- A convergent synthesis of mycophenolic acid
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A new method for the synthesis of Mycophenolic acid using a convergent approach has been developed where the key step is a palladium mediated allyl-aryl tin coupling.
- Ple, Patrick A.,Hamon, Annie,Jones, Geraint
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- Design and Catalyzed Activation of Mycophenolic Acid Prodrugs
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Mycophenolic acid (MPA) and its morpholino ester prodrug mycophenolate mofetil (MMF) are widely used in solid organ transplantation. These drugs prevent rejection due to their potent inhibition of inosine-5′-monophosphate dehydrogenase (IMPDH), an enzyme vital for lymphocyte proliferation. As a strategy to provide localized immunosuppression in cell transplantation, four mycophenolic acid prodrugs designed to release MPA by two distinct mechanisms were synthesized and characterized. A nitrobenzyl ether prodrug was effectively converted to MPA upon exposure to bacterial nitroreductase, while a propargyl ether was converted to the active drug by immobilized Pd0 nanoparticles. In vitro, both prodrugs were inactive against IMPDH and exhibited reduced toxicity relative to the active drug, suggesting their potential for providing localized immunosuppression.
- Plunk, Michael A.,Quintana, Jeremy M.,Darden, Carly M.,Lawrence, Michael C.,Naziruddin, Bashoo,Kane, Robert R.
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- Total synthesis of mycophenolic acid by a palladium-catalyzed decarboxylative allylation and biomimetic aromatization sequence
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This paper describes the total synthesis of the fungal natural product mycophenolic acid through palladium-catalyzed allylation, biomimetic cyclization, and aromatization. Methyl (4E)-6-hydroxy-4-methylhex-4-enoate, which was converted in four steps into the key diketo ester dioxinone via two selective C-acylation reactions, was transformed into a resorcylate. Subsequent phenol methylation, lactonization, iodo-ether formation, and halogenation gave a tricyclic intermediate. Palladium-catalyzed cross-coupling with DABCO-(AlMe3)2 and saponification gave mycophenolic acid. An alternative approach with early stage arene methyl incorporation unexpectedly resulted in the formation of a γ-pyrone. A total synthesis of mycophenolic acid was developed. In a one-pot reaction, a diketo ester dioxinone was transformed into a resorcylate by Pd-catalyzed decarboxylative allylation and biomimetic cyclization and aromatization. Methylation, lactonization, iodo-ether formation, and halogenation led to a tricyclic intermediate. Pd-catalyzed cross-coupling and ester hydrolysis completed the synthesis. Copyright
- Brookes, Paul A.,Cordes, Jens,White, Andrew J. P.,Barrett, Anthony G. M.
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- Biotransformations of imbricatolic acid by Aspergillus niger and Rhizopus nigricans cultures
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Microbial transformation of imbricatolic acid (1) by Aspergillus niger afforded 1α-hydroxyimbricatolic acid (2), while transformation with Rhizopus nigricans yielded 15-hydroxy-8,17-epoxylabdan-19-oic acid (3). When the diterpene 1 was added to a Cunninghamella echinulata culture, the main products were the microbial metabolites mycophenolic acid (4) and its 3-hydroxy derivative 5. All the structures were elucidated by spectroscopic methods. The cytotoxicity of these compounds towards human lung fibroblasts and AGS cells was assessed. While 4 and 5 showed low cytotoxicity, with IC50 values > 1000 μM against AGS cells and fibroblasts, 1α-hydroxyimbricatolic acid (2) presented moderate toxicity towards these targets, with IC50 values of 307 and 631 μM, respectively. The structure of 2 is presented for the first time.
