Inhibition of squalene synthetase by farnesyl pyrophosphate analogs

Abstract

The pyrophosphates of the following farnesol analogues have been synthesized: 2-methylfarnesol; 7,11-dimethyl-3-ethyl-2,6,10-dodecatrien-1-ol; 3-demethylfarnesol; 4-methylthiofarnesol; 7,11-dimethyl-3-iodo-2,6,10-dodecatrien-1-ol; 7,11-dimethyl02-iodo-2,6,10-dodecatrien-1-ol; 7,11-dimethyldodeca-6,10-dien-2-yn-1-ol; phytol; 3,7,11-trimethyl-2-dodecen-1-ol; 3,7,11-trimethyldodecan-1-ol; and geraniol. The double bonds in all the above compounds were in the E configuration, except phytol, which was a 7:3 mixture of 2E and 2Z isomers. Each of the pyrophosphates inhibits the incorporation of labeled farnesyl pyrophosphate into squalene by a yeast enzyme preparation. Free alcohols and monophosphates are inactive. The analogues, listed in order of decreasing inhibitory strength, are, by kinetic analysis, competitive or mixed inhibitors. Irreversible inhibition is not observed. The results suggest that binding to the enzyme is primarily mediated by the pyrophosphate moiety assisted by relatively nonspecific lipophilic interactions. Decreasing the chain length and saturating double bonds severely reduces binding, while substitution at the 2,3, and 4 positions, and lengthening of the chain, is well tolerated.

Structure-Activity Relationships of C1 and C6 Side Chains of Zaragozic Acid A Derivatives

“…Substrate analogues of FPP have been investigated as squalene synthase inhibitors.4-6 A series of isoprenoid (phosphinylmethyl)phosphonates were prepared, and the most potent derivative was reported to have an IC50 value of 50 nM (K 37 nM, a competitive inhibitor with respect to FPP).5 Putative transition-state analogues such as presqualene phosphonophosphates,7 ammonium8 and sulfonium9 analogues of presqualene pyrophosphate, prenyl-substituted cyclobutanones,10 and a series of amphiphilic polyisoprenoid compounds11 were also investigated as squalene synthase inhibitors, but only modest activities were observed. A series of A-(arylalkyl)famesylamines were investigated as squalene synthase inhibitors.12 The most active compound in this series was lV- (3-pyridylmethyl)farnesylamine, which had an IC50 value of 4 nM when tested in the presence of added inorganic pyrophosphate (PPi). Recently, bisphosphonates such as YM 175 (cycloheptylaminomethylene-l,l-bisphosphonic acid)13 and a number of lipophilic 1,1-bisphophonates14 were reported to be potent squalene synthase inhibitors.…”

Zaragozic Acids D and D2: Potent Inhibitors of Squalene Synthase and of Ras Farnesyl-Protein Transferase

“…The search for natural product inhibitors of squalene synthase has resulted in the discovery of the zaragozic acids (6)(7)(8)(9)(10)(11). Zaragozic acids A [1] (6,8,10,11), B [2] (6,9,10), and C [3] (6,7) are potent inhibitors of squalene synthase and most likely act by mimicking presqualene pyrophosphate (6,7). Squalestatin, a compound identical to 1, has also recently been reported (12)(13)(14)(15).…”

The Squalestatins: Novel Inhibitors of Squalene Synthase. Enzyme Inhibitory Activities and in vivo Evaluation of C1-Modified Analogs

“…However, SAR for famesyl diphosphate mimetics have indicated the critical dependence of inhibitory activity on the presence of the double bonds in the farnesyl chain. 20 The loss of inhibitory activity in the cyclohexyl analogue (2f) may be analogous to the 10fold reduction in SQS inhibitory activity observed for Significant homology exists between the rat and fungal enzymes,22 and the inhibitory activities of the squalestatin analogues listed in Table 1 against the fungal enzyme closely resemble those for the rat enzyme. The squalestatin HI analogues tested are devoid of significant whole cell antifungal activity, whereas the analogues possessing the C6 dimethyloctenoate/dimethyloctanoate ester groups are good antifungal agents.…”