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Lipid peroxidation is a biochemically adverse phenomenon with key involvement in many different diseases including premature infant blindness, nonalcoholic steatohepatitis, or Parkinson's disease. Moreover, lipid peroxidation may be the most important universal driver of the biological aging process. Canonic lipid peroxidation is a free radical chain reaction consisting of three kinetically independent steps, initiation, propagation, and termination. During the bulk propagation phase, only lipids and oxygen are consumed as substrates and maintain the chain reaction. In native biological membranes, however, lipid peroxidation takes place in direct vicinity to high concentrations of inserted membrane proteins with their exposed hydrophobic amino acid side chains. In the following, we review the evidence that redox-active intramembrane amino acid residues have a profound impact on the course and extent of lipid peroxidation in vivo. Specifically, tyrosine and tryptophan are concluded to be chain-breaking antioxidants that effectuate termination, whereas cysteine is a chain-transfer catalyst that accelerates propagation and thereby promotes lipid peroxidation. Methionine, in turn, is highly accumulated in mitochondrial membrane proteins of animal species with high metabolic rates and imminent danger of lipid peroxidation, though its specific role has not been entirely defined. Potentially, it interferes with initiation on the membrane protein surface. Nevertheless, all four residues are distinguished by their clear relevance to lipid peroxidation as deduced from either experimental or genetic and comparative data. The latter have uncovered distinct evolutionary pressures in favor or against each residue in lipid membranes and have shed light on formerly unacknowledged chemical mechanisms. [ABSTRACT FROM AUTHOR]

Thiyl radicals are exceptionally interesting reactive sulfur species (RSS), but rather rarely considered in a biological or medical context. We here review the reactivity of protein thiyl radicals in aqueous and lipid phases and provide an overview of their most relevant reaction partners in biological systems. We deduce that polyunsaturated fatty acids (PUFAs) are their preferred reaction substrates in lipid phases, whereas protein side chains arguably prevail in aqueous phases. In both cellular compartments, a single, dominating thiyl radical-specific antioxidant does not seem to exist. This conclusion is rationalized by the high reaction rate constants of thiyl radicals with several highly concentrated substrates in the cell, precluding effective interception by antioxidants, especially in lipid bilayers. The intractable reactivity of thiyl radicals may account for a series of long-standing, but still startling biochemical observations surrounding the amino acid cysteine: (i) its global underrepresentation on protein surfaces, (ii) its selective avoidance in aerobic lipid bilayers, especially the inner mitochondrial membrane, (iii) the inverse correlation between cysteine usage and longevity in animals, (iv) the mitochondrial synthesis and translational incorporation of cysteine persulfide, and potentially (v) the ex post introduction of selenocysteine into the genetic code. [ABSTRACT FROM AUTHOR]

Thiyl radicals are exceptionally interesting reactive sulfur species (RSS), but rather rarely considered in a biological or medical context. We here review the reactivity of protein thiyl radicals in aqueous and lipid phases and provide an overview of their most relevant reaction partners in biological systems. We deduce that polyunsaturated fatty acids (PUFAs) are their preferred reaction substrates in lipid phases, whereas protein side chains arguably prevail in aqueous phases. In both cellular compartments, a single, dominating thiyl radical-specific antioxidant does not seem to exist. This conclusion is rationalized by the high reaction rate constants of thiyl radicals with several highly concentrated substrates in the cell, precluding effective interception by antioxidants, especially in lipid bilayers. The intractable reactivity of thiyl radicals may account for a series of long-standing, but still startling biochemical observations surrounding the amino acid cysteine: (i) its global underrepresentation on protein surfaces, (ii) its selective avoidance in aerobic lipid bilayers, especially the inner mitochondrial membrane, (iii) the inverse correlation between cysteine usage and longevity in animals, (iv) the mitochondrial synthesis and translational incorporation of cysteine persulfide, and potentially (v) the ex post introduction of selenocysteine into the genetic code.

