Biomimetic Study Of Quinolinamide Foldamers At Molecular Level

Functional expression of biological macromolecules such as nucleic acids and proteins is closely related to their three-dimensional advanced assembly structures.The construction of artificial oligomers（foldamers）to simulate the biochemical functions of biological macromolecules is one of the important methods to understand living systems,and also an important way to design functional molecular systems.In the field of foldamers,aromatic amide oligomers have advantages such as predictability,ease of synthesis and crystallization,high stability,and tunability,showing a wide range of theoretical and application potential.In this paper,a series of aromatic amide oligomers were shown that could be used to simulate the specific functions of organisms.1)The study in Chapter 2 demonstrated a series of helical oligomers consisting of 8-amino-2-quinolinecarboxylic acid（Q）and 7-amino-8-fluoro-2-quinolinecarboxylic acid（Q^F）monomers that can be used to mimic the asymmetric reactions of biological enzymes.These helical sequences produced a single helical chirality due to the introduction of chiral oxazolidine at the C-terminus.And then the helical chirality thus provided a chiral microenvironment for the prochiral substrate-phenylethyl ketone which was covalently attached to the inner edge of the helical cavity.Using non-chiral Na BH₄to reduce the substrate,the diastereomeric excess value of the product in different sequences varied greatly,which was closely related to the shielding efficiency of the helical cavity to the substrate.The iterative modification of the helical sequences,such as the addition and replacement of monomers,fine-tuning the helical cavity and changing the degree of wrapping of the helical backbone on the substrate molecules achieved a stepwise optimization of the diastereoselectivity from 9%to 90%.2)Based on the complementary pairing behavior of heterohelices,Chapter 3showed a helical hybridization behavior that could be used to imitate the process of chaperonin-assisted disordered sequences for ordered folding.The helical oligomers composed of Q^Fmonomers,and a series of helical-disordered sequences based on7-amino-8-methyl-2-quinolinecarboxylicacid(Q^Me)and7-amino-8-methoxy-2-quinolinecarboxylic acid(Q^OMe)monomers were used in this research.Due to hydrogen bonding deficiency,oligomers based on Q^Meand Q^OMemonomers could not form a stable helical conformation and present a disordered state in solution,but a class of helices composed of Q^Fmonomers could serve as templates to induce these disordered sequences to form stable heterologous double helices,thus promoting the transformation of disordered structure into ordered one.This phenomenon was similar to the behavior of chaperone proteins in organisms that assist disordered sequences in orderly folding.The introduction of chirality in the systems could achieve full chiral regulation of the heterohelix and complete the transfer of chiral information between molecules.In addition,by iteratively modifying the helicail and the disordered sequences,such as extending or shortening,multi-helical assembles with a single template helix simultaneously inducing multiple disordered molecules to fold could be achieved.3)Based on the above heterohelices studies,a series of helix oligomers whose backbones were constructed by Q^Fand Q^OMe,respectively,were designed and synthesized in Chapter 4,and these sequences could be used for the simulation of self-replication behavior.It shown that the occurrence of the self-replication reaction was closely related to whether or not there was a template-matching between the helix parent and daughter chains.The replication potential of the aromatic amide oligomer system could be stimulated by iteratively modifying the helical units and adjusting the helix length to enhance the heterozygous matching interaction between the parent and daughter chains.In addition,the efficiency of the self-replication reaction was also closely related to the dimerization behavior of the parent chain itself.By replacing the aromatic building blocks and reducing the diameter of some fragments of the helical sequence,the dimerization of the parent chain itself could be largely weakened and the efficiency of the self-replication reaction could be improved.In conclusion,expanding the application of aromatic amide foldamers in molecular bionics can not only develop new chemical synthesis methods,but also explore the chemical changes before the origin of life to a certain extent,and provide more possibilities for the de novo synthesis of artificial life.