Mevalonic acid analogs

Folkers and associates [302] have prepared a number of mevalonic acid analogs. Only one compound, 3,5-dihydroxy-2,3-dimethylpentanoic acid, (CXVII) could be considered as an active metabohte, inasmuch as it inhibited mevalonic acid for growth support of L. acidophilus. All of the analogs prepared by this group gave negative results in tests on the incorporation of acetate into cholesterol by rat liver homogenate. 

Careful interpretation of an unexpected biological activity led to the discovery in the Ayerst Laboratories of a totally new type of hypocholesterolemic agent. Humber and co-workers [337] were engaged in the exploration of mevalonic acid analogs as potential inhibitors of cholesterol biosynthesis and, as a result, made use of the known technique of purification of their oily acids via their crystalline salts with iV,iV -dibenzylethylenediamine (CXLVI). In due course it was discovered that some of the new acids were only active in salt form. Indeed, the dihydrochloride of the base CXLVI was found to inhibit the incorporation of mevalonic acid into cholesterol by rat liver homogenates at a concentration of 1X moles [338]. This observation led to the synthesis of a great number of diamines. A dramatic increase in the hypocholesterolemic activity was observed with compounds containing the rans-l,4-cyclohexane-bis(methylamine) moiety. Subsequent chemical modifications led to the development of r iws-l,4-bis(2-chlorobenzylaminomethyl)-cyclohexane, AY-9944 (CXLVII) [339, 340]. 

The introduction to Section 26 8 pointed out that mevalonic acid is the biosynthetic pre cursor of isopentenyl pyrophosphate The early steps m the biosynthesis of mevalonate from three molecules of acetic acid are analogous to those m fatty acid biosynthesis (Sec tion 26 3) except that they do not involve acyl earner protein Thus the reaction of acetyl coenzyme A with malonyl coenzyme A yields a molecule of acetoacetyl coenzyme A... 

Jemal, M., Schuster, A., and Whigan, D. B. (2003). Liquid chromatography/tandem mass spectrometry methods for quantitation of mevalonic acid in human plasma and urine method validation, demonstration of using a surrogate analyte, and demonstration of unacceptable matrix effect in spite of use of a stable isotope analog internal standard. Rapid Commun. Mass Spectrom. 17, 1723-1734. 

Biological activities of structures similar to mevalonate can be found in WOMBAT. The closest similar molecule is in series 1062, which is (according to the paper it was published in) a novel thiol-containing citric acid analog (Figure 10.8 [53]). It has a measured Ki value that can be compared to other molecules in the series. The figure in bold indicates the common pattern for the majority of compounds in this series. 

In Box 10.12 we saw that nature employs a Claisen reaction between two molecules of acetyl-CoA to form acetoacetyl-CoA as the first step in the biosynthesis of mevalonic acid and subsequenfiy cholesterol. This was a direct analogy for the Claisen reaction between two molecules of ethyl acetate. In fact, in nature, the formation of acetoacetyl-CoA by this particular reaction using the enolate anion from acetyl-CoA is pretty rare. 

Unexpected results have come to light bearing on monoterpenoid biosynthesis (Chapter 1). Banthorpe s group have shown that in the formation of the thujane and camphor skeletons, activity from labelled mevalonic acid can appear predominantly in the C5 unit supposedly derived from isopentenyl pyrophosphate and only to a minor extent in the dimethylallyl pyrophosphate-derived portion. Banthorpe has also presented evidence for a chrysanthemyl intermediate, analogous to presqualene alcohol, in the biosynthesis of artemesia ketone. 

It is possible that an analogous intermediate is involved in phytoene (8) biosynthesis. However, instead of a reductive elimination of pyrophosphate, as in squalene biosynthesis, the 15(15 )-double bond must be derived by elimination. Goodwin and co-workers have shown that both protons of this double bond are labelled by [2- C,3R,5R- H]mevalonic acid. Porter and co-workers have studied the kinetics of an enzyme system from tomatoes for the conversion of geranyl geranyl pyrophosphate (6 n = 3) into phytoene. 

Fig. 5. Analogs that inhibit HMG-CoA reductase. A, mevalonic acid B, compactin C, mevinolin D, mevalonolactone derivatives.

Figure 11-6 represents a simplified analogy mechanism of action for a lovastatin-type drug. 3-Hydroxy-3-methylglutaryl-CoA is reduced to mevalonic acid in two steps, catalyzed by HMG-CoA reductase. It may be suggested that a hypothetical, partially reduced intermediate (in brackets) is reversibly displaced from an assumed enzyme-bound complex by a dihydroxy acid form of lovastatin (derived by hydrolysis of lactone portion of the... 

