Queuine Analogues Incorporating the 7‐Aminomethyl‐7‐deazaguanine Core: Structure–Activity Relationships in the Treatment of Experimental Autoimmune Encephalomyelitis

Abstract

A library of queuine analogues targeting the modification of tRNA isoacceptors for Asp, Asn, His and Tyr catalysed by queuine tRNA ribosyltransferase (QTRT, also known as TGT) was evaluated in the treatment of a chronic multiple sclerosis model: murine experimental autoimmune encephalomyelitis. Several active 7‐deazaguanines emerged, together with a structure–activity relationship involving the necessity for a flexible alkyl chain of fixed length.

A new class of 7-deazaguanine agents targeting autoimmune diseases: dramatic reduction of synovial fibroblast IL-6 production from human rheumatoid arthritis patients and improved performance against murine experimental autoimmune encephalomyelitis

“…The 3-thiophene derivative 11 was previously 29 shown to possess potent in vitro activity in cells from EAE-diseased mice but was not evaluated in EAE itself – here it proved capable of lowering IL-6 production relative to vehicle control, with activity levels close to those obtained using 6. Methyl substitution at the benzylic position ( i.e.…”

“…If sufficiently active, screening progressed to the murine EAE model. 29 While this regime allowed the identification of potentially efficacious candidate molecules, we wished to develop a more streamlined initial screening methodology – preferably not reliant on a two-assay system and the availability of cells from EAE-diseased animals.…”

“…With proof of concept in human RA synovial fibroblasts in hand, attention now switched to the activity of NPPDAG analogues. Earlier studies 29 had shown that changes to the length of the linker chain associated with NPPDAG led to compounds inactive in EAE screening this constraint, coupled with the requirement for a simple aromatic moiety at the chain terminus, pointed to a requirement for the NPPDAG side chain to attain a particular conformation to alter the properties of the tRNA anticodon loop. We therefore began with retention of the NPPDAG structural core and a focus on mild rigidification of the linker chain via substitution ( Fig.…”

“…Compounds 6 , 11–26 were prepared previously to evaluate their QTRT compatibility and their characterisation – melting points, HRMS and copies of the associated 1 H NMR and 13 C NMR spectra which attest to >95% purity have been reported. 25,28,29 The synthesis of key compounds 6 , 17 , 21 , 25 and 26 evaluated in EAE are described below – associated 1 H- and 13 C NMR spectra have been provided in the ESI †…”

“…NPPDAG represents a queuine analogue where the aminomethyl-7-deazaguanine moiety has been retained and the cyclopentene diol unit has been exchanged for a substituent comprising a 3-carbon chain and an aromatic ring (highlighted in blue in structure 6). Subsequent studies 29 aimed at optimising the structure of this substituent revealed an exceptionally narrow structure–activity relationship in the context of EAE treatment ( i.e. through the modification of the behaviour of tRNA by the covalently incorporated artificial nucleobase).…”