Degradable Conjugates
from Oxanorbornadiene Reagents
Alexander
A. Kislukhin
Cody J. Higginson
Vu P. Hong
M. G. Finn
10.1021/ja301491h.s002
https://acs.figshare.com/articles/journal_contribution/Degradable_Conjugates_from_Oxanorbornadiene_Reagents/2531932
Oxanorbornadienedicarboxylate (OND) reagents were explored
for
purposes of binding and releasing drugs from serum albumins as representative
macromolecular carriers. Being highly reactive Michael acceptors,
ONDs form adducts with thiols and amines, which then undergo retro-Diels–Alder
fragmentation. A study of more than 30 model adducts revealed a number
of modifications that can be used to influence adduct stability. For
the most reactive OND linkers, the labeling of the single available
bovine serum albumin (BSA) cysteine residue was complete within minutes
at a mid-micromolar concentration of reactants. While a selectivity
of greater than 1000-fold for thiol over amine was observed with model
amino acids, the labeling of protein amines with ONDs is fast enough
to be practical, as demonstrated by the reaction with thiol-depleted
BSA. The OND–amine adducts were found to be up to 15 times
more stable than OND–thiol adducts, and to be sensitive to
acid by virtue of a stereochemically dependent acceleration of cycloreversion.
The release rate of fluorescent cargo from serum albumins was tuned
by selecting the coupling partners: the available half-lives ranged
from 40 min to 7 days at 37 °C. Such versatility of release profiles
from protein carriers, controlled by the nature of the OND linkage,
is a useful addition to the drug delivery toolbox.
2012-04-11 00:00:00
influence adduct stability
30 model adducts
serum albumins
ONDs form adducts
BSA
drug delivery toolbox
reactive OND linkers
reactive Michael acceptors