The biosynthesis of the juvenile hormones is not yet fully known. Their similarity to famesol, an intermediate product in the biosynthesis of steroles in mammals, leads one to assume that their formation is analogous to that of farnesol. This obvious assumption seems to be supported by publications that have appeared in the early 1970s. Barnes and Goodfellow (1971) showed that isoprenoid biosynthesis in the larva of Sarcophaga bullata proceeds with the participation of mevalonate kinase. This enzyme regulates the formation of mevalonic acid pyrophosphate, an important intermediate product in steroid biosynthesis of mammals. Isopentenyl pyrophosphate, the C, unit of isoprenoid biosynthesis, is formed from mevalonic acid pyrophosphate by decarboxylation and, with the participation of ATP, by dehydration. 

Schmialek (1963) obtained radioactive farnesol and famesal from silkworm moth treated with [2- ]-mevalonic acid. The experiments of Sridhara and Bhat (1965), Happ and Mainwald (1966), Karlson (1970), Meyer et al. (1970) also prove that isoprenoid biosynthesis in insects proceeds via mevalonic acid as intermediate product, i.e. it is analogous to the early stages of mammalian steroid biosynthesis prior to the formation of the sterane skeleton. Early intermediates include acetate (Schooley et al.. 1973), acetyl-CoA (Baker and Schooley, 1978), (3S)-HMG-CoA (Bergot et al., 1979) and (3/ )-mevalonate (Schooley et al., 1973 Lee et al., 1978 Feyereisen et al., 1981). 

In an analogous manner, a carboxyl group may also be transferred to propionyl-CoA (for the biosynthesis of branched or odd-numbered fatty acids, isoleucine synthesis, or cholesterol metabolism) or to 3-methylcrotonyl-CoA (a degradation product of leucine after addition of water, there results hydroxymethyl-glutaryl-CoA, the precursor of mevalonic acid cf. section 7.1.2). [117] Oxaloacetic acid is derived from pyruvate, which is of central importance for gluco-neogenesis. [108] In addition, biotin participates also in the transfer of carboxylic acid functions. In prokaryotes, biotin functions as a cofactor for decarboxylases (Tab. 7.6). 

Condensation of mevalolactone with 8-alanine furnished the amide CXXIV, which has been reported to inhibit cholesterol formation in vivo [311]. A derivative of the thiol analog of mevalonic acid (CXXV) has been found to reduce serum cholesterol levels in the hypercholesterolemic rat at high doses [312]. Cysteine bearing a 5-carbon residue, (CXXVI) has been isolated from cat urine and named fehnine [313]. It has been speculated that felinine may be a normal product of mammalian metabolism and participates in the transfer of Cg isoprene units in the biosynthesis of sterols [313]. Felinine has been synthesized by Trippett [314], Eggerer [315], and more recently by Schoeberl et al. [316]. 

Most of the compounds among the unsaturated sesquiterpenoid derivatives investigated as inhibitors of cholesterol biosynthesis can be classified as farnesinic acid analogs. Farnesinic acid itself (CXXXVIII) has been found to inhibit incorporation of mevalonic acid into cholesterol when tested in rat liver homogenates [329]. Catal3d ic reduction of farnesinic acid furnished the saturated acid... 

CXXXIX which has been found to be a potent inhibitor of mevalonic kinase [330]. Three analogs of famesinic acid, compounds CXL-CXLII, have been prepared in the Merck Laboratories [331, 332] and tested by Popjak and his associates [333]. The ethyl analog of famesinic acid (CXLIII) has been found to reduce serum and Hver concentration of cholesterol in the rat [334]. Bolhofer has prepared the famesinic acid analogs CXLIV [335] and CXLV [336] which have been reported to inhibit the biosynthesis of cholesterol in liver homogenates and as such are claimed to be useful in the treatment of arteriosclerosis. 

Groger et al. (1963) have shown that in Ipomoea rubro-caerulea producing ergot alkaloids chanoclavine-I, lysergic acid amide, 2-hydroxylysergic acid amide, and 2-hydroxyisolysergic acid amide, tryptophan and mevalonic acid were their precursors analogously as in Claviceps. 

In addition to steroids, the carotenoids and the various terpenoids are formed by analogous routes in plants and microorganisms. The side chains of the lipoid quinones (vitamins E and K, and ubiquinone) also arise in this fashion in some mammalian organisms. Furthermore, many microorganisms can synthesize from mevalonate or similar precursors the C skeleton of the branched-chain amino acids (leucine, valine, isoleucine), which are essential for man. 

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