Synthesis and Antibacterial Activity of Doxycycline Neoglycosides

Abstract

A set of 37 doxycycline neoglycosides mediated via a C9 alkoxyamino-glycyl-based spacer reminiscent to that of tigecycline were prepared. The in vitro antibacterial assays against representative drug resistant Gram negative and Gram positive strains revealed a sugar-dependent activity profile and one doxycycline neoglycoside, the 2′-amino-α-D-glucoside conjugate, to rival that of the parent pharmacophore. In contrast, the representative tetracycline-susceptible strains E. coli 25922 was found to be relatively responsive to a range of doxycycline neoglycosides. This study also extends the use of aminosugars in the context of neoglycosylation via a simple two step strategy anticipated to be broadly applicable for neoglycorandomization.

Neoglycosylation and neoglycorandomization: enabling tools for the discovery of novel glycosylated bioactive probes and early stage leads

“…43–44 The low electron-withdrawing nature of alkoxyamine handles typically employed may enhance the impact of aglycon sterics upon anomeric stereoselectivity. This trend holds for aglycons with a significant amount of bulk near the point of glycosylation, 15,19–26 although the effect may be diminished when attachment occurs on a more linear substrate. 16 While many neoglycosides favor formation of a single anomer, it is important to note that any anomeric mixtures observed are in dynamic solution equilibrium.…”

“…However, this can be circumvented by using N -acyl- protected or azidosugars followed by deprotection or reduction, respectively. 26 …”

“…21 A four-step scheme was used to nitrate and attach methoxyglycine to the doxycycline scaffold followed by neoglycosylation with 31 different sugars ( 14 , see Table 3). 26 To extend the study of neoglycosylation, aminosugars were also used, which marks the first instance of these sugars being systematically employed in neoglycosylation. To overcome the incompatibility issue between neoglycosylation and aminosugars, azidosugars were conjugated with the aglycon then reduced via hydrogenolysis.…”

Bioconversion of Tetracycline Antibiotics to Novel Glucoside Derivatives by Single-Vessel Multienzymatic Glycosylation

“…In nature, post-modification reactions such as glycosylation, methylation, alkylation, acylation, and hydroxylation are extensively used to diversify chemical architecture to produce different analogs [8]. Recently, Professor Thorson's group has synthesized 37 different analogs of doxycycline glycoside analogs using the neoglycosylation approach [9]. Among the new analogs, a 2'-amino-α-D-glucoside-conjugated derivative exhibited activity comparable to doxycycline pharmacophore [9].…”

A Simple Strategy for Glycosyltransferase‐Catalyzed Aminosugar Nucleotide Synthesis

“…[6] Within this context, aminosugar conjugation has been reported to improve the unconjugated parental compound’s basicity, [7] pharmacological properties, [8] and/or even alteration of mechanism. [9] Aminosugar conjugation can be accomplished via either chemical [10] or glycosyltransferase (GT)-catalyzed strategies, [11] the latter of which typically depends upon the availability of suitable aminosugar nucleotide donors. Yet, the reported syntheses of aminosugar nucleotides via chemical, [12] enzymatic, [13] or chemoenzymatic [14] strategies still typically are restricted to multi-step, low yielding processes and few, if any, are directly orthogonal to downstream GT-catalyzed reactions.…”