The alternating polymerization of cyclobutene 1-carboxylic esters and cyclohexene derivatives with the precatalyst [(H2IMes)(3-Br-pyr)2Cl2Ru=CHPh] is described. This reaction is synthetically accessible and provides (AB)n heteropolymers with an alternating backbone and alternating functionality. The regiocontrol of heteropolymer formation derives from the inability of the cyclobutene ester and cyclohexene monomers to undergo homopolymerization in combination with the favorable kinetics of cross polymerization.

The ideal wound healing scaffold should provide the appropriate physical and mechanical properties to prevent secondary infection, as well as an excellent physiological environment to facilitate cell adhesion, proliferation and/or differentiation. Therefore, we developed a synthetic cell-adhesive polypeptide hydrogel with inherent antibacterial activity. A series of polypeptides, poly(Lys)x(Ala)y (x+y=100) with varied hydrophobicity via metal-free ring-opening polymerization of NCA-Lys(Boc) and NCA-Ala monomers (NCA = N-carboxylic anhydride) mediated by hexamethyldisilazane (HMDS) were synthesized. These polypeptides were cross-linked with 6-arm PEG-amide succinimidyl glutarate (ASG) (Mw = 10K) to form hydrogels with a gelation time of five minutes and a storage modulus (G') of 1400–3000 Pa as characterized by rheometry. The hydrogel formed by cross-linking of poly(Lys)60(Ala)40 (5 wt%) and 6-arm PEG-ASG (16 wt%) (Gel-III) exhibited cell adhesion and cell proliferation activities superior to other polypeptide hydrogels. In addition, Gel-III displays significant antibacterial activity against E. coli JM109 and S. aureus ATCC25923. Thus, we have developed a novel, cell-adhesive hydrogel with inherent antibacterial activity as a potential scaffold for cutaneous wound healing.

Antibacterial polymers have potential as pharmaceuticals and as coatings for implantation devices. The design of these materials will be optimized when we have a complete understanding of the structural features that impart activity toward target organisms and those that are benign with respect to the mammalian host. In this work, four series of polymers in which cationic and hydrophobic groups were distributed along the backbone were tested against six different bacterial species (both Gram positive and Gram negative) and for host cytotoxicities (red blood cell lysis). The most effective of the polymers studied are regularly spaced, featuring a 6-8 carbon stretch along the backbone between side chains that present positively charged groups. They cause potassium efflux, disorder the bacterial cytoplasmic membrane, and disrupt the membrane potential. These polymers, available from alternating ring opening metathesis polymerization (AROMP), offer proof of principle for the importance of regular spacing in antibacterial polymers and for the synthesis of additional functional materials based on regularly spaced scaffolds.In the more than 80 years since Fleming discovered penicillin, humans have expended a great deal of effort in the search for, optimization of, and testing of new antibiotics. During the same period, new pathogens have appeared and antibiotic-resistant strains have evolved. The war against the microbes is far from over (1).Of particular concern in the western world is the incidence of hospital-acquired infections and the drug resistance of many of the causative phenotypes (2,3). The appearance of methicillin-resistant Staphylococcus aureus (4) and resistant strains of pneumonia and tuberculosis (5,6) as community-acquired infections have served to focus public attention on this growing health problem, leading The Infectious Diseases Society of America to call for renewed efforts to develop antimicrobial therapies (7).One attractive avenue for new antibiotic development is the exploitation or development of "host-defense" antimicrobial peptides (AMPs). Eukaryotes produce these small peptides (about 12 to 80 amino acid residues) as part of their innate immune response against pathogen infection (8-10). Some AMPs are preorganized so that they are amphipathic; i.e. cationic residues are segregated from hydrophobic residues onto opposing faces of the peptide (11). Others, it appears, are induced to adopt an amphipathic topology by contact with cell membranes (or, in laboratory experiments, with micellar surfaces). The inherent or induced amphipathic conformation of an AMP facilitates binding to and insertion into lipid bilayers. Subsequent disruption of the cytoplasmic membrane (8) can lead to bacterial death. Alternatively, some antimicrobial peptides are thought to cause cell death by additional mechanisms (11) including membrane depolarization, binding to cytoplasmic components (12,13), and inhibition of cell wall synthesis (14). Regardless of the killing mechanism, the ability to interact with...

