Microbial Modification of Mycophenolic Acid

Abstract

On incubation with selected micro-organisms mycophenolic acid (1) has been found to undergo one or more of the following transformations: (a) oxygenation of the 4-methyl group giving an alcohol (5) and an aldehyde (6). ( 6 ) oxygenation of the 3'-methyl group and lactonisation giving a S-lactone (31). (c) oxidation at C-3 giving a lactol (3). ( d ) loss of the double bond and oxidation at C -4 , giving a P-hydroxy-acid (1 8). a methyl ketone (1 4). a carboxylic acid (1 0). and, by further hydroxylation, a lactol (1 l ) , a benzyl alcohol (1 2). and a dihydrobenzofuran (29), (e) oxygenation of the double bond giving a hydroxy-lactone (21). ( f ) oxygenation and cyclisation of the terpenoid substituent giving dihydrobenzofurans (26) and ( 28). (g) oxidative cyclisation of the terpenoid substituent giving a chromen (30). and ( h ) combination of the carboxy-group with the amino-groups of glycine and alanine giving amides (1 5) and (1 6). Lactones (20) and ( 22) and diphenylmethane (32) were also obtained from mycophenolic acid fermentations but these compounds may have been artefacts generated during work-up.Fermentations of mycophenolic acid methyl ether (21 and of comlsound (9) gave the benzyl alcohols (7) and (5) respectively, and fermenta'tions of dihydromycophenolic acid gave compounds (1 0). (1 l ) , and (29). The structures of the fermentation products have been established by spectroscopic methods and most of the compounds have been chemically related to mycophenolic acid. The biogenesis of the fermentation products is discussed and some preparations of cyclic ethers from mycophenolic acid derivatives are described.MYCOPHENOLIC ACID (l), a metabolite of several species of Peaicillium, was first isolated in 1896.1 Structure (1) was suggested in 1952 and confirmed in 1957. A total synthesis was reported in 1969. Recently mycophenolic acid has been shown to possess anti-tumour properties. As a way of making analogues of this compound for evaluation as anti-tumour drugs we have investigated its transformation by micro-organisms. More than five hundred micro-organisms, including fungi, yeasts, bacteria, streptomycetes, algae, and protozoa, were examined. Twenty-one micro-organisms modified mycophenolic acid, giving the products listed in Table 1. Compounds (21) and (30) had previously been obtained from a mycophenolic acid-producing strain of Pefiicillium brevicom$actum.Attention was concentrated initially on transformation products which retained the phenolic hydroxy-group, and material having the appropriate RP value was assumed to be unchanged substrate. Consequently it is possible that compound (10), whose cl~romatographic

Microbial transformations of natural antitumor agents: conversion of lapachol to dehydro-alpha-lapachone by Curvularia lunata

“…(iii) An intramolecular attack of an intermediate side-chain epoxide followed by dehydration could occur to provide (2). This would be similar to the mechanism suggested for the formation of a chromene ring with mycophenolic acid (4,10).…”

Synthesis and antimicrobial activity of amino acid and peptide derivatives of mycophenolic acid

“…According to research in molecular modeling, polar group at the end of the side chain of MPA 1 interacts with Ser 276 of IMPDH and is one of the crucial factors for maintenance of its activity [7]. In literature were reported amide MPA analogs bearing glycine [22e24] alanine [22] valine, glutamic acid, leucine and phenylalanine [3] moieties as potential anticancer and immunosupressive agents. In order to obtain an amide bond between the MPA molecule and the amino acid, a very large amount of condensing agents was checked, for example: 2-ethoxy-1-ethoxycarbonyl-1,2dihydroquinoline (EEDQ) with pyridine, N,N 0 -dicyclohexylcarbodiimide (DCC) with NMM O-(Benzotriazol-1-yl)-N,N,N 0 ,N 0tetramethyluronium hexafluorophosphate (HBTU) with N-methylomorpholine (NMM) or method of mixed anhydrides (isobutyl chloroformate).…”

“…d ppm: 10.04, 14.99,18.97 (g-T4),22.59,24.65 (g-K4), 28.43 (g-P4),29.22 (g-R4),31.05 (b-R3),33.94 (d-K5), 35.05 (b-P3), 38.65 (b-K3), 40.53, 42.17, 42.78 (ε-K6), 48.47 (d-R5), 50.77 (d-P5), 51,47 (a-R2), 53.28 (OCH 3 ), 56.93 (a-K2), 57.81 (a-T2), 60.11 (a-P2), 60.15, 66.99 (b-T3), 69.33, 106.38, 122.41, 123.16, 133.57, 145.29, 159.56, 163.41, 171, 171.13 (T1), 172.56 (P1), 172.97 (K1), 173.25 (R1), 174.23 (G1); MS m/z calculated for C 41 H 62 N 10 O 14 918.99; found 919.45 M þ . , 42.151, 46.868 (ε-K6), 48.33 (d-R5), 50.85 (d-P5), 51.80 (a-R2), 53.29 (OCH 3 ), 56.93 (a-K2), 57.81 (a-T2), 60.18, 67.01 (b-T3), 69.37, 106.37, 116.03, 122.37, 123.12, 133.63, 145.31, 159.56, 163.42, 170.96, 170.99 (T1), 172.51 (P1), 172.98, 173.26 (K1), 174.24 (R1, bA1); MS m/z calculated for C 42 H 64 N 10 O 14 933.02; found 933.47 M þ .…”

Bioactive Natural Products from the Marine-Derived Penicillium brevicompactum OUCMDZ-4920

“…143～ 144 ℃ (lit. [17] 142 ～ 144 ℃ ); 1 Norpestaphthalide A (6): 白 色 无 定 型 固 体 , m.p. 206～208 ℃ (lit.…”