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The nucleobases are one of the important building blocks for synthesizing peptide nucleic acid (PNA) monomer.
Peptide nucleic acid is the third generation of antisense nucleic acid after thiophosphate oligonucleotide (first generation antisense nucleic acid) and hybrid antisense nucleic acid (second generation antisense nucleic acid). Because of its unique physical and chemical properties, hybridization characteristics, and regulation of gene transcription and translation, it has shown a broad application prospect in molecular biology research, cancer and infectious disease gene therapy. PNA is a kind of substance with polypeptide as the backbones, similar to nucleotides and without charge. Its structure is composed of repeated N-(2-aminoethyl) glycine as a unit, which is connected to the base through α-N-acyl methyl.And the nucleobases are connected with the backbones by the methylene carbonyl group.
All four bases are alkylated with amine to form base acetic acid derivatives, which are then combined with unprotected nitrogen on the backbones by common peptide synthesis method.
The alkylation reaction of thymine usually does not require the use of protective groups, so thymine acetic acid can be obtained by reacting with bromoacetate, saponification or directly reacting with bromoacetic acid.
The other three bases have active groups, which need to be protected first.
The active group on cytosine is the amino group at position 4, and the optional protective groups are benzyloxycarbonyl (Cbz), 4-tert-butylbenzoyl (4-t-BuBz), Benzoyl (Bz) and 4-methoxyphenyldiphenylmethyl (Mmt). Then it is alkylated with bromoacetate, and saponify to obtain the derivatives of cytosine acetic acid.
The protection process of adenine is basically the same as that of cytosine. The available protective groups are Cbz, Mmt and p-methoxyphenyl (An).
The protection of guanine is relatively complex, so it is necessary to avoid the side reaction interference of N7 alkylation in the process of N9 alkylation. A common method is to use 2-amino-6-chloropurine in alkylation, and then backflow under acidic or alkaline conditions after alkylation to hydrolyze chlorine into carbonyl group or directly alkylate N2 adenine with protective group, separate N7/N9 alkylation products by chromatography, and then saponify them to obtain derivatives of guanine acetic acid.
