Synthesis of Analogues of (E)-1-Hydroxy-2-methylbut-2-enyl 4-Diphosphate, an Isoprenoid Precursor and Human γδ T Cell Activator

Abstract

Abstract:(E)-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate (HMBPP) is an intermediate in the nonmevalonate pathway for the biosynthesis of isoprenoids and also serves as a very strong activator of human  T cells expressing V9/V2 receptors. This paper describes the synthesis of analogues of HMBPP, in which the diphosphate group is replaced by potential isosteric moieties, i.e. carbamate, N-acyl-N'-oxy sulfamate or aminosulfonyl carbamate functionalities. The potential of the synthesized analogues to stimulate V9/V2 T cell response or to inhibit GcpE and LytB, the last enzymes in the non-mevalonate pathway was assessed.

Design and synthesis of screening libraries based on the muurolane natural product scaffold

“…Therefore, we decided to use the allylic hydroxyl group of 1 in reactions with commercially available isocyanates to generate a library of carbamates. 30 In an identical manner to the amide library, a virtual collection of potential carbamates was initially generated using the software Reactor 40 and Instant JChem 41 coupled with a list of commercially available isocyanates (315 in total). 39 Analysis of the in silico physicochemical properties (MW, HBD, HBA, Log P, Log D5.5) of the virtual library 45 identified those members that were compliant with drug-like properties.…”

Bioorganometallic Chemistry with IspG and IspH: Structure, Function, and Inhibition of the [Fe4S4] Proteins Involved in Isoprenoid Biosynthesis

“…Substrate analogues that bind to IspG or IspH but cannot be turned over could be potent inhibitors of interest as new anti‐infective drug leads and herbicides. Replacement of the diphosphate group with carbamate (compounds 14 ), N ‐acyl‐ N ′‐oxysulfamate (compounds 15 ), or aminosulfonyl carbamate groups (compounds 16 ; Scheme ) resulted in only weak inhibitory effects against IspH or IspG 84. The substitution of the diphosphate group also abolished the ability of these compounds to activate human Vγ2Vδ2 T cells ( 4 is an activator at ca.…”

Inhibition of the Fe4S4-Cluster-Containing Protein IspH (LytB): Electron Paramagnetic Resonance, Metallacycles, and Mechanisms

“…The Fe 4 S 4 cluster, while catalytically active, is thus relatively labile, as also found for example in aconitase and in pyruvate-formate lyase activating enzyme 12. To date, there has been only one report of IspH inhibitors,13 with IC 50 values of ~1–2 mM having been obtained. Here, we report progress aimed at obtaining more potent inhibitors.…”