Prooxidative therapy is a well-established concept in infectiology and parasitology, in which prooxidative drugs like artemisinin and metronidazole play a pivotal clinical role. Theoretical considerations and earlier studies have indicated that prooxidative therapy might also represent a promising strategy in oncology. Here, we have investigated a novel class of prooxidative drugs, namely chain-transfer agents, as cytostatic agents in a series of human tumor cell lines in vitro. We have found that different chain-transfer agents of the lipophilic thiol class (like dodecane-1-thiol) elicited half-maximal effective concentrations in the low micromolar range in SY5Y cells (human neuroblastoma), Hela cells (human cervical carcinoma), HEK293 cells (immortalized human kidney), MCF7 cells (human breast carcinoma), and C2C12 cells (mouse myoblast). In contrast, HepG2 cells (human hepatocellular carcinoma) were resistant to toxicity, presumably through their high detoxification capacity for thiol groups. Cytotoxicity was undiminished by hypoxic culture conditions, but substantially lowered after cellular differentiation. Compared to four disparate, clinically used reference compounds in vitro (doxorubicin, actinomycin D, 5-fluorouracil, and hydroxyurea), chain-transfer agents emerged as comparably potent on a molar basis and on a maximum-effect basis. Our results indicate that chain-transfer agents possess a promising baseline profile as cytostatic drugs and should be explored further for anti-tumor chemotherapy.

Electrochemically mediated atom transfer radical polymerizations (ATRPs) provide well‐defined polymers with designed dispersity as well as under external temporal and spatial control. In this study, 1‐cyano‐1‐methylethyl diethyldithiocarbamate, typically used as chain‐transfer agent (CTA) in reversible addition–fragmentation chain transfer (RAFT) polymerization, was electrochemically activated by the ATRP catalyst CuI/2,2′‐bipyridine (bpy) to control the polymerization of methyl methacrylate. Mechanistic study showed that this polymerization was mainly controlled by the ATRP equilibrium. The effect of applied potential, catalyst counterion, catalyst concentration, and targeted degree of polymerization were investigated. The chain‐end functionality was preserved as demonstrated by chain extension of poly(methyl methacrylate) with n‐butyl methacrylate and styrene. This electrochemical ATRP procedure confirms that RAFT CTAs can be activated by an electrochemical stimulus. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 376–381 A dithiocarbamate, 1‐cyano‐1‐methylethyldiethyldithiocarbamate, was electrochemically activated by the ATRP catalyst CuI/2,2′‐bipyridine (bpy) to form well‐defined poly(methyl methacrylate). Mechanistic studies show that this polymerization is controlled by the ATRP equilibrium with no contribution from chain transfer (no reversible addition–fragmentation chain transfer contribution). The effects of applied potential, catalyst concentration, catalyst counterion, and targeted degree of polymerization were investigated. The chain‐end functionality was well preserved as demonstrated by chain extension with n‐butyl methacrylate and styrene. [ABSTRACT FROM AUTHOR]

This study investigates the characteristics of the recently developed catalytic H-shuttling polymerization (HSP) of polar vinyl monomers mediated by cationic zirconocenium catalysts, through examining the scopes of chain transfer agent, catalyst, and monomer. Amongst the three classes of chain transfer agents (metal hydrides, metal aryl/alkyls, organics) investigated for the MMA polymerization catalyzed by Cs-ligated catalyst 1, the Lewis acid B(C6F5)3, metal hydrides MH (M = K, Na, Li) and the organic PhNMe2 promote efficient catalytic polymerization, while metal alkyls such as Et3Al and Et2Zn serve only as the scavenger and/or monomer activator and thus do not promote chain transfer. In the presence of 5 equivalents of KH, both Cs-ligated catalyst 1 and achiral C2v-ligated catalyst 3 promote catalytic MMA polymerization through effective chain transfer, whereas C2-ligated catalyst 2 shows no chain transfer. Of several other conjugated polar vinyl monomers investigated, including acrylamides and α-methylene- γ-butyrolactones, only N,N-diphenylacrylamide (DPAA) exhibits catalytic polymerization behavior. Thus, in the presence of enantiopure pre-catalyst ( S,S)- 4 and excess B(C6F5)3, DPAA is polymerized catalytically and asymmetrically to optically active poly(DPAA) with a narrow MWD of 1.02. [ABSTRACT FROM AUTHOR]

Batch radical polymerization of non-ionized methacrylic acid, 30 wt.-% in aqueous solution, has been studied at 50 °C and ambient pressure with 2-mercaptoethanol (ME) as the chain-transfer agent (CTA). Initial polymerization rate decreases with CTA concentration, which has been varied up to 20 mol-%. A kinetic model is presented which includes chain-length-dependent termination and uses an empirical function to account for the dependence of termination rate on both monomer conversion and molar mass of the polymeric product. In conjunction with P REDICI simulation, this model affords for an adequate representation of the measured monomer conversion vs. time profiles. [ABSTRACT FROM AUTHOR]

