Pyrophosphates enzyme inhibitory activity

Compounds of type 135 and 141 have been synthesised as inhibitors of PFT, an enzyme that catalyses the transfer of the farnesyl group from farne-syl pyrophosphate to the cysteine SH in the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. The parent compound 140 (Ar = (2,4,6-trimethylphenyl) is the most active (ED50 10 xM) [44, 45]. This class of compounds has been tested also on mammalian PFTase and some of them showed inhibitory activity. In particular, none of the dihydro derivatives affects the enzyme in a concentration-dependent manner. 

Nucleotidases have been studied in liver from various species and activity has been identified in lysosomes, cytoplasmic supernatants and plasma membrane preparations. Arsenis and Touster (31) have purified a 5 -nucleotidase from rat liver lysosomes to apparent homogeneity. The enzyme is unusual in that it hydrolyzes 2 -, 3 -, and 5 -mononucleotides equally well with preference for 5 -dAMP. It also hydrolyzes FMN, p-nitrophenyl phosphate, and /J-glycerol phosphate, but not inorganic pyrophosphate or bis(p-nitrophenyl) phosphate. Unlike the 5 -nucleotidases described thus far, divalent cations such as Co2+, Mn2+, and Mg2+ have no activating effect, but EDTA is inhibitory. In spite of the broad substrate specificity kinetic experiments indicate that a single enzyme is involved. Because of its broad substrate specificity it has been suggested (SI) that it may play a key role in lysosomal catabolism of nucleic acids. 

Squalene synthase is an enzyme catalyzing the formation of squalene from farnesyl diphosphate which is a committed step in the cholesterol biosynthetic pathway. Therefore, squalene synthase is considered a better target than HMG-CoA reductase because farnesyl pyrophosphate, a downstream product of HMG-CoA reductase, is needed for prenylation of proteins and for the biosyntheses of ubiquinone and dolichol (Fig. 2). Before squalestatins and zaragozic acids were discovered, a number of squalene synthase inhibitors were synthesized that showed respectable inhibitory potencies in vitro, but none were successful in animal testing [41]. It was the discovery of squalestatins and zaragozic acids that renewed interest in this biological target, and at picomolar potencies they were the most active inhibitors of squalene synthase. 

An alternative mechanism of SAB action could involve its known effects on de novo purine biosynthesis (1, S) and/or nucleoside transport (5). The combined inhibitory effects of SAB and purine analogues on purine biosynthesis could result in sufficient depletion of intracellular nucleotide pools to result in enhanced cellular cytotoxicity. In addition, these effects would lead to an increased bioavailability of 5-phosphoribosyl-l-pyrophosphate (PRPP), the first enzymic product in the de novo pathway. Increased PRPP levels would enhance the activity of hypoxanthine phosphoribosyl transferase, leading to increased salvage of purine analogues. 

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