Synthesis of Alternating Polyisocyanate Copolymers by Anionic Polymerization to Mimic Antimicrobial Peptide

Abstract

Natural peptides have various roles such as antimicrobial, antifreeze, enzymatic hydrolysis and so on. There are many attempts to try mimic the functions of natural peptide with artificial materials including polymer. Polyisocyanate share characteristics such as amide backbone and helical structure and has potential to reproduce structure and function of peptide. Although this similarity between polyisocyanate and peptide, peptide mimic polyisocyanate was not reported yet. In order to reproduce peptide structure with polyisocyanate, sequence control and hydrophilic moiety are important and it can be achieved by alternating copolymerization and thiol-ene click reaction. In the Chapter 2, I explored the possibility of alternating copolymerization from various isocyanate monomer combinations with anionic polymerization method. The anionic polymerization of isocyanates was proceeded at -98 ℃ under 10-6 Torr. The sodium diphenylmethane (Na-DPM) was used as initiator and sodium tetraphenylborate (NaBPh4) was used as additive to prevent trimerization during polymerization. Among isocyanate monomers, allyl isocyanate (AIC) and α-methylbenzyl isocyanate (MBIC) can be copolymerized with alternating sequence. The MBIC cannot be self-propagated because of high steric hindrance (reactivity ratio ≈ 0) and reactivity ratio of AIC (2.76) was found by monomer ratio dependent polymerization and copolymer equation. Optimized monomer ratio between AIC and MBIC was investigated for optimizing alternating sequence and final poly(allyl isocyanate-alt-(S)-(−)-α-methylbenzyl isocyanate). P(AIC-alt-MBIC) was characterized with SEC-MALLS, 1H NMR, FT-IR, ESI-MS and CD. The ESI-MS spectra show clear alternating sequence of P(AIC-alt-MBIC) and chirality of P(AIC-alt-MBIC) from chiral MBIC monomer was identified by CD spectra. In the Chapter 3, several ammonium groups were introduced to P(AIC-alt-MBIC) for obtain water-soluble, amphiphilic helical polyisocyanate. Diethylaminoethanethiol hydrochloride (DEAET-HCl), Aminoethanethiol hydrochloride (AET-HCl), and cysteine hydrochloride (Cyc-HCl) were introduced with thiol-ene click reaction with azobisisobutyronitrile (AIBN) radical initiator. After reaction finished, unreacted thiol and other impurities were removed by dialysis purification. DEAET-HCl attached P(AIC-alt-MBIC) (DEA-P(AIC-alt-MBIC)) and AET-HCl attached polymer (AET-P(AIC-alt-MBIC)) show 93.0 ~ 96.2% of thiol conversion and these polymers have water solubility. In the Chapter 4, antimicrobial effect of DEA-P(AIC-alt-MBIC) and AET-P(AIC-alt-MBIC) were evaluated against Gram-positive (Staphylococcus aureus ATCC25923) and Gram-negative (Escherichia coli ATCC 25922) bacteria. The DEA-P(AIC-alt-MBIC) show poor antimicrobial effect.