Mycophenolic acid compound

The active metabolite of this drug is mycophenolic acid (MPA), which inhibits IMPDH, too. MPA is metabolized in vivo by glucuronidation. It has to be noted that its acyl glucuronide inhibits EVDPDH with similar potency compared to the parent compound. 

Even fully substituted aromatic compounds can be prepared utilizing the Mi-chael/Dieckmann strategy. As reported by Covarrubias-Zuniga and coworkers (Scheme 2.32) [67], reaction of the anion of l-allyl-l,3-acetonedicarboxylate (2-138) and the ynal 2-139 afforded the intermediate 2-140 which led to the resorcinol 2-142 with spontaneous aromatization under acidic conditions via 2-141 in an overall yield of 32 %. 2-142 was transformed into mycophenolic acid (2-143) in only a few additional steps [68]. 

Many natural aromatic compounds are produced from the cyclization of poly- -keto chains by enzymic aldol and Claisen reactions. Examples include simple structures like orsellinic acid and phloracetophenone, and more complex highly modified structures of medicinal interest, such as mycophenolic acid, used as an immunosuppressant drug, the antifungal agent griseofulvin, and antibiotics of the tetracycline group, e.g. tetracycline itself. 

Mycophenolate mofetil, a semisynthetic derivative of mycophenolic acid, isolated from the mould PenicilUum glaucum is used in kidney and liver transplant patient. Another newer compound mizoribine is used in kidney transplantation. 

Mycophenolic acid (MPA) was isolated from cultures of Penicillium spp. in 1896 and was purified in 1913. Initially the compound was studied for its antifungal and antibacterial effects and later for its antitumor effects. Many years later, its immunosuppressive activities were recognized and after further developmental work, an ester prodrug mycophenolate mofetil was developed, which was approved by the United States Food and Drug Administration for the prevention of acute renal allograft rejection in 1995 and for heart transplant recipients in 1998. Mycophenolate mofetil is a cytotoxic agent now used for immunosuppressive therapy and is the mofetil ester of MPA, which is the active immunosuppressive agent. 

The initial success with sirolimus has led to the search of sirolimus analogs, Among these are everolimus (a new macrocylic triene derivative), ABT 578, and other antiimmunosuppressive compounds such as mycophenolic acid, cyclosporine, and tacrolimus, which inhibit proliferation via GI arrest and reduce the immune response. Data from animal experiments suggest that oral everolimus administered for one month effectively inhibits NIH (37) however, human trials have not been conducted. 

A very old broad-spectrum compound, mycophenolic acid, first discovered in 1896 and never commercialized as an antibiotic, has recently been developed as a new immunosuppressant. Its morpholinoethylester is the commercial immunosuppressant molecule. Mycophenolic acid was isolated in the crystalline state in 1896 by Gosio and was the first pure compound to show antibiotic activity. This product of Penicillium glaucum was shown to inhibit the growth of Bacillus anthracis and was then forgotten, until rediscovered in 1913 and given its name. Before being developed into an approved immimosuppressant, mycophenolic acid was used to treat psoriasis. 

Fungizone (Amphotericin B) stock 250 pg/mL, sterilize by filtration. Mycophenolic acid stock 500 pg/mL in phosphate-buffered saline see Step 39 below), neutralize with NaOH, sterilize by filtration. Note that this compound is toxic. 

Jones conditions), aqueous acid, and mild Lewis acids.The Boc group is usually removed by treatment with aqueous HCll or with anhydrous trifluoroacetic acid. In Lai s synthesis of indole analogs of mycophenolic acid, indole derivative 143 was converted to the N-Boc compound (144) using Boc anhydride. Elaboration of the side chain in three steps was followed by deprotection with HCl in dioxane, giving 145 in 72% yield. Trifluoroacetic acid in dichloromethane converted 145 to 146 in 60% yield. 

Two further natural product-derived immunosuppressants have been introduced recently, mycophenclate scdium and everclimus (Fig. 1.7) (44). The active principle of both mycophenolate sodium and an earlier introduced form, mycophenolate mofetil (a morpholinoethyl derivative), is mycophenolic acid, obtained from several Penicillium sp. This compound is a reversible inhibitor of inosine monophosphate dehydrogenase, which is involved in guanosine nucleotide synthesis (80). 

Dr. Gene Ford identified a third fungus, EMIBD, as a Penicillium sp., most likely P. brevicompactum. When grown in mycological broth (21 days, unshaken) and harvested as described above, the methylene chloride extract of the filtrate was active against Candida albicans. When this extract was chromatographed on Sephadex LH-20 size exclusion gel (chloroform/methanol, 1 1) thirteen fractions eluted. All of the antifungal activity resided in fractions 6 and 7. Crystals in fraction 6 were removed by filtration. The crystalline compound was spectroscopically identical to mycophenolic acid (23) which was first identified over 50 years ago as the... 

Mycophenolic acid was synthesized by a three-component coupling between the lactone 26, isoprene and dimethyl malonate (Eq. (23)) [47]. The reaction proceeds by the usual mechanism, with oxidative addition of the aryl halide to Pd(0) and subsequent insertion of isoprene into the Pd-aryl bond to give a t-allyl complex followed by nudeophilic attack by the malonate carbanion. Compound 27 was subsequently transformed to mycophenolic add. 

Immunosuppressive Agents - The immunosuppressive activity of a variety of structural types including purine nucleosides, " DIG, BIC compounds that complex with DNA, benzimidazoleureas, mycophenolic acid, alanosine, " i.-asparaginase, ... 

L-5178Y cells and a number of micro-organisms. Its acute toxicity is low a dose of 2000 mg/kg injected i.p. into mice is tolerated by the animals. Recent studies have suggested that the activity of this compound results from in situ hydrolysis of the drug by j -glucuronidase to mycophenolic acid [221a]. 

The phthalide structure of mycophenolic acid ]88] and phthalideisoquinoline alkaloids [89] were constructed by intramolecular alkoxycarbonylation of substituted 2-bromobenzyl alcohols as substrates. Similar compounds were obtained by employing in situ generated carbon monoxide obtained from solid Mo(CO)6 under micro-wave irradiation [90]. 

The formation of mycophenolic acid and fuscin (Fig. 17) invokes s5mthesis from an acetate-polymalonate route, coupled to biological isopentenylation by mevalonic acid-related compounds, and thus exemplify the build up of natural... 

Mycophenolate mofetil (CdlCept), in conjunction with cyclosporine and corticosteroids, has clinical applications in the prevention of organ rejection in patients receiving allogeneic renal and cardiac transplants. By effectively inhibiting de novo purine synthesis, it can impair the proliferation of both T and B lymphocytes. Following oral administration, mycophenolate mofetil is almost completely absorbed from the GI tract, metabolized in the liver first to the active compound my-cophenolic acid, and then further metabolized to an inactive glucuronide. 

This compound has been synthesised by condensing methyl mycophenolate with methyl(tri-0-acetyl-a-D-glucopyranosyl bromide)-uronate, and hydrolysing the product [221, 221a]. The compound shows significant activity against Ehrlich solid tumour, but is without effect on nucleic acid synthesis of... 

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