Deciphering the conformation of C-linked α-D-mannopyranosides and their application toward the synthesis of low nanomolar E. coli FimH ligands

Abstract

C-Allyl -D-mannopyranosides were prepared via a variety of routes to determine an optimal route to the anomers. The relative conformational energies of the key intermediate was evaluated by molecular modeling which showed the conventional 4 C1 chair conformation to be the lowest energy conformer. This finding was also confirmed by NMR and X-ray crystallography. The perbenzoylated C-allyl mannoside was also converted into 1,1'-biphenyl analogues using a palladium-catalyzed Heck reaction. Two of the resulting minor reaction products were co-crystallized with the uropathogenic E. coli FimH. Alternatively, the KD of the major and expected Heck product was in the low nM range as measured by SPR. Crystal data showed that the C-linked derivatives efficiently bind in the FimH binding cavity near the so-called hydrophobic tyrosine gate.

Comparative Study of Aryl O-, C-, and S-Mannopyranosides as Potential Adhesion Inhibitors toward Uropathogenic E. coli FimH

“…Analogues of O - and C -linked α-D-mannopyranosides with hydrophobic and aryl substituents have already been identified as potent E. coli FimH antagonists having low nanomolar Kds or IC 50 s [5,10,18,21,22]. Para -substituted biphenyl derivatives were shown to be particularly appealing owing to their numerous favorable binding interactions within the identified tyrosine gate formed between Tyr48 and Tyr137 [18,21,23,24,25]. In turn, some derivatives were shown to bind better when the Tyr-gate is either open, half-open, or close, further pointing toward rationally design glycol therapeutics [20,22,26,27,28].…”

“…Similarly to its O - and C -linked congeners, we chose the S -allyl α-D-mannopyranoside 9 as key starting materials. However, rather than using a palladium catalyzed Heck reaction and a series of aryl iodides for the cross-coupling as before [18,21], we decided to extend its alkenyl functionality by a metathesis reaction using 4-vinyl-1,1′-biphenyl ( 10 ) and Grubbs 2 nd generation catalyst. This alternative strategy was considered equally appealing owing to its potential to access a diversified library of analogs.…”

“…Fortuitously, we accessed to two crystalline structures, namely, those of the O - and C -linked analogues 5 and 6 , respectively. In addition, we previously resolved fourteen X-ray co-crystal data of several O -linked analogues bound to the E. coli FimH, thus giving us access to several docking opportunities [10,18,21,29,30]. One of them in particular ( 7 ) is of interest (PDB 4AV5) [29] as it also contains a 1,1′-biphenyl ring, albeit with a more rigid alkynyl linkage (see Figure S37 in SI for superimposed figure containing 5 and 7 ).…”

Insightful Improvement in the Design of Potent Uropathogenic E. coli FimH Antagonists

“…In previous studies, several aryl C -mannopyranosides carrying alkenyl aglycons were shown as promising candidates with excellent binding affinities against E. coli FimH [ 40 , 41 ]. However, their poor water solubility has restricted their further development as drug candidates.…”

“…Amid the various α-D-mannopyranoside inhibitors described thus far, C -linked glycomimetics residues harboring hydrophobic aglycons are still considered worthy candidates as potent FimH inhibitors. Several of these synthetic candidates showed improved binding affinities and increased hydrolytic stability [ 30 , 40 , 41 ].…”