title: Efficient synthesis of diverse heterobifunctionalized clickable oligo(ethylene glycol) linkers: potential applications in bioconjugation and targeted drug delivery.
abstract: Herein we describe the sequential synthesis of a variety of azide-alkyne click chemistry-compatible heterobifunctional oligo(ethylene glycol) (OEG) linkers for bioconjugation chemistry applications. Synthesis of these bioorthogonal linkers was accomplished through desymmetrization of OEGs by conversion of one of the hydroxyl groups to either an alkyne or azido functionality. The remaining distal hydroxyl group on the OEGs was activated by either a 4-nitrophenyl carbonate or a mesylate (-OMs) group. The -OMs functional group served as a useful precursor to form a variety of heterobifunctionalized OEG linkers containing different highly reactive end groups, e.g., iodo, -NH(2), -SH and maleimido, that were orthogonal to the alkyne or azido functional group. Also, the alkyne- and azide-terminated OEGs are useful for generating larger discrete poly(ethylene glycol) (PEG) linkers (e.g., PEG(16) and PEG(24)) by employing a Cu(I)-catalyzed 1,3-dipolar cycloaddition click reaction. The utility of these clickable heterobifunctional OEGs in bioconjugation chemistry was demonstrated by attachment of the integrin (α(v)β(3)) receptor targeting peptide, cyclo-(Arg-Gly-Asp-D-Phe-Lys) (cRGfKD) and to the fluorescent probe sulfo-rhodamine B. The synthetic methodology presented herein is suitable for the large scale production of several novel heterobifunctionalized OEGs from readily available and inexpensive starting materials.
authors.affiliation: International Institute of Nano and Molecular Medicine, School of Medicine, University of Missouri, 1514 Research Park Drive, Columbia, Missouri 65211-3450, USA.
authors.forename: Lalit N
authors.initials: LN
authors.lastname: Goswami
authors.forename: Zachary H
authors.initials: ZH
authors.lastname: Houston
authors.forename: Saurav J
authors.initials: SJ
authors.lastname: Sarma
authors.forename: Satish S
authors.initials: SS
authors.lastname: Jalisatgi
authors.forename: M Frederick
authors.initials: MF
authors.lastname: Hawthorne
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D001386:Azides / Q000737:chemistry*; D057930:Click Chemistry; D016503:Drug Delivery Systems; D019855:Ethylene Glycol / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000480:Alkynes; D001386:Azides; D019855:Ethylene Glycol