An optimised Cu(0)-RDRP approach for the synthesis of lipidated oligomeric vinyl azlactone

toward a versatile antimicrobial materials screening platform

James L Grace, Maite Amado, Janet C Reid, Alysha G Elliott, Cornelia B Landersdorfer, Nghia P Truong , Kristian Kempe, Matthew A Cooper, Thomas P Davis, Veronique Montembault, Sagrario Pascual, Laurent Fontaine, Tony Velkov, John F Quinn, Michael R Whittaker

Research output: Contribution to journalArticleResearchpeer-review

Abstract

This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers via an optimised Cu(0)-mediated reversible-deactivation radical polymerisation approach, and the use of these oligomers as a versatile functional platform for the rapid generation of antimicrobial materials. The relative amounts of CuBr2 and Me6TREN were optimised to allow the fast and controlled polymerisation of VDM. These conditions were then used with the initiators ethyl 2-bromoisobutyrate, dodecyl 2-bromoisobutyrate, and (R)-3-((2-bromo-2-methylpropanoyl)oxy)propane-1,2-diyl didodecanoate to synthesise a library of oligo(VDM) (degree of polymerisation = 10) with ethyl, dodecyl or diglyceride end-groups. Subsequently, ring-opening of the pendant oxazolone group with various amines (i.e., 2-(2-Aminoethyl)-1,3-di-Boc-guanidine, 1-(3-Aminopropyl)imidazole, N-Boc-ethylenediamine, or N,N-dimethylethylenediamine) expanded the library to give 12 functional oligomers incorporating different cationic and lipid elements. The antimicrobial activities of these oligomers were assessed against a palette of bacteria and fungi: i.e. Staphylococcus aureus, Escherichia coli, Candida albicans, and Cryptococcus neoformans. The oligomers generally exhibited the greatest activity against the fungus, C. neoformans, with a minimum inhibitory concentration of 1 μg mL-1 (comparable to the clinically approved antifungal fluconazole). To assess haemocompatibility, the oligomers were assayed against erythrocytes, with the primary amine or guanidine containing C12 and 2C12 oligomers exhibiting greater lysis against the red blood cells (HC10 values between 7.1 and 43 μg mL-1) than their imidazole and tertiary amine counterparts (HC10 of >217 μg mL-1). Oligomers showed the greatest selectivity for C. neoformans, with the C12-and 2C12-Tertiary amine and C12-imidazole oligomers possessing the greatest selectivity of >54-109. These results demonstrate the utility of reactive oligomers for rapidly assessing structure-property relationships for antibacterial and antifungal materials.

Original languageEnglish
Pages (from-to)6796-6809
Number of pages14
JournalJournal of Materials Chemistry B
Volume7
Issue number43
DOIs
Publication statusPublished - 21 Nov 2019

Cite this

@article{ea306c35323c43cfb4a7c80ac1d76487,
title = "An optimised Cu(0)-RDRP approach for the synthesis of lipidated oligomeric vinyl azlactone: toward a versatile antimicrobial materials screening platform",
abstract = "This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers via an optimised Cu(0)-mediated reversible-deactivation radical polymerisation approach, and the use of these oligomers as a versatile functional platform for the rapid generation of antimicrobial materials. The relative amounts of CuBr2 and Me6TREN were optimised to allow the fast and controlled polymerisation of VDM. These conditions were then used with the initiators ethyl 2-bromoisobutyrate, dodecyl 2-bromoisobutyrate, and (R)-3-((2-bromo-2-methylpropanoyl)oxy)propane-1,2-diyl didodecanoate to synthesise a library of oligo(VDM) (degree of polymerisation = 10) with ethyl, dodecyl or diglyceride end-groups. Subsequently, ring-opening of the pendant oxazolone group with various amines (i.e., 2-(2-Aminoethyl)-1,3-di-Boc-guanidine, 1-(3-Aminopropyl)imidazole, N-Boc-ethylenediamine, or N,N-dimethylethylenediamine) expanded the library to give 12 functional oligomers incorporating different cationic and lipid elements. The antimicrobial activities of these oligomers were assessed against a palette of bacteria and fungi: i.e. Staphylococcus aureus, Escherichia coli, Candida albicans, and Cryptococcus neoformans. The oligomers generally exhibited the greatest activity against the fungus, C. neoformans, with a minimum inhibitory concentration of 1 μg mL-1 (comparable to the clinically approved antifungal fluconazole). To assess haemocompatibility, the oligomers were assayed against erythrocytes, with the primary amine or guanidine containing C12 and 2C12 oligomers exhibiting greater lysis against the red blood cells (HC10 values between 7.1 and 43 μg mL-1) than their imidazole and tertiary amine counterparts (HC10 of >217 μg mL-1). Oligomers showed the greatest selectivity for C. neoformans, with the C12-and 2C12-Tertiary amine and C12-imidazole oligomers possessing the greatest selectivity of >54-109. These results demonstrate the utility of reactive oligomers for rapidly assessing structure-property relationships for antibacterial and antifungal materials.",
author = "Grace, {James L} and Maite Amado and Reid, {Janet C} and Elliott, {Alysha G} and Landersdorfer, {Cornelia B} and Truong, {Nghia P} and Kristian Kempe and Cooper, {Matthew A} and Davis, {Thomas P} and Veronique Montembault and Sagrario Pascual and Laurent Fontaine and Tony Velkov and Quinn, {John F} and Whittaker, {Michael R}",
year = "2019",
month = "11",
day = "21",
doi = "10.1039/C9TB01624D",
language = "English",
volume = "7",
pages = "6796--6809",
journal = "Journal of Materials Chemistry B",
issn = "2050-750X",
publisher = "The Royal Society of Chemistry",
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}

An optimised Cu(0)-RDRP approach for the synthesis of lipidated oligomeric vinyl azlactone : toward a versatile antimicrobial materials screening platform. / Grace, James L; Amado, Maite ; Reid, Janet C; Elliott, Alysha G; Landersdorfer, Cornelia B; Truong , Nghia P; Kempe, Kristian; Cooper, Matthew A; Davis, Thomas P; Montembault, Veronique; Pascual, Sagrario; Fontaine, Laurent; Velkov, Tony; Quinn, John F; Whittaker, Michael R.

