Neomycin B–cyclen conjugates and their Zn(II) complexes as RNA-binding agents

Aminoglycosides are one of the most well-studied classes of naturally occurring antibacterial agents [1]. Their antibiotic activity derives from their selective binding to the bacterial ribosomal RNA A-site, which ultimately leads to disruption of protein synthesis. Unfortunately, despite exhibiting a promising antibacterial profile, the widespread use of aminoglycosides as antibiotics has been hampered by their adverse side effects and the emergence of bacterial resistance. Herein, we present the synthesis of a series of new neomycin B conjugates featuring a polyazamacrocycle, 1,4,7,10-tetraazacyclododecane (cyclen), appended to the D-ribose ring, together with an examination of their A-site binding properties, as well as those of the corresponding Zn(II) complexes (C1–C3 and Zn(II)-C1–Zn(II)-C3). Since the high affinity of aminoglycosides for RNA is associated with the formation of complementary electrostatic interactions between protonated amine groups on the aminoglycosides and the RNA, the tethered cyclen macrocycle, enhances affinity for the A-site RNA motif due to the introduction of additional ionisable amino groups [2,3]. Furthermore, in agreement with previous findings that Zn(II)-cyclen complexes form reasonably strong interactions with phosphate groups as well as the deprotonated imide groups of the nucleobases, uracil and thymine, complexation of Zn(II) by cyclen in the neomycin B conjugates serves to enhance the affinity further still by allowing the conjugates to form coordination bonds with the RNA target [2,3]. The conjugates are worthy of further investigation as potential new antibiotic agents.

References: [1] Y. Tor, ChemBioChem 2003, 4, 998. [2] B. Kong, T. Joshi, et al., J. Inorg. Biochem. 2016, 162, 334. [3] T. Joshi, et. al., Acc. Chem. Res. 2015, 48, 2366.