Biotransformation of sclareolide by filamentous fungi: cytotoxic evaluations of the derivatives

Abstract

O esclareolido (1) foi incubado com oito diferentes espécies de fungos filamentosos usados convencionalmente para bio-oxidações. O composto 1 metabolizado pelo fungo Aspergilus niger em um meio de cultura A forneceu o 3-cetoesclareolido (2) e 3b-hidroxiesclareolido (4). Quando em um meio de cultura B (mais rico em nutrientes em relação ao meio de cultura A), foram obtidos os compostos 2, 4, e ainda 3a,6b-diidroxiesclareolido (16), 1-cetoesclareolido (17), 3-ceto-15-hidroxiesclareolido (18) e 3b, 15-diidroxiesclareolido (19). Os produtos 16-19 resultantes da biotransformação de 1 são relatados como substâncias inéditas. A fermentação de 1 com Cunninghamella blackesleeana usando o meio de cultura A forneceu os compostos 2 e 4, enquanto que empregando o meio de cultura B, forneceu os compostos 2, 4, 16 e 17. Os compostos 2, 4 e 17 foram obtidos também com Curvularia lunata. A biotransformação de 1 com Beauveria bassiana forneceu o composto 4 com rendimento satisfatório; com Rhizopus oligosporus e com Mucor miehei forneceu os compostos 2 e 4, enquanto que com R. nigricans and Fusarium moliniforme os compostos 2, 4 e 16 foram obtidos. A avaliação dos efeitos citotóxicos do composto 1 e dos produtos obtidos frente as linhagens de células cancerosas humanas selecionadas (U251, PC-3, K562, HCT-15, MCF-7 e SKUL-1) indicaram que o composto 16 (3a,6b-diidroxiesclareolido) apresenta um efeito citotóxico moderado (IC 50 < 100 mM) contra a U251, a PC-3, a HCT-15 e a MCF-7.Sclareolide (1) was incubated with eight different species of filamentous fungi conventionally used for bio-oxidations. Compound 1 was metabolized with Aspergillus niger in medium A to yield 3-ketosclareolide (2) and 3b-hydroxysclareolide (4), while in medium B (containing major number of nutrients with respect to medium A), compounds 2, 4, 3a,6b-dihydroxysclareolide (16), 1-ketosclareolide (17), 3-keto-15-hydroxysclareolide (18) and 3b,15-dihydroxysclareolide (19) were obtained. The biotransformation products 16-19 were found to be new substances. Fermentation of 1 with Cunninghamella blackesleeana using medium A afforded 2 and 4, while using medium B yielded 2, 4, 16 and 17. Compounds 2, 4 and 17 were also obtained with Curvularia lunata. Biotransformation of 1 with Beauveria bassiana yielded 4 in satisfactory yield, with Rhizopus oligosporus and Mucor miehei afforded 2 and 4, while with R. nigricans and Fusarium moliniforme yielded 2, 4 and 16. Cytotoxic evaluation of 1 and the obtained products against selected human cancer cell lines (U251, PC-3, K562, HCT-15, MCF-7 and SKUL-1) indicated that 16 (3a,6b-dihydroxysclareolide) displayed moderate cytotoxic (IC 50 < 100 mM) against U251, PC-3, HCT-15 and MCF-7.

The Iron(II) Complex [Fe(CF3SO3)2(mcp)] as a Convenient, Readily Available Catalyst for the Selective Oxidation of Methylenic Sites in Alkanes

“…In addition, 62 mg of 23 (2.4% yield) resulting from oxidation at C-2 are also ob-tained. Despite the low yield of 23, its isolation can be regarded as significant since it had only been synthesized by means of biological methods, [21] which require high reaction times, and with Fe-pdpp [11] under very low temperature catalytic conditions. Overall, the mass balance of the reaction is moderate (~64%), but it should be considered as quite good for a C À H oxidation reaction of a complex molecule.…”

Transformations of Some Sesquiterpene Lactones by Filamentous Fungi and Cytotoxic Evaluations

“…oligosporus , and F . moliniforme , were screened for their capabilities to metabolize compounds 1 – 9 at analytical scale (10 – 15 mg), and according with these results, experiments were carried out on a preparative scale (150 – 220 mg), following the same experimental processes . Erlenmeyer cell culture flasks (250 ml) containing 125 ml of medium A or medium B were inoculated with a dense suspension (2 ml) of the corresponding fungi.…”

“…Eight fungi, R. nigricans, B. bassiana, C. lunata, A. niger, C. blakesleeana, M. miehei, R. oligosporus, and F. moliniforme, were screened for their capabilities to metabolize compounds 1 -9 at analytical scale (10 -15 mg), and according with these results, experiments were carried out on a preparative scale (150 -220 mg), following the same experimental processes. [38] Erlenmeyer cell culture flasks (250 ml) containing 125 ml of medium A or medium B were inoculated with a dense suspension (2 ml) of the corresponding fungi. Incubation was maintained at 25°C with gyratory shaking (125 rpm) for 14 days after which the substrates (2 -4 ml) in acetone were added.…”

“…[23 -27] Thus, with the aim of exploring the bioreactivity and bioactivity of several SLs, we carried out the transformations of arglanin (1), [28 -30] 11,13-dehydroeriolin (2), [31] [32] budlein B (3), [33] [34] ludovicin A (4), [28] santamarin (5), [28] , epoxysantamarin (6), [28] parthenolide (7), [35] sphaerocephalin (8) [36] and deacetylconfertiflorin (9) [37] by eight filamentous fungi previously used by our group. [38] The biotransformations afforded the products 10 -17, which were previously characterized as natural products. Therefore, these derivatizations imitate their natural biosynthesis.…”

Biotransformation of Salpichrolides A, C, and G by Three Filamentous Fungi

“…An oxidation reaction of alcohols has been reported with whole cells of R. miehei. 28,29 With other filamentous fungi, regioselective oxidation of the hydroxy group has also been found in one of the hydroxy groups of entmanoyl oxides. 30,31 The reduction of the keto group in derivative 4, by action of a dehydrogenase present in R. miehei, would lead to compound 6 with the S-configuration for the 12-hydroxy derivative obtained (Figure 4).…”