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Fluoride-promoted esterification (FPE) chemistry: A robust route to Bis-MPA dendrons and their postfunctionalization
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Coating Technology.
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology.ORCID iD: 0000-0002-8474-9478
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Coating Technology.ORCID iD: 0000-0002-9200-8004
2016 (English)In: Molecules, ISSN 1431-5157, E-ISSN 1420-3049, Vol. 21, no 3, article id 366Article in journal (Refereed) Published
Resource type
Text
Abstract [en]

Bifunctional dendrons based on 2,2-bis(methylol)propionic acid (bis-MPA) are highly desirable scaffolds for biomedical applications. This is due to their flawless nature and large and exact number of functional groups as well as being biodegradable and biocompatible. Herein, we describe a facile divergent growth approach to their synthesis from monobenzylated tetraethylene glycol and post functionalization utilizing fluoride-promoted esterification (FPE) chemistry protocols. The scaffolds, presenting selectively deprotectable hydroxyls in the periphery and at the focal point, were isolated on a multigram scale with excellent purity up to the fourth generation dendron with a molecular weight of 2346 Da in seven reactions with a total yield of 50%. The third generation dendron was used as a model compound to demonstrate its functionalizability. Selective deprotection of the dendron's focal point was achieved with an outstanding yield of 94%, and biotin as well as azido functionalities were introduced to its focal point and periphery, respectively, through FPE chemistry. Bulky disperse red dyes were clicked through CuAAC to the dendron's azido groups, giving a biotinylated dendron with multivalent dyes with a molecular weight of 6252 Da in a total yield of 37% in five reactions with an average yield of 82% starting from the third generation focally and peripherally protected dendron. FPE chemistry proved to be a superb improvement over previous protocols towards bis-MPA dendrons as high purity and yields were obtained with less toxic solvents and greatly improved monomer utilization.

Place, publisher, year, edition, pages
MDPI AG , 2016. Vol. 21, no 3, article id 366
Keywords [en]
Biotin, Bis-MPA, Carbonyl diimidazole, CuAAC click chemistry, Dendritic polymers, Dendron, FPE chemistry, Polyesters
National Category
Polymer Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-187297DOI: 10.3390/molecules21030366ISI: 000373802200117PubMedID: 26999090Scopus ID: 2-s2.0-84963650366OAI: oai:DiVA.org:kth-187297DiVA, id: diva2:929637
Note

QC 20160519

Available from: 2016-05-19 Created: 2016-05-19 Last updated: 2024-03-15Bibliographically approved
In thesis
1. Polyester dendrimers for biomedical applications
Open this publication in new window or tab >>Polyester dendrimers for biomedical applications
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Dendrimers are perfectly defined and highly branched large molecules with a high density of functional groups that makes them interesting for a variety of biomedical applications such as drug delivery, theranostics and as antimicrobials. Their synthesis can be complicated, time-consuming and expensive which has been an obstacle to their success. This work was aimed towards exploring a recently developed synthesis method for the synthesis of polyester dendrimers based on 2,2-bis(methylol)propionic acid (bis-MPA) and to evaluate these for biomedical applications. This synthesis method makes use of N,N'-carbonyldiimidazole for the formation of esters, and the reaction is catalyzed by the inorganic salt cesium fluoride. In comparison to previously established methods, this technique proved itself throughout this work as an excellent tool for the synthesis of precise ester-based structures by having no competing side-reactions and producing only easy-to-remove by-products while still being highly efficient. Complex dendrimers with multifunctionality or chargeable functional groups could be synthesized with relatively low efforts and good chemical and structural purity. Some of the charged dendrimers were found to be antibacterial, most likely due to their strong interactions with bacterial membranes, while being non-toxic to cells. New antibacterial materials are highly sought after as replacements for conventional penicillin towards which bacterial resistance is constantly increasing. These dendrimers were also incorporated into a water-absorbent gel – a hydrogel – that in turn was shown to be highly efficient at reducing the viability of bacteria. Large molecules with positive charges are also used for the delivery of short interfering RNA (siRNA) into cells. siRNA has the potential to cure a wide array of diseases by silencing the genes that causes these diseases, but it requires the aid of another molecule or particle to be efficient. The dendrimers synthesized in this work were shown to be efficient at forming complexes with siRNA, but not capable of efficiently delivering it into cells. This was most likely due to either the dendrimers degrading too fast or the interactions between the pH-dependent charges and the siRNA being too weak as the complex attempts to cross the cell membrane.

Abstract [sv]

Dendrimerer är perfekt definierade och kraftigt förgrenade stora molekyler med hög densitet av funktionella grupper vilket gör dem intressanta för olika biomedicinska applikationer som frisättning av läkemedel, teranostik och som antibakteriella material. Deras syntes kan vara komplicerad, tidskrävande och dyr vilket har hindrat deras framgång. Inom detta arbete har en nyligen utvecklad metod för syntes av polyesterdendrimerer baserade på 2,2-bis(metylol)propansyra (bis-MPA) undersökts, och dessa material har utvärderats för biomedicinska applikationer. Metoden bygger på användandet av N,N’-karbonyldiimidazol för att bilda estrar, och reaktionen katalyseras av det oorganiska saltet cesiumfluorid. I jämförelse med äldre metoder visade sig denna teknik under detta arbete vara ett utmärkt redskap för syntes av precisa esterbaserade strukturer genom en avsaknad av sidoreaktioner och att alla biprodukter var mycket lätta att rena bort medan den samtidigt var mycket effektiv. Komplexa dendrimerer med multifunktionalitet och funktionella grupper som kan bära laddning syntetiserades med enkelhet och med hög kemisk och strukturell renhet. Vissa av de laddade dendrimererna visade sig vara antibakteriella, troligtvis genom deras starka interaktioner med bakteriella membran, samt ej giftiga för celler. Nya antibakteriella material eftersöks för att ersätta konventionella penicillinämnen mot vilka bakteriell resistans ständigt ökar. Dessa dendrimerer användes också i vattenabsorberande geler – hydrogeler – som i sin tur visade sig vara antibakteriella. Stora molekyler med positiva laddningar används även för leverans av ”short interfering RNA” (siRNA) in i celler. siRNA har potential för att bota många sjukdomar genom att avaktivera gener i kroppen som orsakar dessa, men en annan molekyl eller partikel måste agera bärare. Dendrimererna i detta arbete visade sig vara effektiva som komplexbildare med siRNA, men ej kapabla att leverera detta in i celler. Detta berodde troligtvis på att dendrimererna bröts ner för fort, eller att interaktionen mellan deras pH-beroende laddningar och siRNA:t var för svaga när detta komplex försökte korsa cellmembranet.

Place, publisher, year, edition, pages
KTH Royal Institute of Technology, 2020
Series
TRITA-CBH-FOU ; 2020:21
National Category
Chemical Sciences
Research subject
Fibre and Polymer Science
Identifiers
urn:nbn:se:kth:diva-271971 (URN)978-91-7873-508-2 (ISBN)
Public defence
2020-05-15, https://kth-se.zoom.us/webinar/register/WN_cf9_srx2QCWFusIMUgd2TA, 09:00 (English)
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Supervisors
Note

QC 2020-04-15

Available from: 2020-04-15 Created: 2020-04-14 Last updated: 2022-06-26Bibliographically approved

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Stenström, PatrikAndrén, Oliver C. J.Malkoch, Michael

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