Abstract
2’-O-Methylribo phosphorothioate oligonucleotides incorporating cyclopalladated benzylamine conjugate groups at their 5’-termini have been prepared and their ability to hybridize with a designated target sequence was assessed by conventional UV melting experiments. The oligonucleotides were further examined in splice-switching experiments in human cervical cancer (HeLa Luc/705), human liver (HuH7_705), and human osteosarcoma (U-2 OS_705) reporter cell lines. Melting temperatures of duplexes formed by the modified oligonucleotides were approximately 5 °C lower than melting temperatures of the respective unmodified duplexes. The cyclopalladated oligonucleotides functioned as splice-correcting agents in the HeLa Luc/705 cell line somewhat more efficiently than their unmodified counterparts. Furthermore, the introduction of this chemical modification did not induce toxicity in cells. These results demonstrate the feasibility of using covalently metalated oligonucleotides as therapeutic agents.
Highlights
IntroductionAfter five decades of intense research, nucleic acids are maturing into useful drugs [1,2] in the form of antisense [3,4,5,6,7,8,9], antimiR [10,11,12,13,14,15], siRNA [16], and splice-switching oligonucleotides [17,18,19,20].Modified oligonucleotides are needed in all of these approaches to overcome problems with cellular delivery and stability [21,22,23,24,25,26]
The 5’-modified oligonucleotides ON1b, ON2b, and ON2b-Pd were assembled on an automated DNA/RNA synthesizer using conventional
The N donor of the benzylamine moiety is flanked by two sp3 -hybridized carbon atoms that may be difficult to accommodate within the base stack and this problem would probably be more pronounced with the relatively rigid and tightly wound A-type double helix favored by RNA
Summary
After five decades of intense research, nucleic acids are maturing into useful drugs [1,2] in the form of antisense [3,4,5,6,7,8,9], antimiR [10,11,12,13,14,15], siRNA [16], and splice-switching oligonucleotides [17,18,19,20].Modified oligonucleotides are needed in all of these approaches to overcome problems with cellular delivery and stability [21,22,23,24,25,26]. One way to achieve this is by metal coordination, as exemplified by numerous studies on metal-mediated base pairing [27,28,29,30]. A number of oligonucleotide conjugates of kinetically inert metal complexes, such as those of Pt(II) and Ru(II), have been described and in many cases shown to hybridize more efficiently than their unmodified counterparts [31,32,33,34,35,36,37]. On the other hand, have been interested in oligonucleotides covalently metalated with more labile transition metals and have recently reported on the synthesis and hybridization properties of the first oligonucleotides incorporating palladacyclic base moieties or conjugate groups [38,39]
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