Synthesis and biological evaluation of a monocyclic, fully functional analogue of compactin.
Compound 8, a monocyclic analogue of compactin, has been prepared and its efficacy as an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGR) evaluated. The synthesis (Schemes I and II) requires seven steps starting with di-(-)-menthyl fumarate and employs the useful RR-phosphonate reagent 14 to attach the mevinic acid side chain to aldehyde 13. A molecular mechanics study shows that the preferred conformations of 18 (a model for compactin) and 19 (a model for 8) are nearly identical. Compound 8 inhibits HMGR with IC50 = 320 microM, compared to a corresponding value of 32 nM for the compactin ketone, 5. The factor of 10,000 difference in the two inhibitors corresponds to a difference in binding energy of 5.45 kcal mol-1, or 1.36 kcal mol-1 for each of the four carbons of 5 that are missing in analogue 8. This quantitative difference is consistent with the idea that the decalin moiety of the mevinic acids play a purely hydrophobic role in binding the inhibitors to the enzyme.
Heathcock
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Department of Chemistry, University of California, Berkeley 94720.
Davis
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Hadley
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D055598:Chemical Phenomena; D002621:Chemistry; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007651:Keto Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D003510:Cyclohexanes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007651:Keto Acids; C058117:7-(2'-((2''-methyl-1''-oxobutoxy)methyl)-1'-cyclohexyl)-3-hydroxy-5-oxoheptanoic acid