- Schmeda-Hirschmann, Guillermo,Aranda, Carlos,Kurina, Marcela,Rodriguez, Jaime A.,Theoduloz, Cristina
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- Method of Synthesis for Mycophenolic Acid and Its Phenylsulfenyl and Phenylseleny Analogues
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The present invention relates to: a method for synthesizing mycophenolic acid and phenylsulfenyl and phenylselenyl derivatives thereof; and novel phenylsulfenyl and phenylselenyl derivative compounds of mycophenolic acid synthesized by the synthesis method. The novel synthesis method of mycophenolic acid of the present invention does not use a protecting group compared to a conventional synthesis method, has a simple reaction step, and has a high yield. Therefore, the synthesis method of the present invention can usefully use mycophenolic acid in a high-yield mass production method.
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- Diels-Alder and Stille Coupling Approach for the Short Protecting-Group-Free Synthesis of Mycophenolic Acid, Its Phenylsulfenyl and Phenylselenyl Analogues, and Reactive Oxygen Species (ROS) Probing Capacity in Water
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A short, protecting-group-free synthesis is achieved. The synthesis is step-efficient and general. A Diels-Alder and Stille cross-coupling approach includes key transformations, allowing for a competitive synthesis which involves a rare halophenol Stille cross-coupling study. The phenylselenyl and phenylsulfenyl analogues were prepared as novel compounds in good overall yield. The applicability of one of the intermediates as a potential probe for reactive oxygen species (ROS) in water is investigated.
- Halle, Mahesh B.,Yudhistira, Tesla,Lee, Woo-Hyun,Mulay, Sandip V.,Churchill, David G.
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supporting information
p. 3557 - 3561
(2018/06/26)
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- Pharmaceutical composition against influenza virus containing s. officinalis l.
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The present invention relates to a pharmaceutical composition against influenza virus. The pharmaceutical composition comprises a therapeutically effective amount of the extract of S. officinalis L., or active compounds obtained from the extract of S. officinalis L., hydrolyzed compounds or pharmaceutically acceptable salts thereof.
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Page/Page column 18
(2018/02/27)
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- Functional characterization of MpaG′, the O-methyltransferase involved in the biosynthesis of mycophenolic acid
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Mycophenolic acid (MPA, 1) is a clinically important immunosuppressant. In this report, a gene cluster mpa′' responsible for the biosynthesis of 1 was identified from Penicillium brevicompactum NRRL 864. The S-adenosyl-L-methionine-dependent (SAM-dependent) O-methyltransferase encoded by the mpaG′ gene was functionally and kinetically characterized in vitro. MpaG′ catalyzes the methylation of demethylmycophenolic acid (DMMPA, 6) to form 1. It also showed significant substrate flexibility by methylating two structural derivatives of 6 prepared by organic synthesis.
- Zhang, Wei,Cao, Shaona,Qiu, Li,Qi, Fengxia,Li, Zhong,Yang, Ying,Huang, Shaohua,Bai, Fali,Liu, Changning,Wan, Xiaobo,Li, Shengying
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p. 565 - 569
(2015/03/30)
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- METHOD FOR THE PURIFICATION OF BIO-MOLECULES
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The present invention provides a method for purifying a compound of interest comprising the steps of: i.) Adjusting the pH of an aqueous mixture comprising biomass and said compound of interest to a value at which the amount of dissolved compound of interest is less than 10% of the total amount of said compound of interest present in said mixture; ii.) Isolating a slurry from the mixture obtained in step i.) by removing at least 40% of the water present in the mixture obtained in step L); iii.) Adjusting the pH of the slurry obtained in step ii.) to a value at which the amount of dissolved compound of interest is more than 90% of the total amount of said compound of interest present in said slurry; iv.) Removing solids from the mixture obtained in step iii.) to give a solution comprising said compound of interest, wherein said removing in steps ii.) and iv.) is carried out with the same means.
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Page/Page column 6-7
(2008/12/08)
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- Process for preparation of mycophenolate mofetil and other esters of mycophenolic acid
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Provided are processes for the preparation of mycophenolate mofetil and other esters of mycophenolic acid.