A new azlactone-derived trithiocarbonate is prepared and used as a chain-transfer agent to mediate the reversible addition-fragmentation chain transfer (RAFT) polymerization of styrene, ethyl acrylate, and N-isopropyl acrylamide. Well-defined polymers with controlled molecular weights ( Mn = 1000-7000 g mol−1) and narrow molecular weight distributions (PDI = 1.05-1.10) are thus obtained that retain the azlactone functionality at the chain end. The ability of the resulting end-functionalized polymers to react quantitatively at room temperature with a stoichiometric amount of amino groups with retention of the thiocarbonylthio moiety is ascertained by using 4-fluorobenzylamine and allylamine. [ABSTRACT FROM AUTHOR]

Abstract: A multicriteria optimization approach based on an evolutionary algorithm has been developed to determine the optimal control policy for a fed-batch emulsion copolymerization reactor, particularly for styrene and butyl acrylate in the presence of n-C12 mercaptan as chain transfer agent. The process model was elaborated and validated experimentally in order to predict the global monomer conversion, the number and weight average molecular weights, the particle size distribution and the residual monomers mass fraction. The process objectives were to produce core–shell particles (hard core and smooth shell) with specific end-use properties and high productivity. This has been achieved by the maximization of the monomers overall conversion at the end of the process and the minimization of the error between the glass transition temperature and a designed profile subject to a set of operational constraints. The nondominated Pareto solutions obtained were ranked according to a decision making aid method based on a decision maker preferences and experience using multi-attribute utility theory. Finally, the best solution was implemented experimentally. [Copyright &y& Elsevier]

Abstract: The cyclodimerization of 1,3-butadiene was performed to synthesize 1,5-cyclooctadiene by using nickel-phosphite based catalyst system. The optimization of cyclodimerization reaction was done to achieve up to 80% selectivity towards 1,5-cyclooctadiene. 1,5-Cyclooctadiene, thus synthesized, was subsequently employed as a chain transfer agent (CTA) for controlling the molecular weight (M.W.) of cis-polybutadiene rubber (BR) in cobalt-complex catalyzed 1,3-butadiene polymerization reaction. The M.W. of BR was reduced from 6.7 to 1.88×105 g/mol by escalating the concentration of 1,5-cyclooctadiene from 0% to 0.5% with respect to 1,3-butadiene (monomer) concentration. Similar reducing trend was observed for the Mooney viscosity and gel content of BR with increasing 1,5-cyclooctadiene concentration. The efficacy of 1,5-cyclooctadiene as a CTA for 1,3-butadiene polymerization reaction was further explored by conducting polymerization reaction in various solvents and at higher monomer conversion (∼70%). The effect of 4-vinyl cyclohexene, which was a dominant byproduct during cyclodimerization of 1,3-butadiene, was also investigated. The presence of 4-vinyl cyclohexene has shown adverse effect in the polymerization reaction and was not functioning as a chain transfer agent. Finally, a feasibility of replacement of commercially used gaseous CTA, 1,2-butadiene, by in-house synthesized liquid CTA, 1,5-cyclooctadiene, was also investigated. [Copyright &y& Elsevier]

Abstract: The identification of longevity-related structural adaptations in biological macromolecules may yield relevant insights into the molecular mechanisms of aging. In screening fully sequenced animal proteomes for signals associated with longevity, it was found that cysteine depletion in respiratory chain complexes was the by far strongest predictor on the amino acid usage level to co-vary with lifespan. This association was though restricted to aerobic animals, whereas anaerobic animals showed variable cysteine accumulation. By contrast, methionine accumulation, a prominent feature of mitochondrially encoded proteins affording competitive antioxidant protection, was not predictive of longevity, but rather paralleled aerobic metabolic capacity. Hence, the easily oxidized sulfur-containing amino acids cysteine (a thiol) and methionine (a thioether) show doubly diametrical behaviour in two central paradigms of respiratory oxidative stress. From this comparison, it is concluded that only the one–electron oxidation of thiols to thiyl radicals contributes to aging, whereas other forms of sulfur oxidation, especially even-electron oxidation of both thiols and thioethers, are less critically involved, presumably as their consequences may be much more easily repaired. Thiyl radicals may yet act as chain-transfer agents to entail an irreversible intramembrane cross-linking (“plastination”) of some of the a priori most hydrophobic and insoluble proteins known, the respiratory chain complexes. [ABSTRACT FROM AUTHOR]

