Synthesis and DNA/RNA Binding Properties of Conformationally Constrained Pyrrolidinyl PNA with a Tetrahydrofuran Backbone Deriving from Deoxyribose

Abstract

Sugar-derived cyclic β-amino acids are important building blocks for designing of foldamers and other biomimetic structures. We report herein the first synthesis of a C-activated N-Fmoc-protected trans-(2S,3S)-3-aminotetrahydrofuran-2-carboxylic acid as a building block for Fmoc solid phase peptide synthesis. Starting from 2-deoxy-d-ribose, the product is obtained in a 6.7% overall yield following an 11-step reaction sequence. The tetrahydrofuran amino acid is used as a building block for a new peptide nucleic acid (PNA), which exhibits excellent DNA binding affinity with high specificity. It also shows preference for binding to DNA over RNA and specifically in the antiparallel orientation. In addition, the presence of the hydrophilic tetrahydrofuran ring in the PNA structure reduces nonspecific interactions and self-aggregation, which is a common problem in PNA due to its hydrophobic nature.

Hydrophilic and Cell-Penetrable Pyrrolidinyl Peptide Nucleic Acid via Post-synthetic Modification with Hydrophilic Side Chains

“…Thus, the modifier A3EG seems to be a good combination in terms of water solubility and DNA binding properties. This is in contrast to the case of atfcPNA, whereby the complete replacement of the cyclopentane ring in acpcPNA by tetrahydrofuran ring in atfcPNA did not provide significant improvement in the water solubility.…”

“…Accordingly, a reliable modification that can increase both water solubility and cellular uptake of acpcPNA is highly desirable. Recently, we reported the synthesis and the DNA- and RNA-binding properties of pyrrolidinyl PNA-carrying polar backbone by the replacement of the cyclopentane ring in the backbone of acpcPNA with tetrahydrofuran (atfcPNA), oxetane (aocPNA), or pyrrolidine (apcPNA) moieties. , Among these modifications, the apcPNA bearing a pyrrolidine ring in place of the cyclopentane ring in acpcPNA is the most promising in terms of DNA-binding affinity. Importantly, the nitrogen atom of the pyrrolidine ring in the apc spacer provide a convenient handle for attaching label or other functional groups to the PNA backbone via acylation, reductive alkylation, or click chemistry …”

Thermostability, Tunability, and Tenacity of RNA as Rubbery Anionic Polymeric Materials in Nanotechnology and Nanomedicine—Specific Cancer Targeting with Undetectable Toxicity

“…The site-specific incorporation of labels and reactive groups can be introduced through synthetic chemistry. Solid-phase synthesis is the widely used method to incorporate the labels/functional tools by incorporating modified nucleotides/terminal modifiers having various functional groups such as alkyne, − thiol, − aldehyde, − amine, − carboxylic acid, − and biotin ,− into the extending RNA site specifically. These functional groups can be modified with drug molecules or imaging markers with orthogonal functional groups with appropriate chemistries, and they include N -hydroxysuccinimide (NHS) chemistry, copper-catalyzed click reaction, copper-free click chemistry, thiol chemistry, periodate chemistry, imine formation, and 5′-phosphate activation. ,− Among them, the NHS, thiol as well as copper-catalyzed and copper-free click chemistries are widely used for both internal and terminal modifications, whereas 5′-phosphate activation and periodate chemistry are mainly employed for terminal modifications.…”

Peptide Nucleic Acid Conjugated with Ruthenium‐Complex Stabilizing Double‐Duplex Invasion Complex Even under Physiological Conditions

“…Because Ru–polypyridyl complexes have been reported to be effectively transported into living cells, we anticipate that Ru complex conjugation can broaden the applicability of PNA, especially for in cellulo or in vivo applications, such as DNA mismatch detection, DNA cleavage, and cancer therapy by gene silencing . Furthermore, the strategy reported herein to enhance DNA affinity may also be employed in combination with other artificial nucleic acid modifications, including backbone modification or peptide introduction …”