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

Complementing ourearlier syntheses of the gentamicinsB1, C1a,C2b, and X2, we describe the synthesis of gentamicins C1, C2, andC2a characterized by methyl substitution at the 6 & PRIME;-position,and so present an alternative access to previous chromatographic methodsfor accessing these sought-after compounds. We describe the antiribosomalactivity of our full set of synthetic gentamicin congeners againstbacterial ribosomes and hybrid ribosomes carrying the decoding A siteof the human mitochondrial, A1555G mutant mitochondrial, and cytoplasmicribosomes and establish structure-activity relationships withthe substitution pattern around ring I to antiribosomal activity,antibacterial resistance due to the presence of aminoglycoside acetyltransferases acting on the 6 & PRIME;-position in ring I, and literaturecochlear toxicity data.

Automated summary

In this study, we synthesized gentamicins C1, C2, and C2a with methyl substitution at the 6'-position, providing an alternative method for accessing these compounds compared to previous chromatographic methods. We also explored the antiribosomal activity of the synthetic gentamicin congeners against bacterial ribosomes and different types of ribosomes, establishing structure-activity relationships with the substitution pattern around ring I, antibacterial resistance, and cochlear toxicity data from literature.