Mycophenolic Acid

Mycophenolic acid (Figure 3.36) is produced by fermentation cultures of the fungus Pénicillium brevicompactum. It has been known for many years to have antibacterial, antifungal, antiviral, and antitumour properties. It has recently been introduced into medicine as an immunosuppressant drug, to reduce the incidence of rejection of transplanted organs, particularly kidney and heart transplants. It is formulated as the N-morpholinoethyl ester mycophenolate mofetil (Figure 3.37), which is metabolized after ingestion to mycophenolic

mycophenolate mofetil

Figure 3.37

mycophenolate mofetil

Figure 3.37

acid, and is usually administered in combination with cyclosporin (see page 429). The drug is a specific inhibitor of mammalian inosine monophosphate dehydrogenase and has an antiproliferative activity on cells due to inhibition of guanosine nucleotide biosynthesis. This enzyme catalyses the NAD+-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), a key transformation in the synthesis of guanosine triphosphate (GTP) (see also caffeine biosynthesis, page 394). Rapidly growing cells have increased levels of the enzyme, so this forms an attractive target for anticancer, antiviral, and immunosuppressive therapy.

SEnz

aldol reaction, aromatization

SEnz aldol reaction, aromatization

SEnz

"YY

HO2C

citrinin dehydration leads to quinone formation

reduction

citrinin

Figure 3.38

reduction i OH H

reduction i OH H

OH COH formati°n o OH 0

Figure 3.38

of-chain carboxyl. The chain length of the far-nesyl alkyl group is then shortened by oxidation of a double bond giving demethylmycophenolic acid, which is then O-methylated, again involving SAM, to produce mycophenolic acid. Note that the O-methylation step only occurs after the C-alkylations, so that the full activating benefit of two meta positioned phenols can be utilized for the C-alkylation.

Three C-methyl substituents are inserted into the acetate-derived skeleton of citrinin (Figure 3.38), an antimicrobial metabolite from Pénicillium citrinum and several Aspergillus species, which also displays potentially dangerous carcinogenic and nephrotoxic (kidney-damaging) activity. <ne of these introduced methyls has undergone oxidation to a carboxyl, adding to the difficulties in immediately recognizing the biosynthetic origins of this compound which contains a quinonemethide system rather than the simpler aromatic ring. The methyls are probably introduced into the polyketide prior to release of the first aromatic intermediate, which could well be an aldehyde rather than the corresponding acid if a reductase component also forms part of the synthase complex. The hemiacetal can be produced after reduction of the side-chain carbonyl, and then in the later stages, oxidation of one methyl to a carboxyl will follow. The quinonemethide system in citrinin is simply the result of a dehydration reaction on the hemiacetal (Figure 3.38).

Khellin* and visnagin (Figure 3.39) are furochromones found in the fruits of Ammi visnaga (Umbelliferae/Apiaceae), and the active principles of a crude plant drug which has a long history of use as an antiasthmatic agent. Figure 3.39 presents the sequence of steps utilized in the biosynthesis of these compounds, fully consistent with the biosynthetic rationale developed above. The two carbons C-2' and C-3' forming part of the furan

Claisen reaction, aromatization heterocyclic ring formation via Michael-type nucleophilic attack (+)

of OH on to enol tautomer followed by loss of leaving group H

SEnz O*

SEnz O*

OH O

OH OH

OH O

OH OH

OH O

OH O

oxidative cleavage of side-chain: see furocoumarins Figure 4.35

OMe O visnagin cyclization of hydroxyl on to dimethylallyl group: see furocoumarins Figures 4.33 and 4.34

OH O

OMe O khellin

OH O

OH O

C-alkylation with DMAPP

Biosynthesis Khelline

OMe O visnagin

OH O

OMe O khellin

DMAPP

DMAPP

OH O

OH O

5,7-dihydroxy-2-methylchromone

Figure 3.39

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