A collection of twenty three selectively mono-protected di- and triamines, masked with the Boc, Fmoc or Ddiv protecting groups, were synthesised via continuous flow synthesis in a self-assembled meso-scale PTFE flow reactor. The continuous flow strategy offered direct access to the mono-protected compounds in good yields, especially in the case of the Fmoc carbamates which circumvented the use of another sacrificial protecting group. Two of the mono-Boc-protected carbamates were used as starting materials to generate N-alkylglycine monomers; synthesised via tandem mono-alkylation and Fmoc carbamation, linked by an in-line scavenging protocol using a silica-based trisamine scavenger resin. The final step of the monomer synthesis employed catalytic transfer hydrogenolysis using 20% Pd(OH)2/C and 1,4- cyclohexadiene. The three-step flow procedure gave access to two monomers, with one of them being a novel N-alkylglycine unit bearing a triethylene glycol bridge. The monomers were used as building blocks to assemble new oligo-N-alkylglycines (peptoids) via microwave-assisted solid phase synthesis. Three different types of peptoids were synthesised: (i) oligo-N-(6-aminohexyl)glycines (“standard” peptoids), (ii) oligo-N-{2-[2-(2-aminoethoxy)ethoxy]ethyl}glycines (“triethylene glycol” [TEG] peptoids) and (iii) hetero-oligomers of alternating “standard” and “TEG” monomers (“hybrid” peptoids). The peptoids were evaluated for their cellular permeability and cytotoxicity with HeLa, HEK-293 and CHO cells. All the peptoids were shown to be non-cytotoxic at 10 μM based on cell proliferation assays. In general, it was found that the cellular uptake of the hybrid peptoids outperformed their standard and TEG analogues. Flow cytometry and confocal microscopy results revealed that the hybrid nonamer had the highest cellular uptake efficiency of all the peptoids synthesised. At a concentration of 1 μM, it outperformed the second best molecular transporter (standard nonamer) by a factor of seven.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:699962 |
| Date | January 2014 |
| Creators | Jong, Thing Soon |
| Contributors | Bradley, Mark ; Lam, Hon |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/17938 |
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