α-PNA:  A Novel Peptide Nucleic Acid Analogue of DNA

Abstract

Peptide nucleic acid (PNA) analogues of DNA have attracted interest as potential pharmacological regulators of gene expression since they have the capacity to invade duplex DNA forming Watson−Crick base paired PNA:DNA heteroduplexes. Unfortunately, strand invasion is limited to homopurine and homopyrimidine sequences and there is the need to explore further PNA analogues for the purpose of expanding the strand invasion alphabet. Accordingly, we have designed a true peptide mimic of DNA (designated α-PNA) involving novel l-α-amino acids, with side chains comprising the four DNA bases attached via an ethylene linkage, interspaced with glycine. The four base-containing amino acids have been synthesized from N-Boc-l-homoserine, via alkylation of the appropriate base with the key intermediate (S)-2-(N-Boc-amino)-4-bromobutyric acid methyl ester followed by hydrolysis. These amino acids have been incorporated into α-PNA oligomers using both solution and solid phase methods.

Sugar amino acids in designing new molecules

“…These molecules and Peptide Nucleic Acids (PNA) [11] are finding useful applications in antisense-oligonucleotide therapies. Large varieties of modified PNAs have also been developed [11,12].…”

“…To whom correspondence should be addressed: Tushar Kanti Chakraborty, Indian Institute of Chemical Tecnology, Hyderabad -500 007, India, Fax: +91-40-27193108; E-mail: chakraborty@iict.res.in * Based on the invited lecture presented at the XVII International Symposium on Glycoconjugates held in January [12][13][14][15][16]2003 at Bangalore, India.…”

Novel heterocyclic α-amino acids with sulfur-containing side-chains

“…As part of a programme to explore this possibility, we have previously reported on α-amino acids 3 (n = 0, 2, 3) carrying heterocycles in their side chains, including pyridine and isoxazole derivatives but in particular the pyrimidine and purine nucleobases tethered to the backbone with varying length carbon chains. 1,2 These are potential α-PNA monomers, 3,4 amongst many other possible applications, and are analogues of natural products such as discadenine. 5 They are obtained by stereoselective conjugate radical addition to an optically active methylene oxazolidinone derived from S-methylcysteine, 1 or by stereoselective C-alkylation of an ephedrine-based glycinamide.…”

“…This C-S bond formation is distinct from those employed by others, and extends the portfolio of heterocycles beyond the nucleobases. 3,6,7 The product amino acids are possible components in novel non-natural amino acid sequences with potential biological properties. …”

Synthesis, DNA Binding, and Cleavage Studies of Novel PNA Binding Cyclen Complexes

“…One of the most interesting modifications turns out to be the replacement of glycine by a-amino acids with hydrophobic, hydrophilic, or charged a-substituents [12] [13]. Howarth and Wakelin reported aPNAs, in which the basic amino acid moieties are derived from homoserine, and in which the basic amino acids are interspaced with glycine [14]. However, as an ideal DNA-binding material, PNA has hardly been reported as DNA cleavage reagent.…”