We report the controlled radical copolymerization of N-(2-hydroxypropyl)methacrylamide (HPMA) with a monomer containing an active ester, N-methacryloyloxysuccinimide (NMS), by reversible addition fragmentation chain transfer (RAFT). The large difference in the reactivity ratios of HPMA and NMS resulted in significant variations in copolymer composition with increasing conversion during batch copolymerization. The use of a semi-batch copolymerization method, involving the gradual addition of the more reactive NMS, allowed uniformity of copolymer composition to be maintained during the polymerization. We synthesized polymers in a wide range of molecular weights (M(n) = 3000-50,000 Da) with low polydispersities (1.1-1.3). The effect of the ratio of monomer to chain transfer agent (CTA) on the molecular weight of the polymer was investigated. Given the numerous applications of poly(HPMA)-based conjugates in designing polymeric therapeutics, these controlled molecular weight activated polymers represent attractive scaffolds for biofunctionalization. As a demonstration, we attached a peptide to the activated polymer backbone to synthesize a potent controlled molecular weight polyvalent inhibitor of anthrax toxin.
We describe the synthesis of activated homopolymers and copolymers of controlled molecular weight based on the controlled radical polymerization of N-acryloyloxysuccinimide (NAS) by reversible addition fragmentation chain transfer (RAFT). We synthesized activated homopolymers in a range of molecular weights with polydispersities between 1 and 1.2. The attachment of an inhibitory peptide to the activated polymer backbone yielded a potent controlled molecular weight polyvalent inhibitor of anthrax toxin. To provide greater control over the placement of the peptides along the polymer backbone, we also used a semi-batch copolymerization method to synthesize copolymers of NAS and acrylamide (AAm). This approach enabled the synthesis of copolymers with control over the placement of peptide-reactive NAS monomers along an inert backbone; subsequent functionalization of NAS with peptide yielded well-defined polyvalent anthrax toxin inhibitors that differed in their potencies. These strategies for controlling molecular weight, ligand density, and ligand placement will be broadly applicable for designing potent polyvalent inhibitors for a variety of pathogens and toxins, and for elucidating structure-activity relationships in these systems.
Electrophilic alkylations of phenol/2,6-dimethylphenol were performed with vinylideneterminated poly(1-hexene)s using BF 3 ·OEt 2 catalyst. Vinylidene-terminated poly(1-hexene)s with M n varying from 400 to 10000 were prepared by bulk polymerization of 1-hexene at 50 to −20 • C using Cp 2 ZrCl 2 /MAO catalysts. The phenol/2,6-dimethylphenol-terminated poly(1-hexene)s was characterized by NMR ( 1 H, 13 C), UV, IR and vapor phase osmometer (VPO). The isomer distribution (ortho, para and ortho/para) was determined by 13 P NMR using a phosphitylating reagent, namely 2-chloro-1,3,2dioxaphospholane. The number-average degree of functionality (F n ) >0.9 with >95 % para selectivity could be achieved using low-molecular-weight oligomers of poly(1-hexene)s.
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