Synthesis and Biological Applications of Oligopeptide-Substituted Polynorbornenes

Citation

Okada, Sheldon Yoshio (2001) Synthesis and Biological Applications of Oligopeptide-Substituted Polynorbornenes. Master's thesis, California Institute of Technology. doi:10.7907/76ch-0t79. https://resolver.caltech.edu/CaltechTHESIS:09172018-160205705

Abstract

Chapter 1

Synthetic fibronectin mimics have been constructed usmg functionalised norbomenyl polymers synthesized via ring-opening metathesis polymerization (ROMP). The ROMP reactions were catalyzed by newly developed ruthenium initiators. Prior to the synthesis of the fibronectin mimics, the polymerization reactions of a number of norbornene derivatives with pendent glycine or penta(ethylene oxide) (EO₅) units were studied in order to select the derivatives with optimal characteristics: high yields, fast polymerization times, and narrow PDI's. For these initial studies Ru = CHPh(Cl₂)(PCy₃)₂ (1) was used as the initiator. Based on these studies poly(5-norbomene-2-carboxyl) and poly(4-(Exo-3,5-dioxo-10-oxa-4-azatricyclo[5.2.1.0]dec-8-en-4-yl)-butyric acid) were chosen as the ideal backbones for a series of polymers functionalised with pendent arginine-glycine-aspartic acid (RGD) and serine-arginineasparagine (SRN) oligopeptides. The polymers containing a propyl spacer between the pendant group and the backbone were synthesized in an attempt to demonstrate that the presentation of the peptide units could be altered to closely mimic the natural presentation of these peptides in fibronection. Homopolymers and random copolymers containing various combinations of norbomene monomers with pendant EO₅ (21 & 14), GRGD/RGD (24 & 29), and SRN (25 & 30) units were made. Copolymers with large RGD or SRN contents (> 10 mol %) could only be synthesised in high yields and narrow PDI's by using the newly developed ruthenium 2,3-dihydroimidazolylidene initiators Ru = CHPh(Cl)₂(PCy₃)(DHIMes) (2) or Ru = CH-CH = CH₂(CH₃)₂(Cl)₂ PCp₃)(DIHMes) (3). In addition, the ROMP reactions of the norbornene monomers containing the propyl spacers also required the new initiator 2. Attempts to synthesize these polymers using ruthenium initiator 1 resulted in either low yields, bimodal molecular weight distributions, or a combination of both.

Chapter 2

Polynorbomenes substituted with two different peptide sequences from the RGD containing integrin cell binding domain of fibronectin are potent inhibitors of human foreskin fibroblast cell adhesion to fibronectin-coated surfaces. Ring-opening metathesis polymerization (ROMP) using Ru = CHPh(Cl)₂(PCy₃)(DHIMes) (1) as an initiator produced polymers substituted with GRGDS and PHSRN peptide sequences. The inhibitory activity was quantified for these polymers and compared to the free peptides and GRGES containing controls. A homopolymer substituted with GRGDS peptides was significantly more active than the free GRGDS peptide (IC₅₀ of 0.18 ± 0.03 and 1.33 ± 0.20 mM respectively), and the copolymer containing both GRGDS and PHSRN was the most potent inhibitor (IC₅₀ of 0.04 ± 0.01 mM). These results demonstrate that significant enhancements of observed biological activity can be obtained from polymeric materials containing more than one type of multivalent ligand and that ROMP is a useful method to synthesize such well-defined copolymers.

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