Chiral peptide nucleic acids with a substituent in the N-(2-aminoethy)glycine backbone

Abstract

A peptide nucleic acid (PNA) is a synthetic nucleic acid mimic in which the sugar-phosphate backbone is replaced by a peptide backbone. PNAs hybridize to complementary DNA and RNA with higher affinity and superior sequence selectivity compared to DNA. PNAs are resistant to nucleases and proteases and have a low affinity for proteins. These properties make PNAs an attractive agent for biological and medical applications. To improve the antisense and antigene properties of PNAs, many backbone modifications of PNAs have been explored under the concept of preorganization. This review focuses on chiral PNAs bearing a substituent in the N-(2-aminoethyl)glycine backbone. Syntheses, properties, and applications of chiral PNAs are described.

Figure 1

Chemical structures of DNA, PNA, and chiral (α-,β-,γ-)PNAs.

Scheme 1

Submonomeric cycle for the insertion of a chiral monomer into a PNA chain on resin [23].

Figure 2

Structures of α-PNAs bearing functional molecules [27,30,31,32,33].

Figure 3

Structures of L- or D-leucine-based α-PNAs [34].

Figure 4

Structures of α,α-dimethyl PNAs [35] and alanine-based α-PNA.

Figure 5

(A) Pseudo-complementary bases 2,6-diaminopurine and 2-thiouracil used in pcPNA; (B) D-lysine-base α-PNA; (C) Illustration of double-duplex invasion process of pcPNAs with additional positive charges. Electrostatic repulsion further destabilized the PNA-PNA duplex [36,37].

Figure 6

Structures of α-L-GPNA [43] and α-D-GPNA [47].

Scheme 2

Synthesis of γ-PNA monomer by (A) reductive amination [51,53,54,58,59] or by (B) Mitsunobu-Fukuyama reaction as a key step [60,61].

Scheme 3

Synthesis of γ-PNA monomers with Mtt/Boc protecting group combination [63].

Figure 7

Structures of γ-PNAs [51,52,53,54,64,67,68].

Figure 8

(A) Illustration of duplex invasion process of γ-PNA; (B) Structures of L-alanine-based γ-PNA, acridine-linked L-lysine residue, and G-clamp-G base pair [75,76,77,78].

Figure 9

Structure of γ-MiniPEG PNA [60,79].

Figure 10

Structures of γ-GPNAs [59,80].

Figure 11

Structure of the modified PNA containing the embedded NLS sequence [82].

Figure 12

Structures of aminomethyl-PNAs [83,84].

Scheme 4

Synthesis of β-(S)-Methyl PNA thymine monomer [93].