As more evidence emerges supporting the possibility that nonsteroidal anti-inflammatory drugs, especially aspirin (acetyl salicylic acid), might have a role in the prevention and management of certain types of cancer, there have been several attempts to fabricate salicylic acid-based polymers that can be employed in the targeted therapy of tumors. The primary disadvantage so far has been in use of nontherapeutic polymeric backbones that constitute the majority of the therapeutic particle's size. The focus of this research is the creation of a biodegradable polymer consisting only of salicylic acid, and its use as the main building block in targeted nanotherapeutics that would consequently provide both high local dose and sustained release of the active moiety. This work demonstrates the synthesis and degradation of polysalicylates, and modulation of their size and hydrolytic stability through the formation of nanostructures.
Site-selective
chemical methods for protein bioconjugation have
revolutionized the fields of cell and chemical biology through the
development of novel protein/enzyme probes bearing fluorescent, spectroscopic,
or even toxic cargos. Herein, we report two new methods for the bioconjugation
of α-oxo aldehyde handles within proteins using small molecule
aniline and/or phenol probes. The “α-oxo-Mannich”
and “catalyst-free aldol” ligations both compete for
the electrophilic α-oxo aldehyde, which displays pH divergent
reactivity proceeding through the “Mannich” pathway
at acidic pH to afford bifunctionalized bioconjugates, and the “catalyst-free
aldol” pathway at neutral pH to afford monofunctionalized bioconjugates.
We explore the substrate scope and utility of both of these bioconjugations
in the construction of neoglycoproteins, in the process formulating
a mechanistic rationale for how both pathways intersect with each
other at different reaction pH’s.
We present catalyst-free “green” site-selective protein bioconjugations that utilise aldol condensations and are compatible with click chemistries, and construct a nanobody-derived bioconjugate capable of selectively labelling prostate cancer cells.
The bioconjugation of proteins to small molecules serves as an invaluable tool for probing biological mechanisms and creating biomaterials. The most powerful bioconjugation stratagems are those which have rapid kinetics, are site-selective, can be conducted in aqueous solvent under mild conditions and do not require the use of additional potentially toxic catalysts. Herein we present spontaneous coupling via aldol ligation of proteins (SCALP) a catalyst-free “green” site-selective protein ligation between α-oxo aldehyde functionalised proteins and enolisable aldehyde probes at neutral pH, and demonstrate the utility of this system in the targeting of prostate cancer cells with functionalised nanobodies.
<div><div><div><p>Site-selective chemical methods for protein bioconjugation have revolutionised the fields of cell and chemical biology through the development of novel protein/enzyme probes bearing fluorescent, spectroscopic or even toxic cargos. Herein we report two new methods for the bioconjugation of a-oxo aldehyde handles within proteins using small molecule aniline and/or phenol probes. The ‘a-oxo-Mannich’ and ‘catalyst-free aldol’ ligations both compete for the electrophilic a-oxo aldehyde which displays pH divergent reactivity proceeding through the “Mannich” pathway at acidic pH to afford bifunctionalised bioconjugates, and the “catalyst-free aldol” pathway at neutral pH to afford monofunctionalised bioconjugates. We explore the substrate scope and utility of both these bioconjugations in the construction of neoglycoproteins, in the process formulating a mechanistic rationale for how both pathways intersect with each other at different reaction pH.</p></div></div></div>
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