The reactivities of a series of 1-substituted cyclobutene derivatives (carboxylate esters, carboxamides and carbinol esters) were investigated as substrates for ring-opening metathesis polymerization (ROMP) with [(H 2 IMes)(3-Br-pyridine) 2 (Cl) 2 Ru=CHPh]. Both the secondary amides of 1-cyclobutenecarboxylic acid and the esters of 1-cyclobutene-1-methanol undergo polymerization. The secondary amides provide translationally invariant polymers (E-olefins). Although the carbinol esters yield stereo-and regiochemically heterogeneous polymers, the 1-cyclobutenecarboxylic acid esters and tertiary amides undergo ring opening metathesis (ROM) but not ROMP. The regio-and stereochemical outcomes of these ROMP and ROM reactions were analyzed at the B3LYP/6-31G* and LANL2DZ levels of theory. Calculations suggest that the regiochemistry and stereochemistry of the addition to the propagating carbene to form the metallocyclobutane intermediate depend on both charge distribution and steric interactions.

Catalysis of alternating ROMP with (H 2 IMes)Cl 2 Ru=CHPh(OiPr), the second generation Hoveyda-Grubbs catalyst, provided an entirely cyclic alternating polymer. Conditions for the cyclic AROMP were used to prepare a polymer in which one of the repeat units bore a primary alkyl chloride that was used for further elaboration.Cyclic polymers1 exhibit thermodynamic,1b optical,2 and biophysical3 properties different from those of their linear counterparts. However, the potential applications of cyclic polymers that result from these altered properties have yet to be developed. Particularly intriguing are applications in drug delivery.4The pharmacokinetics of cyclic polymers favor their use as vehicles for carrying drugs to solid tumors. Presumably because the minimum cross section of a cyclic polymer is larger than that of the corresponding linear polymer, cyclic polymers are filtered more slowly through the pores of the kidney. Relative to similar linear polymers of comparable molecular weights, they have reduced rates of clearance and extended plasma circulation times.5 In addition, and again as a consequence of topology, cyclic polymers exhibit greater tumor accumulations than the related linear polymers; this difference has been attributed to the enhanced permeation and retention (EPR) effect. 6Cyclic polymers are formed as by-products during the preparation of high molecular weight polymers by intramolecular reactions termed back-biting. In principle, the formation of kathlyn.parker@stonybrook.edu; nicole.sampson@stonybrook.edu. Supporting Information Available. Detailed descriptions of the experimental procedures and spectra. This material is free of charge via the Internet at http://pubs.acs.org. It is likely that there is much to be learned about the synthesis of cyclic polymers.7 , 1b Notable recent contributions include strategies based on ring expansions and on "click chemistry.8 The production of cyclic polymers in ROMP experiments has been optimized by the use of custom-synthesized catalysts.9 NIH Public AccessIn 2009, we reported the preparation of copolymers of cyclobutene-1-carboxylic acid esters (1, monomer A) and cyclohexenes (2, Z = H or D, monomer B) by alternating ring opening metathesis polymerization (AROMP)10 with the 3 rd generation Grubbs catalyst (3) ( Figure 1 and Scheme 1).11Analysis of the 1 H NMR spectrum of the product mixture derived from cyclobutenecarboxylic acid methyl ester (monomer 1a) and cyclohexene D 10 (2-D 10 ) led us to conclude that the anticipated alternating linear polymer PhCH=(AB) n =CH 2 , (1a-2-D 10 ) n was formed, but that it was contaminated with cyclic polymer cyclic (1a-2-D 10 ) n 1a in which there was a single AA repeat and cyclic (1a-2-D 10 ) n .Although we were able to isolate the cyclic AROMP polymers from their linear co-products, this method of preparation was clearly not ideal. Because we recognized the advantages of cyclic polymers for certain applications, we considered modifying the conditions of the AROMP reaction to maximize the back-biting r...