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Abstract The creation of complementary products via templating is a hallmark feature of nucleic acid replication. Outside of nucleic acid‐like molecules, the templated synthesis of a hetero‐complementary copy is still rare. Herein we describe one cycle of templated synthesis that creates homomeric macrocyclic peptides guided by linear instructing strands. This strategy utilizes hydrazone formation to pre‐organize peptide oligomeric monomers along the template on a solid support resin, and microwave‐assisted peptide synthesis to couple monomers and cyclize the strands. With a flexible templating strand, we can alter the size of the complementary macrocycle products by increasing the length and number of the binding peptide oligomers, showing the potential to precisely tune the size of macrocyclic products. For the smaller macrocyclic peptides, the products can be released via hydrolysis and characterized by ESI‐MS.
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Synthetic mimics of cyclic antimicrobial peptides via templated ring-opening metathesis (TROM)
We utilized a templated ring-opening metathesis (TROM) strategy to synthesize a series of precision macrocyclic olefins, each containing two, three or four repeating units of a cyclooctene with pendant carboxylic acid side chains. The structures were confirmed by a combination of NMR spectroscopy, MALDI, and MALDI ms/ms fragmentation studies. In accordance with previous work, we found that cyclooctene monomers covalently tethered to precision oligo(thiophene)s yield exclusively macrocyclic products when subjected to the Grubbs 3 rd generation catalyst in highly dilute solution (10 −4 M in DCM, 0 °C). Upon hydrolytic liberation of the daughter oligo(olefin) product, further derivatization with cationic groups confers antibacterial and hemolytic activities. We compare the biological activity of these precision macrocycles to that of a polydisperse sample prepared by direct ROM in the absence of a template. Surprisingly, the relatively ill-defined, disperse mixture of oligomeric species exerted biological activity comparable to that of the precision oligomeric macrocycles, suggesting a remarkable degree of tolerance for heterogeneity. These findings provide nuance to the structure–activity relationships understood thus far for AMPs and their mimics, especially in the context of relatively underexplored macrocyclic compounds.
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- Award ID(s):
- 1653418
- PAR ID:
- 10123073
- Date Published:
- Journal Name:
- Polymer Chemistry
- ISSN:
- 1759-9954
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Desalting oligonucleotides (ONs) for matrix assisted laser desorption ionization mass spectrometry (MALDI MS) analysis was achieved using a simple dissolve-spin approach. The ON is dissolved in an organic solvent. Insoluble salts are removed by centrifugation. ONs are highly polar molecules, and are generally believed insoluble in organic solvents with moderate polarity such as acetonitrile (ACN), 1,4-dioxane, ethyl acetate and THF. However, we found that in the presence of a suitable proton source such as pyridinium chloride, a quantity of ON that is sufficient for MALDI MS analysis could be dissolved. Because inorganic salts are insoluble in such relatively non-polar solvents, the finding can be utilized for desalting ONs for MALDI MS analysis. Comparisons of MS spectra of intentionally salted ONs that underwent the new desalting procedure with those that did not undergo the procedure provided unambiguous evidence that the desalting method is highly effective.more » « less
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/C9PY01271K
