28254-53-7Relevant articles and documents
Acyl Derivatives of Eudesmanolides To Boost their Bioactivity: An Explanation of Behavior in the Cell Membrane Using a Molecular Dynamics Approach
Mejías, Francisco J. R.,Durán, Alexandra G.,Zorrilla, Jesús G.,Varela, Rosa M.,Molinillo, José M. G.,Valdivia, Manuel M.,Macías, Francisco A.
, p. 1297 - 1307 (2021/02/09)
Semisynthetic analogs of natural products provide an important approach to obtain safer and more active drugs and they can also have enhanced physicochemical properties such as persistence, cross-membrane processes and bioactivity. Acyl derivatives of different natural product families, from sesquiterpene lactones to benzoxazinoids, have been synthesized and tested in our laboratories. These compounds were evaluated against tumoral and nontumoral cell lines to identify selective derivatives with a reduced negative impact upon application. The mode of action of these compounds was analyzed by anti-caspase-3 assays and molecular dynamics simulations with cell membrane re-creation were also carried out. Aryl derivatives of eudesmanolide stand out from the other compounds and are better than current anticancer drugs such as etoposide in terms of selectivity and activity. Computational studies provide evidence that lipophilicity plays a key role and the 4-fluorobenzoyl derivative can pass easily through the cell membrane.
Facile synthesis of anhydrojudaicin and 11,13-dehydroanhydrojudaicin, two eudesmanolide-skeleton lactones with potential allelopathic activity
Zorrilla, Jesús G.,Rial, Carlos,Varela, Rosa M.,Molinillo, José M.G.,Macías, Francisco A.
, p. 229 - 236 (2019/04/26)
Natural product anhydrojudaicin (7) is a eudesmanolide that has been synthesized from costunolide (1) in three steps with good yield, simplifying procedures available in the literature. The key step was the efficient oxidation and rearrangement using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Following the same methodology, 11,13-dehydroanhydrojudaicin (8) was prepared for the first time. All compounds were characterized and tested in three specific bioassays: phytotoxicity bioassays on wheat coleoptile and on weed seeds (Amaranthus viridis, Echinochloa crus-galli and Panicum maximum); as well as bioassay of germination of parasitic weed seeds of broomrape (Orobanchaceae). The final products showed better activity profiles than the starting eudesmanolide in all bioassays. The data allow us to propose compounds 7 and 8 as leads for new natural product-based agrochemicals.
Inhibition of TNF- α -Induced Inflammation by Sesquiterpene Lactones from Saussurea lappa and Semi-Synthetic Analogues
Choodej, Siwattra,Pudhom, Khanitha,Mitsunaga, Tohru
, p. 329 - 335 (2017/10/11)
We investigated the tumor necrosis factor-alpha (TNF- α) inhibitory activity of sesquiterpenes from Saussurea lappa root extracts. According to the hexane and EtOAc extracts showing significant activity with IC 50 values of 0.5 and 1.0 μg/mL, respectively, chromatographic fractionation of the extracts was performed and led to the isolation of 10 sesquiterpenes (1 - 10). Costunolide (1), a major compound, and dehydrocostus lactone (4) exhibited high efficiency in decreasing TNF- α levels, with IC 50 values of 2.05 and 2.06 μM, respectively. In addition, sesquiterpene analogues were synthesized to establish their structure-activity relationship (SAR) profile. Among the semi-synthetic analogues, compounds 6a and 16 showed the most potent activity with IC 50 values of 1.84 and 1.97 μM, respectively. More importantly, compound 6a showed less toxicity than costunolide and 16. These results provided the first SAR profile of sesquiterpene lactones and indicated that the α -methylene- γ -lactone moiety plays a crucial role in TNF- α inhibition. Additionally, the epoxide derivative 6a might represent a lead compound for further anti-TNF- α therapies, owing to its potent activity and reduced toxicity.
