Synthesis of Gentamicin Minor Components: Gentamicin B1 and Gentamicin X2

Abstract

The clinical aminoglycoside antibiotic gentamicin is a mixture of several difficult-to-separate major and minor components. The relative inaccessibility of the minor components in particular complicates efforts to separate antibacterial activity from nephro- and/or ototoxicity and to clarify the origin of the potentially therapeutically important read-through activity. With a view to facilitating such studies, the synthesis of a fully and selectively protected garamine-based acceptor has been developed from readily available sisomicin. Glycosylation of this acceptor with a 6-azido-6,7-dideoxy-d-glycero-d-glucohepto­pyranosyl donor affords gentamicin B1 after deprotection, whereas employment of a 2-azido-2-deoxy-d-glucopyranosyl donor under N,N-dimethylformamide-directed glycosylation conditions affords gentamicin X2 after deprotection.

Design of Photosensitizing Agents for Targeted Antimicrobial Photodynamic Therapy

“…Upon contact with the pathogen, gentamicin diffuses through porins in the outer membrane and transfers into the cytosol. The mode of action is based on impedimentation of the initiation and further translation of protein synthesis by binding to 30S and 16S ribosomal RNA [ 79 , 80 ]. The co-administration of this antibiotic with Rose Bengal (RB) in aPDT has been studied by Perez-Laguna et al [ 81 ], and following their work, Nonell and co-workers demonstrated the use of gentamicin as a targeting unit in a covalent conjugation strategy [ 82 ] ( Figure 5 ).…”

Micromonospora: A Prolific Source of Bioactive Secondary Metabolites with Therapeutic Potential

“…These molecules act to inhibit bacterial protein synthesis by irreversibly binding to the bacterial 30 S ribosomal subunit at the amino-acyl-tRNA acceptor A site, thereby leading to codon misreading, translocation inhibition, and the suppression of disease causing premature termination of human mRNAs. , To separate the minor components from the gentamicin mixture and clarify the origin of therapeutic activity, the semisyntheses of gentamicins B1 ( 24 ) and X ( 25 ) were developed using readily available AG sisomicin ( 45 ) as the precursor and then glycosylating with a 6-azido-6,7-dideoxy- d -glycero- d -glucoheptopyranosyl and 2-azido-2-deoxy- d -glucopyranosyl donors, respectively (Scheme ). Kanamycins first isolated from S. kanamyceticus had been found in several Micromonospora strains, such as 3″- N -methyl and 3″- N -methyl-4″- C -methyl derivatives ( 33 – 35 ) from M.…”

Synthesis of Gentamicins C1, C2, and C2a and Antiribosomal and Antibacterial Activity of Gentamicins B1, C1, C1a, C2, C2a, C2b, and X2

“…Not surprisingly, these efforts to characterize structure activity relationships and separate activity from toxicity among the difficult-to-separate components of the commercial gentamicin mixtures have spurred efforts for the preparation of single components. Such efforts have taken the path of either understanding and manipulating the biosynthetic pathways from sisomicin ,− or of chemical synthesis. − Following the latter path, in our laboratory, we have described syntheses of gentamicins B1 and X2 from sisomicin by a route involving ring I cleavage and reglycosylation and of gentamicins C1a and C2b by manipulation of the sisomicin ring I …”

“…Such efforts have taken the path of either understanding and manipulating the biosynthetic pathways from sisomicin 16,37−39 or of chemical synthesis. 40−43 Following the latter path, in our laboratory, we have described syntheses of gentamicins B1 and X2 from sisomicin by a route involving ring I cleavage and reglycosylation 44 and of gentamicins C1a and C2b by manipulation of the sisomicin ring I. 45 The antibacterial activity of aminoglycosides derives from their well-known ability to bind to the decoding A site of the bacterial ribosome and their consequent inhibition of bacterial protein synthesis.…”