Synthesis of Stable Analogues of Geranylgeranyl Diphosphate Possessing a (Z,E,E)‐Geranylgeranyl Side Chain, Docking Analysis, and Biological Assays for Prenyl Protein Transferase Inhibition

Abstract

Herein, we report the synthesis of novel stable analogues of geranylgeranyl diphosphate (GGPP), in which the "natural" all-trans geranylgeranyl portion has been replaced by a (Z,E,E)-geranylgeranyl chain. The change in configuration and consequent change in the relative position of the polar portion with the lipophilic side chain did not improve the properties of the E,E,E analogues in their inhibition of geranylgeranyl protein transferase I (GGTase I). However, a significant level of GGTase I inhibition and selectivity for GGTase I over farnesyl transferase (FTase) was maintained the unsubstituted phosphonoacetamidoxy derivative 4 a. This has shed light on the relative importance of the configuration at the C2=C3 double bond among GGPP derivatives. Moreover, the biological activities of all the compounds reported herein, in particular the preferential FTase inhibitory activity shown by compound 6, were in good agreement with the results of docking analysis.

Engineering Production of a Novel Diterpene Synthase Precursor in Nicotiana benthamiana

“…Research has shown that a mutated triterpene synthase actually prefers this double-oxygenated substrate to the normal 2,3-oxidosqualene, leading to the production of unusual triterpenes that incorporate an additional oxygen atom in the fifth ring ( Salmon et al, 2016 ). There are also examples of synthetic chemistry work focusing on obtaining analogues of the sesquiterpene precursor farnesyl pyrophosphate ( Dolence and Dale Poulter, 1996 ; Placzek and Gibbs, 2011 ) or even (Z,E,E)-geranylgeranyl pyrophosphate ( Minutolo et al, 2006 ), demonstrating the interest of alternative substrates for terpenoid production.…”

The Kabachnik–Fields and Pudovik Reactions on the Basis of E,Z‐Citral and Its Imines and (R,S)‐Citronellal

“…The native isoprenoids and their phosphorylated derivatives such as geranyl pyrophosphate, geranylgeranic acid amides, and methyl ether of farnesylacetic acid have been reported to possess metabolic regulation activity such as antiulcering, gastritis‐ and wound‐healing, lowering blood pressure, antithrombic, and antiplatelet aggregation activities . Phosphorylated isoprenoid derivatives are expected to be a prospective class of nontoxic bioregulators for creating of new drugs .…”

The Synthesis of Malonganenone Analogues for Antiparasitic Structure-Activity Relationship Analyses

“…74,75 The terpenoid bromides are prone to degradation over time but storage at -20 °C slows down this process. 76,77 The cost of the terpenoid alcohols increase with each additional isoprenoid unit and the use of geranylgeraniol starting material was too expensive for a library of analogues. A significantly cheaper alternative was geranyllinalool, where 10-fold more was available in comparison to geranylgeraniol for the same cost.…”

“…62 Only one example of non-selective terpenoid alkylation of adenine (28) was found in the literature. Alkylation of 28 with three equivalents of geranyl bromide gave a trialkylated product (76), with two geranyl chains at N-6 and one at N-9 (Scheme 2.8). 83 The use of less terpenoid bromide could yield monoalkylated products.…”

“…88,89 First, the phthalimide intermediate must be synthesised, which has previously been achieved by reaction of potassium phthalimide and terpenoid halide in DMF or THF at room temperature. 90 The use of the terpenoid halides based on geranyl, 90 farnesyl, 91,92 and geranylgeranyl 76,93 frameworks have already been established in Gabriel syntheses. Alternatively, terpenoid phthalimides could be synthesised in a Mitsunobu reaction between the terpenoid alcohol and phthalimide with diethyl azodicarboxylate in the presence of triphenylphosphine.…”