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Page/Page column 8
(2008/06/13)
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- Total synthesis of mycophenolic acid
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A convergent total synthesis of the natural compound mycophenolic acid 1 is described. The synthetic strategy for the construction of the hexasubstituted aromatic nucleus was based on a ring annulation sequence, involving a Michael addition reaction and intramolecular Dieckmann condensation reaction in situ as the key step. Subsequent transformations of the substituents afforded the target mycophenolic acid 1.
- Covarrubias-Zú?iga, Adrián,Gonzalez-Lucas, Armando,Domínguez, Mireya M.
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p. 1989 - 1994
(2007/10/03)
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- Syntheses of mycophenolic acid and its analogs by palladium methodology
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Syntheses of mycophenolic acid (MPA, 1) and its analogs were carried out using palladium-catalyzed Heck carbonylation and olefination. Thus, the reaction of 2-bromo-3,5-dimethoxybenzyl alcohol (4) in toluene under carbon monoxide at 180 °C in the presence of palladium catalyst using sodium carbonate as a base gave 5,7-dimethoxyphthalide (5) in 88% yield. The phthalide 7 was converted to 6-iodo-5,7-dimethoxy-4-methylphthalide (8). Reaction of aromatic iodide 8 with isoprene and dimethyl malonate in the presence of palladium(0) catalyst gave the three component coupling product 9, which was converted into 1 in three steps. 4-NorMPA (16) and 4-homoMPA (22) were synthesized similarly.
- Lee,Fujiwara,Ujita,Nagatomo,Ohta,Shimizu
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p. 1437 - 1443
(2007/10/03)
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- Synthesis of mycophenolic acid by palladium-catalyzed three component coupling reaction
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Reaction of aromatic iodide 3 with isoprene and dimethyl malonate in the presence of palladium(0) catalyst gave the coupling product 4, which was converted into mycophenolic acid (1) in three steps.
- Shimizu,Lee,Fujiwara
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p. 1285 - 1286
(2007/10/03)
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- A total synthesis of mycophenolic acid
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A total convergent synthesis of mycophenolic acid 1 from 2-geranyl- dimethyl-1,3-acetonedicarboxylate 2 and 4-pivaloyloxy-2-butynal using a Michael addition-Dieckmann cyclization as key step is described.
- Covarrubias-Zuniga, Adrian,Gonzalez-Lucas, Armando
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p. 2881 - 2882
(2007/10/03)
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- Total synthesis of mycophenolic acid
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A total synthesis of mycophenolic acid is reported. Diels-Alder reaction of [5-methoxy-3-(1-methoxypropenyl)-4,5-dihydrofuran-2-yloxy]-trimethylsilane with 3-benzenesulfinyl-5H-furan-2-one afforded the hexasubstituted nucleus. The side chain was constructed from the unveiled aldehyde. A total synthesis of mycophenolic acid is reported. Diels-Alder reaction of [5-methoxy-3-(1-methoxypropenyl)-4, 5-dihydrofuran-2-yloxy]-trimethylsilane with 3-benzenesulfinyl-5H-furan-2-one afforded the hexasubstituted nucleus. The side chain was constructed from the unveiled aldehyde.
- De La Cruz, Ricardo A.,Talamas, Francisco X.,Vazquez, Alfredo,Muchowski, Joseph M.
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p. 641 - 645
(2007/10/03)
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- The synthesis of mycophenolic acid
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A new synthesis of mycophenolic acid 1, has been accomplished using silyloxy-1,3-cyclohexadiene 9 which undergoes cycloaddition to dimethyl acetylenedicarboxylate and subsequent elimination of ethylene (Alder-Rickert reaction) to give the trisubstituted dimethyl phthalate 11. After conversion of 11 to phthalide 16, the (E)-4-methyl-4-hexenoic acid side-chain was constructed via an orthoester Claisen rearrangement using allylic alcohol 19 and triethyl orthoacetate.
- Patterson, John W.