In: Journal of Materials Chemistry B, Vol. 7, No. 43, 21.11.2019, p. 6796-6809.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - An optimised Cu(0)-RDRP approach for the synthesis of lipidated oligomeric vinyl azlactone

T2 - toward a versatile antimicrobial materials screening platform

AU - Grace, James L

AU - Amado, Maite

AU - Reid, Janet C

AU - Elliott, Alysha G

AU - Landersdorfer, Cornelia B

AU - Truong , Nghia P

AU - Kempe, Kristian

AU - Cooper, Matthew A

AU - Davis, Thomas P

AU - Montembault, Veronique

AU - Pascual, Sagrario

AU - Fontaine, Laurent

AU - Velkov, Tony

AU - Quinn, John F

AU - Whittaker, Michael R

PY - 2019/11/21

Y1 - 2019/11/21

N2 - This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers via an optimised Cu(0)-mediated reversible-deactivation radical polymerisation approach, and the use of these oligomers as a versatile functional platform for the rapid generation of antimicrobial materials. The relative amounts of CuBr2 and Me6TREN were optimised to allow the fast and controlled polymerisation of VDM. These conditions were then used with the initiators ethyl 2-bromoisobutyrate, dodecyl 2-bromoisobutyrate, and (R)-3-((2-bromo-2-methylpropanoyl)oxy)propane-1,2-diyl didodecanoate to synthesise a library of oligo(VDM) (degree of polymerisation = 10) with ethyl, dodecyl or diglyceride end-groups. Subsequently, ring-opening of the pendant oxazolone group with various amines (i.e., 2-(2-Aminoethyl)-1,3-di-Boc-guanidine, 1-(3-Aminopropyl)imidazole, N-Boc-ethylenediamine, or N,N-dimethylethylenediamine) expanded the library to give 12 functional oligomers incorporating different cationic and lipid elements. The antimicrobial activities of these oligomers were assessed against a palette of bacteria and fungi: i.e. Staphylococcus aureus, Escherichia coli, Candida albicans, and Cryptococcus neoformans. The oligomers generally exhibited the greatest activity against the fungus, C. neoformans, with a minimum inhibitory concentration of 1 μg mL-1 (comparable to the clinically approved antifungal fluconazole). To assess haemocompatibility, the oligomers were assayed against erythrocytes, with the primary amine or guanidine containing C12 and 2C12 oligomers exhibiting greater lysis against the red blood cells (HC10 values between 7.1 and 43 μg mL-1) than their imidazole and tertiary amine counterparts (HC10 of >217 μg mL-1). Oligomers showed the greatest selectivity for C. neoformans, with the C12-and 2C12-Tertiary amine and C12-imidazole oligomers possessing the greatest selectivity of >54-109. These results demonstrate the utility of reactive oligomers for rapidly assessing structure-property relationships for antibacterial and antifungal materials.

AB - This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers via an optimised Cu(0)-mediated reversible-deactivation radical polymerisation approach, and the use of these oligomers as a versatile functional platform for the rapid generation of antimicrobial materials. The relative amounts of CuBr2 and Me6TREN were optimised to allow the fast and controlled polymerisation of VDM. These conditions were then used with the initiators ethyl 2-bromoisobutyrate, dodecyl 2-bromoisobutyrate, and (R)-3-((2-bromo-2-methylpropanoyl)oxy)propane-1,2-diyl didodecanoate to synthesise a library of oligo(VDM) (degree of polymerisation = 10) with ethyl, dodecyl or diglyceride end-groups. Subsequently, ring-opening of the pendant oxazolone group with various amines (i.e., 2-(2-Aminoethyl)-1,3-di-Boc-guanidine, 1-(3-Aminopropyl)imidazole, N-Boc-ethylenediamine, or N,N-dimethylethylenediamine) expanded the library to give 12 functional oligomers incorporating different cationic and lipid elements. The antimicrobial activities of these oligomers were assessed against a palette of bacteria and fungi: i.e. Staphylococcus aureus, Escherichia coli, Candida albicans, and Cryptococcus neoformans. The oligomers generally exhibited the greatest activity against the fungus, C. neoformans, with a minimum inhibitory concentration of 1 μg mL-1 (comparable to the clinically approved antifungal fluconazole). To assess haemocompatibility, the oligomers were assayed against erythrocytes, with the primary amine or guanidine containing C12 and 2C12 oligomers exhibiting greater lysis against the red blood cells (HC10 values between 7.1 and 43 μg mL-1) than their imidazole and tertiary amine counterparts (HC10 of >217 μg mL-1). Oligomers showed the greatest selectivity for C. neoformans, with the C12-and 2C12-Tertiary amine and C12-imidazole oligomers possessing the greatest selectivity of >54-109. These results demonstrate the utility of reactive oligomers for rapidly assessing structure-property relationships for antibacterial and antifungal materials.

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U2 - 10.1039/C9TB01624D

DO - 10.1039/C9TB01624D

M3 - Article

VL - 7

SP - 6796

EP - 6809

JO - Journal of Materials Chemistry B

JF - Journal of Materials Chemistry B

SN - 2050-750X

IS - 43

ER -