Abstract
Here we present the synthesis and post-polymerisation modification of poly(acryloyl hydrazide), a versatile scaffold for the preparation of functional polymers: poly(acryloyl hydrazide) was prepared from commercially available starting materials in a three step synthesis on a large scale, in good yields and high purity. Our synthetic approach included the synthesis of a Boc-protected acryloyl hydrazide, the preparation of polymers via RAFT polymerisation and the deprotection of the corresponding Boc-protected poly(acryloyl hydrazide). Post-polymerisation modification of poly(acryloyl hydrazide) was then demonstrated using a range of conditions for both hydrophilic and hydrophobic aldehydes. These experiments demonstrate the potential of poly(acryloyl hydrazide) as a scaffold in the synthesis of functional polymers, in particular those applications where in situ screening of the activity of the functionalised polymers may be required (e.g. biological applications).
Highlights
There is an increasing interest in developing polymers for biomedical applications and we increasingly see polymers that play an “active” role in biology and reproduce or interact with biological functions
Our results demonstrate that poly(acryloyl hydrazide) is a versatile reactive scaffold that can mediate the synthesis of polymers carrying a wide range of functionalities, including acidic and basic moieties, biologically relevant functionalities, and aliphatic and aromatic side-chains
Several conditions have been reported in the literature for the synthesis of poly(acryloyl hydrazide) and poly(methacryloyl hydrazide),[29,32,33,34] including the recently
Summary
Despite the progress in this area, one potential limitation of these post-polymerisation strategies is the low aqueous solubility and stability of some of these reactive polymer scaffolds. The coupling reaction between hydrazides and aldehydes is orthogonal to many biologically relevant functional groups (e.g. hydroxyls, acids or amines) and produces water as a by-product.[28] in the absence of interference from the used aldehydes, there is no need to purify candidate polymers after the post-polymerisation reaction This is often the case for biological applications that benefit from a multivalent effect such as lectin binding.[29] the formed hydrazone is relatively stable at physiological pH (i.e. 5–7),[29] and the biological activity of the functional polymers can be evaluated without having to reduce the hydrazone.[27,30] hydrazides are weakly protonated under physiological conditions ( pKaH ∼ 5) and poly(hydrazide)s are normally non-toxic.[27] Despite all of these features, the use of poly(hydrazide)s as a reactive scaffold had been limited to the preparation of glycopolymers,[29,31] and for pH-responsive drug delivery.[32,33,34,35,36] Alternative elegant strategies using poly (alkoxyamine)s37,38 and poly(aldehyde)s39–41 have been explored. Water was removed by lyophilisation to afford a white crystalline powder (0.9 g, 68% yield): 1H-NMR (300 MHz, DMSO-d6) δ ( ppm) 11.44 (s, 1H), 6.26–6.39 (m, 2H), 5.85 (dd, 3JH,H = 9.6, 2.5 Hz, 1H). 200 μl of a 100 mM‡ solution of Px in acetic acid (AcOH)/D2O buffer§ was mixed with 200 μl of a 100 mM solution of the aldehyde in the required solvent.‡ This mixture was shaken at 60 °C for 24 h.¶ Polymers were used without further purification
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