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p. 4789 - 4798
(2007/10/02)
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- The Orthoester Claisen Rearrangement in the Synthesis of Mycophenolic Acid
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The orthoester Claisen rearrangement is used as a key reaction in the facile conversion of an acetaldehyde moiety stereospecifically into the (E)-4-methylhex-4-enoic acid side-chain of mycophenolic acid.
- Patterson, J. W.,Huang, Glenn T.
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p. 1579 - 1580
(2007/10/02)
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- Prodrug derivatives of carboxylic acid drugs
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Novel ester derivatives of carboxylic acid medicaments of formula (I), wherein R--COO--represents the acyloxy residue of a carboxylic acid drug or medicament, n is an integrer from 1 to 3, and R1 and R2 are the same or different and are selected from a group consisting of an alkyl, an alkenyl, an aryl, an aralkyl, a cycloalkyl and which group may be unsubstituted or substituted, or R1 and R2 together with the N forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which heterocyclic group may be substituted. These compounds are highly biolabile prodrug forms of the corresponding carboxylic acid compounds and are highly susceptible to undergoing enzymatic hydrolysis in vivo whereas they are highly stable in aqueous solution. The novel derivatives are less irritating to mucosa than the parent carboxylic acids and may provide an improved bio-availability of the drugs.
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- Effects Various Adsorbents on Mycelium Formation and Mycophenolic Acid Production by Penicillium brevicompactum
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A drug-resistant mutant, No. 4-23-11, which had been derived from Penicillium brevicompactum ATCC 16024, was cultured in a liquid medium for the production of mycophenolic acid (MPA) in the presence and absence of various adsorbents, that is, celites, zeolites, aluminas, talc, silica, charcoals, carbon blacks, natural graphite and carbonaceous mesophase spheres.In the absence of an adsorbent, MPA production (0.2-4.8 g/l) and the size of mycelium pellets (5-0.5 mm) markedly depended on the concentration of spores inoculated (104-107ml), whereas in the presence of one of these adsorbents, small pellets (smaller than 1 mm in diameter) were formed and the high production of MPA (4.5-5.4 g/l) was observed, independently of the spore concentration between approximately 104-107/ml.Microscopic observation of the pellets revealed that numerous particles of the adsorbents adhered to the surface of the hyphae.These results suggest that the adsorbents might interfere with the adhesion of hyphae to each other and thus retard the formation of large pellets.
- Ozaki, Hachiro,Kubota, Koji,Takahashi, Hiroshi
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p. 2503 - 2508
(2007/10/02)
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- Mycophenolic Acid Production by Drug-resistant and Methionine or Glutamic-Acid Requiring Mutants of Penicillium brevicompactum
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Penicillium brevicompactum ATCC 16024 produced 1.7 g/l of mycophenolic acid (MPA) in the culture medium.Various drug-resistant mutants, showing resistance to such as polyene antibiotics, chemotherapeutic agents, redox indicator and surfactants, were derived from the fungus.Most of the mutants produced 2.0-2.5 g/l of MPA.A clofibrate and dodecyltrimethylammonium chloride double resistant mutant, No. 4-23-11, produced 4.7 g/l of MPA.A monofluoracetic acid resistant strain, No. 5-1, derived from No. 4-23-11 produced 5.3 g/l of MPA.A methionine auxotroph, M-1, derived from ATCC 16024, produced 4.0 g/l of MPA.A glutamate auxotroph, G-42, derived from strain No. 4-23-11 produced 5.8 g/l of MPA.G-42 grew on L-aspartate instead of L-glutamate, and showed one-third the pyruvate carboxylase activity of the parent.Another glutamate auxotroph, G-78, did not produce MPA but accumulated 1.5 g/l of acetate in the culture medium, and showed one-fifth the citrate synthase activity of the parent strain.
- Ozaki, Hachiro,Ishihara, Masaru,Kida, Takao,Yamanaka, Shigeru,Shibai, Hiroshiro
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p. 2509 - 2514
(2007/10/02)
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