Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid.

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Nelson PH, Eugui E, Wang CC, Allison AC

Synthesis and immunosuppressive activity of some side-chain variants of mycophenolic acid.

J Med Chem. 1990 Feb;33(2):833-8.

PubMed ID

1967654 [ View in PubMed

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Abstract

The syntheses and immunosuppressive bioassays of 12 side-chain variants of mycophenolic acid are described. The compounds were made either from mycophenolic acid itself or from 5-(chloromethyl)-1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisoben zofuran, a versatile intermediate for the synthesis of diverse side-chain variants. Replacement of the methylated E double bond of the natural product with a triple bond, a Z double bond, a saturated bond, or a sulfur atom, with overall chain lengths equal to or greater than that of mycophenolic acid, produced compounds devoid of significant activity. Replacement of the side-chain double bond with difluoro, dibromo, or unsubstituted cyclopropane rings also removed most activity. Replacement of the double bond with an allenic linkage yielded a compound with about one-fifth of the immunosuppressive activity of mycophenolic acid. Some possible causes for the unusual specificity of structure and activity are discussed.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Mycophenolic acid	Inosine-5'-monophosphate dehydrogenase 1	IC 50 (nM)	20	N/A	N/A	Details