Mycophenolic acid, structure

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. 

Essentially the same sort of enolate anion aldol and Claisen reactions occur in the production of the more complex structures mycophenolic acid, griseofulvin, and tetracycline. However, the final structure is only obtained after a series of further modifications. 

Birch, A. J., R. J. English, R. A. Massy-Westropp and H. Smith Studies in relation to biosynthesis, 15. Origin of terpenoid structures in mycelianamide and mycophenolic acid. J. Chem. Soc. 369 (1958). 

In inosine monophosphate dehydrogenase, the monovalent metal ion accelerates the hydride transfer step of the reaction with apparently few other effects on the enzyme structure. Probably the monovalent cation is involved in helping position the nicotinamide cofactor. The active site and location of the potassium ion are shown in Figure 2. Mycophenolic acid in this diagram is an inhibitor that is thought to lock inosine monophosphate into the active site, as shown. Note the large distance between the inhibitor (in the active site) and the K+. 

Although it may be considered as a meroterpenoid (see Chapter 5) mycophenolic acid (4.32) is discussed here because its structure reveals the interaction between polyketides and terpenoids. A metabolite of a Penicillium species, which was probably mycophenolic acid, was first described by Gosic in 1896. It was more firmly characterized by Alsberg and Black in 1913 as a metabolite of... 

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, ... 

Mycophenolic acid (Lla), an antibiotic produced by several species of Penicillia and first isolated seventy years ago [210, 211], has recently been shown to have useful antitumour activity. Its structure was established by chemical means [212], and has been confirmed by synthesis [213a]. Birch reduction of (Lila) followed by rearrangement afforded the diene (LIII), which gave (Lllb) on condensation with dimethyl acetylenedicarboxylate. Selective demethylation of (Lllb) followed by cyclisation furnished the anhydride (Lib). Reduction of the anhydride ring to a y-lactone ring and... 

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]. 

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