Design And Synthesis Of A Novel Non-Classical Peptide Nucleic Acids And Some Other Derivatives Based On L-phenylalanine

Peptide nucleic acids(PNA) was the third generation antisense oligonucleotides after the phosphorothioate oligonucleotides and hybrid antisense oligonucleotides,which designed and synthesized by Nielsen's co-worker in 1991.Because of its unique biochemical characteristics,such as following the complementary nature of the base pairs,protease degradation,high chemical and biological stability,PNA has been widely applied to bioresearch,diagnose,biological probe,drug research and development,biosensor and treatment.However,due to the characteristics of the structure of PNA itself,it has the defects of poor water-soluble,weak membrane permeability, selfaggregation easily and so on.In view of this,it is necessary to design and synthesis the new types of PNA.In our study,a new-type of non-classical PNA monomer was designed and synthesized,whose basic framework was natural L-phenylalanine,and its structure was quite different from classic PNA. Firstly,the amino group was introduced into the side-chain of L-phenylalanine,and then let the base connect with it by acetyl group.The design has following advantages:1.The PNA have chiral structure and aromatic system in side-chain by introducing natural amino acid into it.2.The three-six rules in classical PNA was broke down because the distance between the base and basic framework was more than three chemical bonds.3.The base derivative was connected with the aromatic amino compared with aliphatic amino in classical PNA.Seventeen PNA molecules were prepared by SPPS after the non-classical PNA monomer was synthesized.By improving the synthesis technology of some key intermediates,a series of the L-phenylalanine derivatives were prepared.(1) Synthesis of PNA monomerα-Boc-L-4-nitrophenylalanine was prepared by protecting reaction and coupling reaction.And then,we find an optimal route for the synthesis of PNA monomer after employing three methods. (2) Investigation of some intermediatesBy a series of experiments,the optimal technical conditions were found for 4-nitrophenyt-alanine,α-Boc-L-4-nitro-phenylalanine and thymine acetic acid.And the method was environ-mentally benign,commercially available,safe and low cost.(3) Synthesis of the PNA oligomerA series of PNA were synthesized by SPPS after obtaining the PNA monomer.We linked the amino acids or the PNA monomer to the Wang resin or Rink amide resin,and then prepare PNA molecules according to the basic mode of operation of SPPS.All the compounds were confirmed by MAIDI-TOF and the purity of the 12 PNA were more than 80%which detected by HPLC.(4) Synthesis of the Other derivativesTwo serious of L-p-nitroPhenylalanine dipeptide derivatives and L-phenylalanine Schiff base whichα-amino and carboxy were diprotected were prepared due to their structures are similar to tyrosine derivatives that have a strong PPAR agonist activity and designed by Thiazolidinediones insulin sensitizers.Some biological activities such as antibacterial,antidiabetes,antitumor were expected.At last,60 compounds were designed and synthesized,while 45 of these compounds were not reported in reference.It contained 4 important intermediates and 17 PNA molecules.The structures of crucial intermediates and target products have been confirmed.The result of it has set a fairly substantial foundation for further investigating of non-classical PNA.