.
, p. 1188 - 1199 (2019/06/08)
Sclareol, a plant-derived diterpenoid widely used as a fragrance and flavoring substance, is well-known for its promising antimicrobial and anticancer properties. However, its activity on helminth parasites has not been previously reported. Here, we show that sclareol is active against larval (IC50 ≈ 13 μM), juvenile (IC50 = 5.0 μM), and adult (IC50 = 19.3 μM) stages of Schistosoma mansoni, a parasitic trematode responsible for the neglected tropical disease schistosomiasis. Microwave-assisted synthesis of Heck-coupled derivatives improved activity, with the substituents choice guided by the Matsy decision tree. The most active derivative 12 showed improved potency and selectivity on larval (IC50 ≈ 2.2 μM, selectivity index (SI) ≈ 22 in comparison to HepG2 cells), juvenile (IC50 = 1.7 μM, SI = 28.8), and adult schistosomes (IC50 = 9.4 μM, SI = 5.2). Scanning electron microscopy studies revealed that compound 12 induced blebbing of the adult worm surface at sublethal concentration (12.5 μM); moreover, the compound inhibited egg production at the lowest concentration tested (3.13 μM). The observed phenotype and data obtained by untargeted metabolomics suggested that compound 12 affects membrane lipid homeostasis by interfering with arachidonic acid metabolism. The same methodology applied to praziquantel (PZQ)-treated worms revealed sugar metabolism alterations that could be ascribed to the previously reported action of PZQ on serotonin signaling and/or effects on glycolysis. Importantly, our data suggest that compound 12 and PZQ exert different antischistosomal activities. More studies will be necessary to confirm the generated hypothesis and to progress the development of more potent antischistosomal sclareol derivatives.
Substrate specificity of Rv3378c, an enzyme from Mycobacterium tuberculosis, and the inhibitory activity of the bicyclic diterpenoids against macrophage phagocytosis
Hoshino, Tsutomu,Nakano, Chiaki,Ootsuka, Takahiro,Shinohara, Yosuke,Hara, Takashi
experimental part, p. 2156 - 2165 (2011/05/14)
The Rv3378c gene product from Mycobacterium tuberculosis encodes a diterpene synthase to produce tuberculosinol (3), 13R-isotuberculosinol (4a), and 13S-isotuberculosinol (4b) from tuberculosinyl diphosphate (2). The product distribution ratios are 1:1 for 3 to 4 and 1:3 for 4a to 4b. The substrate specificity of the Rv3378c-encoded enzyme was examined. The 3 labdadienyl diphosphates, copalyl diphosphate (CDP) (7), ent-CDP (8), and syn-CDP (9), underwent the conversion reaction, with good yields (67-78%). Copalol (23) and manool (24) were produced from 7, ent-copalol (25) and ent-manool (26) from 8, and syn-copalol (27) and vitexifolin A (28) from 9. The ratio of 23 to 24 was 40:27, that of 25:26 was 22:50, and that of 27:28 was 16:62. Analysis on a GC-MS chromatograph equipped with a chiral column revealed that 24, 26, and 28 consisted of a mixture of 13R- (a) and 13S-stereoisomers (b) in the following ratio: ca. 1:1 for 24a to 24b, ca. 1:5 for 26a to 26b, and ca. 1:19 for 28a to 28b. The structures of these products indicate that the reactions of the 3 CDPs proceeded in the same fashion as that of 2. This is the first report on the enzymatic synthesis of natural diterpenes manool, ent-manool, and vitexifolin A. Both Rv3377c and Rv3378c genes are found in virulent Mycobacterium species, but not in avirulent species. We found that 3 and 4 inhibited the phagocytosis of opsonized zymosan particles by human macrophage-like cells. Interestingly, the inhibitory activity was synergistically increased by the coexistence of 3 and 4b. Other labdane-related diterpenes, 13-16 and 23-28, had little or no inhibitory activity. This synergistic inhibition by 3 and 4 may provide further advantage to the impairment of phagocyte function, which might contribute to pathogenicity of M. tuberculosis.
TERPENOIDS AND STEROLS FROM THE WOOD OF ABIES PINSAPO
Barrero, Alejandro,Sanchez, Juan F.,Alvarez-Manzaneda, E. J.,Dorado, M. Munoz,Haidour, Ali
, p. 1261 - 1266 (2007/10/02)
From the neutral fraction of the hexane extract of the wood of Abies pinsapo 11 sesquiterpenoids, seven diterpenoids, three triterpenoids and two sterols have been identified.Three of them are new natural products: 3β-hydroxy-13-epimanool, (23R,25R)-3α-methoxy-9,19-cyclo-9β-lanostan-26,23-olide and (22S)-5α-ergostane-3α,22-diol.Their structure were established by spectroscopic methods and chemical correlations. Key words: Abies pinsapo; Pinaceae; wood; labdane diterpenoids; cyclolanostanolides; sterols.
