6-Hydroxy to 6‴-amino tethered ring-to-ring macrocyclic aminoglycosides as probes for APH(3′)-IIIa kinase

Based on molecular modeling and available X-ray structure data on aminoglycosides complexed with a bacterial ribosomal surrogate or with a kinase, two analogues of paromomycin were prepared by tethering the 6-OH and the 6‴-NH2 group with a five-carbon bridge. Only one of two possible hydroxyl groups was phosphorylated by the kinase. The application of ring closure metathesis is presented for the first time to construct bridged macrocyclic analogues in the aminoglycoside series.