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5'-Phosphoramidite Approach for the Synthesis of Piperidino Oligomer and Its Chimeras in an Automated Oligo Synthesizer and Their Biophysical Properties
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DOI：10.1002/ajoc.70485.png)
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Abstract
En 中文
Chemically modified oligonucleotide synthesis has emerged as a major driving force in modern nucleic acid chemistry. Recently, phosphorodiamidate morpholino oligonucleotide (PMO) has gained much interest, for the treatment of rare disease like Duchenne Muscular Dystrophy (DMD), warranting its further exploration. In this vein, the synthesis of carbocyclic analog of PMO, called phosphorodiamidate piperidino oligomers (PPOs) was reported earlier. However, the use of chlorophosphoramidate chemistry for the synthesis of PPOs limited its overall yield and applicability. Herein, we explored the amidite chemistry for the synthesis of tert-butyl-protected (5′-tBu)-piperidino phosphoramidite monomers. Furthermore, their use for the synthesis of full length 19-mer PPO sequence and diverse chimeric backbones like PPO-PMO, PPO-psDNA, and PPO-DNA chimeras in an automated oligo synthesizer are also investigated. Thermal melting (Tm) and circular dichroism (CD) analyses of their duplexes with complementary RNA strand are also reported. Interestingly, we observed a reasonable Tm in our newly reported chimeras which indicated a strategy to deal with the destabilizing effects of PPO for their potential applications in ASOs. CD spectra indicated non-canonical helical conformations for pure PPO and altered B-form features in chimeras, underscoring their structural versatility for RNA-targeted therapeutics.
Keywords:
phosphorodiamidate piperidino oligonucleotides
5’-tert-butyl phosphoramidite piperidino monomers
automated PPO synthesis
PPO-PMO chimera
PPO-DNA chimera
PPO-psDNA chimera
thermal melting study
circular dichroism
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