Biotransformation of two ent-Pimara-9(11),15-diene derivatives by Gibberella fujikuroi.
ABSTRACT The incubation of 19-hydroxy-13-epi-ent-pimara-9(11),15-diene (4) with Gibberella fujikuroi gave 8 alpha,19-dihydroxy-9 alpha,11alpha-epoxy-13-epi-ent-pimara-15-ene (6), 7-oxo-11 alpha,19-dihydroxy-13-epi-ent-pimara-8(9),15-diene (7), 7-oxo-11beta,19-dihydroxy-13-epi-ent-pimara-8(9),15-diene (9), and 8 alpha,19-dihydroxy-9 alpha,11 alpha:15,16-diepoxy-13-epi-ent-pimarane (11), while the feeding of 13-epi-ent-pimara-9(11),15-diene-19-oic acid (5) with this fungus afforded 1-oxo-2 alpha,9 alpha-dihydroxy-13-epi-ent-pimara-11,15-dien-19-oic acid (13), 1-oxo-2 beta,9 alpha-dihydroxy-13-epi-ent-pimara-11,15-dien-19-oic acid (14), 13-epi-ent-pimara-9(11),15-dien-1,19-dioic acid 1,2-lactone (15), and 1-oxo-12 beta-hydroxy-13-epi-ent-pimara-9(11),15-dien-19-oic acid (16). In both biotransformations, the main reaction was the epoxidation of the 9(11)-double bond, followed by rearrangement to afford allylic alcohols. The formation of lactone 15 represents the first time that a Baeyer-Villiger oxidation has been observed in a microbiological transformation with this fungus.
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ABSTRACT: According to the structure of podophyllotoxin and its structure-function relationship, a novel tandem biotransformation process was developed for the directional modification of the podophyllotoxin structure to directionally synthesize a novel compound, 4-(2,3,5,6-tetramethylpyrazine-1)-4'-demethylepipodophyllotoxin (4-TMP-DMEP). In this novel tandem biotransformation process, the starting substrate of podophyllotoxin was biotransformed into 4'-demethylepipodophyllotoxin (product 1) with the demethylation of the methoxyl group at the 4' position by Gibberella fujikuroi SH-f13, which was screened out from Shennongjia prime forest humus soil (Hubei, China). 4'-Demethylepipodophyllotoxin (product 1) was then biotransformed into 4'-demethylpodophyllotoxone (product 2) with the oxidation of the hydroxyl group at the 4 position by Alternaria alternata S-f6, which was screened out from the gathered Dysosma versipellis plants in the Wuhan Botanical Garden, Chinese Academy of Sciences. Finally, 4'-demethylpodophyllotoxone (product 2) and ligustrazine were linked with a transamination reaction to synthesize the target product 4-TMP-DMEP (product 3) by Alternaria alternata S-f6. Compared with podophyllotoxin (i.e., a 50% effective concentration [EC(50)] of 529 μM), the EC(50) of 4-TMP-DMEP against the tumor cell line BGC-823 (i.e., 0.11 μM) was significantly reduced by 5,199 times. Simultaneously, the EC(50) of 4-TMP-DMEP against the normal human proximal tubular epithelial cell line HK-2 (i.e., 0.40 μM) was 66 times higher than that of podophyllotoxin (i.e., 0.006 μM). Furthermore, compared with podophyllotoxin (i.e., log P = 0.34), the water solubility of 4-TMP-DMEP (i.e., log P = 0.66) was significantly enhanced by 94%. For the first time, the novel compound 4-TMP-DMEP with superior antitumor activity was directionally synthesized from podophyllotoxin by the novel tandem biotransformation process developed in this work.Applied and environmental microbiology 03/2011; 77(9):3023-34. · 3.69 Impact Factor
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ABSTRACT: The hydrocarbon 9,13-epi-ent-pimara-7,15-diene has been obtained from its 18-hydroxy derivative by treatment with Ph3/CCl4 and subsequent reduction with tri-n-butyltin hydride. The incubation of this diterpene with the fungus Gibberella fujikuroi afforded 1α,9α-dihydroxy-7α,8α-epoxy-13-epi-ent-pimara-15-ene. The main difference between the biotransformation of the hydrocarbon and that of the corresponding 18-alcohol is that in the former, the rearrangement of the epoxy group to give 7-oxo-derivatives was not observed. However, the sequence of reactions 7α,8α-epoxidation, hydroxylation at C-9α and subsequent C-1α hydroxylation occurred in both biotransformations.Phytochemistry Letters - PHYTOCHEM LETT. 01/2009; 2(4):201-203.