Effects of solvents and water in Ti(III)-mediated radical cyclizations of epoxygermacrolides. Straightforward synthesis and absolute stereochemistry of (+)-3α-hydroxyreynosin and related eudesmanolides
Barrero, Alejandro F.,Enrique Oltra,Cuerva, Juan M.,Rosales, Antonio
, p. 2566 - 2571 (2007/10/03)
The Cp2TiCl-mediated rearrangement of 1,10-epoxy-11β,13-dihydrocostunolide (4) was carried out using different solvents and additives to develop an expeditious procedure for the synthesis of natural eudesmanolides via free-radical chemistry. In the nonhalogenated solvents THF, benzene, and toluene the transannular cyclization, initiated by the homolytic opening of the oxirane ring, selectively led to the desired exocyclic alkene 5. When water was added to THF, however, the main product was reduced eudesmanolide 8. Experiments with D2O confirmed that the H-4 of 8 comes from water. To rationalize these results, a mechanistic hypothesis based on a water-solvated Cp2TiCl complex is proposed. Finally, the usefulness of Cp2TiCl for the synthesis of natural eudesmanolides has been proved using this reagent in the key step for the chemical preparation of (+)-3α-hydroxyreynosin (1) and (+)-reynosin (17). These syntheses confirmed the chemical structure of 1 and established the absolute stereochemistry of the natural products 1 and 17. The results obtained suggest that the combination of the biomimetic strategy employed, with Ti(III)-mediated free-radical chemistry, may come to represent a general method for the enantiospecific synthesis of more than 170 natural eudesmanolides containing an exocyclic double bond between C-4 and C-15.
Absolute stereostructures and syntheses of saussureamines A, B, C, D and E, amino acid-sesquiterpene conjugates with gastroprotective effect, from the roots of Saussurea lappa
Matsuda, Hisashi,Kageura, Tadashi,Inoue, Yasunao,Morikawa, Toshio,Yoshikawa, Masayuki
, p. 7763 - 7777 (2007/10/03)
From the methanolic extract of the dried roots of Saussurea lappa Clarke, Saussureae Radix, five amino acid-sesquiterpene conjugates, saussureamines A, B, C, D and E, were isolated together with a lignan glycoside, (-)-massoniresinol 4-O-β-D-glucopyranoside. Their stereostructures were determined on the basis of chemical and physicochemical evidence. In addition, saussureamines and the related amino acid-sesquiterpene conjugates were synthesized using a Michael type addition reaction of amino acid to the α-methylene-γ-lactone moiety of sesquiterpenes. Saussureamines A, B and C, costunolide and dehydrocostus lactone showed a gastroprotective effect on acidified ethanol-induced gastric mucosal lesions in rats. Saussureamines A also exhibited an inhibitory effect on gastric mucosal lesions induced by water-immersion stress in mice. (C) 2000 Elsevier Science Ltd.
Microbial transformation of sesquiterpene lactones by the fungi Cunninghamella echinulata and Rhizopus oryzae
Barrero, Alejandro F.,Oltra, J. Enrique,Raslan, Delio S.,Saude, Denia A.
, p. 726 - 729 (2007/10/03)
Incubations of the fungi Cunninghamella echinulata and Rhizopus oryzae with the sesquiterpene lactones (+)-costunolide (1), (+)-cnicin (2), (+)- salonitenolide (3), (-)-dehydrocostuslactone (4), (-)-lychnopholide (5), and (-)-eremantholide C (6) were performed. Incubation of 1 with C. echinulata afforded Δ(11(13))-dihydrogenation and Δ(1(10))-epoxidation products (7- 10). C. echinulata also hydrolyzed the side chain of 2, and transformed 4 into (+)-11α,13-dihydrodehydrocostuslactone (12), a new natural product. R. oryzae converted 4 into both Δ(11(13))-dihydrogenation and Δ(10(14))- epoxidation products (16 and 17). Both fungi transformed 5 into (-)-16-(1- methyl-1-propenyl)eremantholanolide (13), providing experimental evidence for the biosynthesis of the eremantholide hemiketal unit. Compounds 3 and 6 were not metabolized by either fungus under the test conditions.
Influence of Conformational Factors on Acid-Catalyzed Cyclizations of Germacranolides: Molecular Structure of the Cyclization Products of Gallicin and 8α-Hydroxygallicin (Shonachalin A)
Marco, J. Alberto,Sanz-Cervera, Juan F.,Garcia-Lliso, Vicente,Domingo, Luis R.,Carda, Miguel,et al.
, p. 1837 - 1842 (2007/10/03)
Acid-catalyzed cyclization of the natural germacranolide gallicin (8) yielded, among other products, the 1,4-epoxyeudesmanolide 9, which has a trans-fused decaline system.Under the same conditions the closely related germacranolide shonachalin A (8α-hydroxygallicin) (3) cyclized to the eudesmanolide 4 with a cis-fused decaline system.The structures of these cyclization products were secured by means of chemical correlations and X-ray diffraction analyses. - Keywords: Sesquiterpene lactones / Germacranolides, acid-catalyzed cyclization of, influence of conformation in / Eudesmanolides
