Structural (im)perfection in antibacterial oligomers

Abstract

In this dissertation, we designed a fully abiotic way to synthesize discrete unimolecular weight polyolefins by using a molecular template. We synthesized discrete and unimolecular oligo(thiophene)s template with alternating sequence by iterative convergent/divergent couplings and then pendant cyclic olefin monomers are attached in the side chains. Once the Grubbs third-generation catalyst loaded in dilute DCM solution, the attached monomers underwent templated ring-opening metathesis (TROM). Then, we liberated the daughter olefin from the parent template by hydrolysis. Cyclooctenes underwent TROM to generate macrocyclic polyolefins that exactly replicate the template’s chain length. As a comparison, we treated norbornene attached template molecules in the same TROM condition, which formed linear products with styrenic groups at the chain end. Then a heterogenous template, which contains one norbornene monomer at the α chain end followed five cyclooctene monomers along the template, was synthesized. The heterogenous template molecule was treated under same TROM condition to afford the macrocyclic daughter olefin. Intertemplate metathesis can be controlled by adjusting the reaction time and concentration.

The rapid increase of antibiotic drug-resistant bacterial infections in parallel to the slow development of new antibiotic drugs has created a looming global public health crisis. Although host defense peptides (HDPs) and novel synthetic antimicrobial polymers provide us an effective method to show promising antibiotics without inducing resistance, designing a more efficient routine to produce sequence and structure defined antimicrobial polymers is always a challenge. From the 2000’s, more and more research groups have started to design and study synthetic oligomers/polymers with similar physiochemical features of HDPs. Since the antimicrobial activity is mostly dependent on physiochemical properties such as hydrophobicity, molecular chain length and cationic charge, the stereochemistry seems to play no important role in their activity. Therefore, synthetic polymers and oligomers with imperfections of dispersity, stereochemistry and sequence have mimicked the physiochemical properties of HDPs with minimal toxicity and potent antibacterial activity, despite their chemical heterogeneity. However, it is a common sense that the dispersity and monomer sequence of polymer chains does play a vital role in their physiochemical attributes, thus the biological activity can be impacted.

Finally, a series of precision oligo(thiophene)s with primary amines cationic groups were synthesized by the convergent and divergent iterative organometallic couplings method. The most effective candidate compound, named AABA, showed more than 1300-fold cell type selectivity. Then based on AABA, we further synthesized a HDPs mimic oligo(thiophen) with the same monomer sequence but different cationic side groups to compare the relativity of different kinds of cationic groups with antimicrobial and hemolytic activity. This time we choose a guanidinium salt as the cationic group in order to reflect arginine rich HDPs; we named this compound GGBG. Because of the conjugated structure of thiophen backbone, these HDPs mimic oligo(thiophene)s can generate reactive oxygen species (ROS) in aqueous solution after absorbing visible light. Therefore, the compounds show antimicrobial activity in the dark with significantly enhanced potency upon visible light illumination. Compared with primary amine groups the guanidium groups enhanced the antimicrobial activity of the oligo(thiophene) in the dark but weakened its light-induced antimicrobial activity enhancement.

Then we synthesized a library of macrocyclic olefins by using this templated ring-opening metathesis (TROM) method. We characterized the structure by using a combination of MALDI, MALDI ms/ms fragmentation and hydrogen/carbon NMR spectroscopy studies. The daughter oligo(olefin) product was liberated from the template by hydrolysis, then functionalized with cationic groups to get antibacterial activities. In the next stage, we synthesized a polydisperse sample by traditional ROM without a template and compared the antimicrobial and hemolytic activity with the precision macrocycles. The result shows quite similar bioactivity, which suggests a big tolerance for molecules heterogeneity.