A Simple and Versatile Synthetic Strategy to Functional Polypeptides via Vinyl Sulfone-Substituted l-Cysteine N-Carboxyanhydride

Abstract

Vinyl sulfone-substituted L-cysteine N-carboxyanhydride (VSCys-NCA) monomer was designed and developed to afford a novel and versatile family of vinyl sulfone (VS)-functionalized polypeptides, which further offer a facile access to functional polypeptide-based materials including glycopolypeptides, functional polypeptide coatings, and in situ forming polypeptide hydrogels through Michaeltype addition chemistry under mild conditions. VSCys-NCA was obtained in two straightforward steps with a high overall yield of 76%. The copolymerization of γ-benzyl L-glutamate NCA (BLG-NCA), N-benzyloxycarbonyl-L-lysine NCA (ZLL-NCA), or L-leucine NCA (Leu-NCA) with VSCys-NCA using 1,1,1-trimethyl-N-2-propenylsilanamine (TMPS) as an initiator proceeded smoothly in DMF at 40°C, yielding P(BLG-coVSCys), P(ZLL-co-VSCys), or P(Leu-co-VSCys) with defined functionalities, controlled molecular weights, and moderate polydispersities (PDI = 1.15−1.50). The acidic deprotection of P(BLG-co-VSCys) and P(ZLL-co-VSCys) furnished water-soluble VS-functionalized poly(L-glutamic acid) (P(Glu-co-VSCys)) and VS-functionalized poly(L-lysine) (P(LL-co-VSCys)), respectively. These VS-functionalized polypeptides were amenable to direct, efficient, and selective postpolymerization modification with varying thiol-containing molecules such as 2-mercaptoethanol, 2-mercaptoethylamine hydrochloride, L-cysteine, and thiolated galactose providing functional polypeptides containing pendant hydroxyl, amine, amino acid, and saccharide, respectively. The contact angle and fluorescence measurements indicated that polymer coatings based on P(Leu-coVSCys) allowed direct functionalization with thiol-containing molecules under aqueous conditions. Moreover, hydrogels formed in situ upon mixing aqueous solutions of P(Glu-co-VSCys) and thiolated glycol chitosan at 37°C. These vinyl sulfonefunctionalized polypeptides have opened a new avenue to a broad range of advanced polypeptide-based materials. ■ INTRODUCTIONSynthetic polypeptides inherit many intriguing properties of proteins such as excellent biocompatibility, biodegradability, unique hierarchical assembly property, versatile structures and functionalities, and biological activity. 1−4 They have been widely used as biomimetic materials, 5−7 drug nanocarriers, 8−15 tissue engineering scaffolds, 16−18 and potent catalysts. 19,20 The ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is the most viable strategy for the large-scale synthesis of high molecular weight (MW) polypeptides. 21 In particular, the recent development of controlled NCA polymerization techniques e.g. using transition metal complexes, 22 amine hydrochloride, 23 amine under high vacuum, 24 amine under low temperature, 25 or silazane derivatives 26 renders it possible to prepare polypeptides with controlled MWs and low polydispersities.The emerging biomedical technology demands advancement of functional biomaterials. 27−29 Functional polypeptides containing e.g. carboxylic acid, amine, hydroxyl, and saccharide groups have been obtained by ...

Synthesis of Side-Chain Modified Polypeptides

“…This S-(2-vinylsulfonylethyl)-L-cysteine NCA ( Figure 8E) was copolymerized with a variety of other NCAs using Ntrimethylsilyl allylamine as initiator in DMF. 66 The monomer could also be homopolymerized to give poly(S-(2-vinylsulfonylethyl)-L-cysteine) with M n of 16 kDa and polydispersity index of 1.58.…”

“…67 Recently, Zhong's lab also reported copolypeptides containing vinyl sulfone functionalized Lcysteine residues, which underwent PPM Michael reactions with a variety of thiol containing molecules ( Figure 19E). 66 Due to the reactivity of the vinyl sulfone group, no catalyst was required. However, a potential drawback of this strategy is the poor solubility of functional polycysteines, necessitating the use of copolymers.…”

Comb-like poly(l-cysteine) derivatives with different side groups: synthesis via photochemistry and click chemistry, multi-responsive nanostructures, triggered drug release and cytotoxicity

“…[42][43][44][45][46] Although the deprotection of S-tert-butylmercapto-L-cysteine to generate thiol group took several days by using DTT reducing agent at 60 o C, the S-tert-butylmercapto-L-cysteine-containing polypeptides provided a versatile platform for various chemical modifications including thiol-ene addition. 48 By utilizing photocleavage reaction and thiol-ene addition chemistry, herein, we can easily manipulate the side chain groups of photo-caged poly(S-(o-nitrobenzyl)-L-cysteine) (PNBC) to generate a series of comb-like graft polypeptides (Scheme 1). 48 By utilizing photocleavage reaction and thiol-ene addition chemistry, herein, we can easily manipulate the side chain groups of photo-caged poly(S-(o-nitrobenzyl)-L-cysteine) (PNBC) to generate a series of comb-like graft polypeptides (Scheme 1).…”

Modification of polypeptide materials by Thiol-X chemistry

“…Thiol-yne chemistry works in the same basic way as thiol-ene chemistry but with the added benefit of doubling the functionalization, with the possibility of even heterofunctionalization [39]. This type of chemistry is typically used to end modify, functionalize, and synthesize block copolymers of polypeptides.…”