Synthesis of a library of stereo- and regiochemically diverse aminoglycoside derivatives

Abstract

A library of forty modified aminoglycosides was prepared in which the configuration and regiochemistry of two or three rings was widely varied. The library was based around three core ring systems: the 2-deoxystreptamine ring system found in the natural products, and both enantiomers of (1R*,2R*,4R*,5R*)-2,5-diamino-cyclohexane-1,4-diol and (1R*,3R*,4R*,6R*)-4,6-diaminocyclohexane-1,3-diol. In each case, the core was modified by glycosylation with one or two sugar rings. The absolute configuration of the sugar substituents (d or l), the configuration of the anomeric centres (alpha or beta), and the regiochemical arrangement of the amine(s) were varied.

A review of patents (2011–2015) towards combating resistance to and toxicity of aminoglycosides

“…Building AG analogues by using glycosylation has obviously been previously reported. [60][61][62][63][64][65] In this patent, by using this method, twelve ABK analogues (5-8) were synthesized and eleven of them were tested for their antibacterial MedChemComm Review activity against nine strains of MRSA. These ABK derivatives contained a hydroxyl moiety at the 4″-position oriented either axially or equatorially (Note: this orientation was introduced prior to glycosylation) as well as various side-chains ((S) or (R)-3-amino-2-propionate, (S) or (R)-AHB, (S) or (R)-5-amino-2valerate, and (S) or (R)-6-amino-2-hexanoate) at the N1-position.…”

“…163) In patent US 2011/0130357 A1, a glycodiversification strategy was used to synthesize various analogues of KANA and KANB as antifungal agents (Fig. 7A, [58][59][60][61]. The present invention relates to novel analogues of AGs with substituents at the 6″position of ring III which exhibit enhanced antifungal activity, but with minimum antibacterial property.…”

The use of aminoglycoside derivatives to study the mechanism of aminoglycoside 6′-N-acetyltransferase and the role of 6′-NH2 in antibacterial activity

“…The chemical synthesis of aminoglycoside-coenzyme A (CoA) bisubstrates is challenging in part because of the judicious functional protection chemistry needed with aminoglycosides and CoA, and the water solubility of the starting materials. [13][14][15][16] We recently developed an effective one-pot regio-and chemo-selective method for the direct N-6′-derivatization of unprotected aminoglycosides in high yield. 7 This facilitated the preparation of the first generation of synthetic AAC nanomolar inhibitors.…”