Stereochemistry‐dependent inhibition of RAS farnesylation by farnesyl phosphonic acids

Abstract

This investigation compares the effects of three farnesyl pyrophosphate analogs on selected aspects of isoprenoid metabolism. E,E-alpha-Hydroxyfarnesylphosphonate was prepared by an improved variation on a literature synthesis, which also gave access to the new Z,E-alpha-hydroxyfarnesyl- and alpha-hydroxygeranylphosphonates. A striking find is that only E,E-alpha-hydroxyfarnesylphosphonate induces alteration of RAS processing in intact human-derived leukemia cells and inhibits farnesyl protein transferase in enzyme assays, while the Z,E-alpha-farnesyl- and geranylphosphonates are inactive. The inhibitory activity of E,E-alpha-hydroxyfarnesylphosphonate is greater in enzyme than intact cell assays. This active compound does not significantly inhibit geranylgeranyl protein transferase I or squalene synthase, nor does it diminish cholesterol synthesis. These results indicate that the length of the terpenoid chain and olefin stereochemistry allow selective inhibition of critical enzymes of terpenoid metabolism. Discrimination was observed between inhibition of farnesyl protein transferase and squalene synthase by E,E-alpha-hydroxyfarnesylphosphonate, even though both enzymes utilize farnesyl pyrophosphate as their natural substrate.

Amido rare-earth complexes supported by an ansa bis(amidinate) ligand with a rigid 1,8-naphthalene linker: synthesis, structures and catalytic activity in rac-lactide polymerization and hydrophosphonylation of carbonyl compounds

“…The catalytic hydrophosphonylation of aldehydes, ketones and imines is a straightforward and atom-economic method for the formation of P-C bonds, which allows for the synthesis of a-amino and a-hydroxy phosphonic acids possessing important biological activities. [77][78][79][80][81][82][83][84][85] The amido complexes 2-4 were tested as catalysts for hydrophosphonylation of aldehydes and ketones (Scheme 3). The reactions of aldehydes with diethyl phosphite (1 : 1 molar ratio) were carried out at 25 1C in the presence of 1 mol% of complexes 2-4.…”

Non-Peptidic Prenyltransferase Inhibitors: Diverse Structural Classes and Surprising Anti-Cancer Mechanisms

“…Despite this toxicity, the Merck group was able to use HFP to provide some of the first evidence of selective inhibition of Ras processing by an FTI in cells [135]. Hohl, Wiemer and their coworkers have recently reported additional SAR and biological selectivity studies on HFP and related analogues [136]. They have demonstrated that HFP is a relatively poor squalene synthase inhibitor, and in accord with this it does not significantly affect cholesterol biosynthesis in whole cells.…”

Self-condensation reactions of acyl phosphonates: synthesis of tertiary $O$-protected $\alpha $-hydroxyphosphonates

“…Hydroxy phosphonic acids and their ester derivatives have gained considerable attention due to their inhibitory activity towards various important groups of enzymes. For example, they have inhibitory effects on renin, 1,2 HIV protease, 3 farnesyl protein transferase, 4,5 (FPTase), and 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase. 6 Many hydroxy phosphonic acid derivatives have also been reported to have a broad range of biological activities such as antiviral, 7 antitumor, 8,9 and antibiotic properties.…”