Abstract: This paper deals with the development of a mathematical model for emulsion copolymerization of styrene and butyl acrylate carried out in the presence of n-dodecyl mercaptan as chain transfer agent (CTA). The model consisted of a system of differential algebraic equations in which the population balances are based on a new approach that reduces significantly the number of equations involved and the corresponding computational time. Most of the unknown kinetic and thermodynamic parameters of the model were estimated from experimental measurements using a stochastic optimization method based on a genetic algorithm. The results showed a fairly good agreement between model predictions and experiments. The model was then successfully validated through additional experiments carried out in batch and fedbatch reactors and clearly showed that the model was able to predict the time-evolution of overall conversion, amounts of each residual monomer, number and weight average molecular weights of the resulting copolymers and average diameters of the corresponding latex particles for different operating conditions, mainly CTA concentration and reaction temperature. The model was finally used to investigate and confirm the effects of CTA concentration, previously observed by several authors, on the kinetics of this polymerization process and on the main properties of the resulting macromolecules and latex particles. [Copyright &y& Elsevier]

Functionalization of chain terminals of hyperbranched polymer can be both beneficial and challenging due to the large number of terminals originating from the hyperbranched architecture. Direct terminal functionalization is even more difficult for hyperbranched polyolefin via coordination polymerization due to the compatibility of the catalytic system and some terminal functionalization reagents. To overcome this issue, herein we report the synthesis of hyperbranched polyolefins via ring-opening metathesis polymerization from a substituted cyclooctene monomer with bi-functional acyclic olefin as chain-transfer agent via one-pot process. We envision that this work will provide a new route for the synthesis of functional hyperbranched polyolefin materials. The synthesis of terminal functionalized hyperbranched polyolefin via ROMP with a branched monomer and chain-transfer agents (repeating units of the hyperbranched olefin are placed between brackets). [Display omitted] • Synthesis of hyperbranched polyolefins via ROMP with various types of chain terminals. • One-pot synthetic method with ROMP and cross-metathesis reaction performing together. • Functional hyperbranched polyolefin materials with high degree of branching. [ABSTRACT FROM AUTHOR]

Time optimal monomer and chain-transfer agent feed profiles were computed and implemented experimentally for the simultaneous control of copolymer composition and molecular weight distribution in non-linear emulsion copolymerization systems. Iterative dynamic programming was used for the off-line calculation of the optimal feed policies. This approach can deal with constrained optimization of systems described by complex mathematical models, as those needed for the emulsion copolymerization kinetics, especially when the computation of the whole molecular weight distribution is included. The proposed approach was applied to the semibatch methylmethacrylate (MMA)/n-butylacrylate (n-BA) emulsion copolymerization, using n-dodecanethiol as chain-transfer agent, and allowed the production of copolymers with constant composition and with well-defined molecular weight distributions. [Copyright &y& Elsevier]

Prooxidative therapy is a well-established concept in infectiology and parasitology, in which prooxidative drugs like artemisinin and metronidazole play a pivotal clinical role. Theoretical considerations and earlier studies have indicated that prooxidative therapy might also represent a promising strategy in oncology. Here, we have investigated a novel class of prooxidative drugs, namely chain-transfer agents, as cytostatic agents in a series of human tumor cell lines in vitro. We have found that different chain-transfer agents of the lipophilic thiol class (like dodecane-1-thiol) elicited half-maximal effective concentrations in the low micromolar range in SY5Y cells (human neuroblastoma), Hela cells (human cervical carcinoma), HEK293 cells (immortalized human kidney), MCF7 cells (human breast carcinoma), and C2C12 cells (mouse myoblast). In contrast, HepG2 cells (human hepatocellular carcinoma) were resistant to toxicity, presumably through their high detoxification capacity for thiol groups. Cytotoxicity was undiminished by hypoxic culture conditions, but substantially lowered after cellular differentiation. Compared to four disparate, clinically used reference compounds in vitro (doxorubicin, actinomycin D, 5-fluorouracil, and hydroxyurea), chain-transfer agents emerged as comparably potent on a molar basis and on a maximum-effect basis. Our results indicate that chain-transfer agents possess a promising baseline profile as cytostatic drugs and should be explored further for anti-tumor chemotherapy. [ABSTRACT FROM AUTHOR]

Epoxide- and oxetane-α,ω-telechelic (co)polyolefins have been successfully synthesized by the tandem ring-opening metathesis polymerization (ROMP)/cross-metathesis (CM) of cyclic olefins using Grubbs' second-generation catalyst (G2) in the presence of a bifunctional symmetric alkene epoxide- or oxetane-functionalized chain-transfer agent (CTA). From cyclooctene (COE), trans,trans,cis-1,5,9-cyclododecatriene (CDT), norbornene (NB), and methyl 5-norbornene-2-carboxylate (NBCOOMe), with bis(oxiran-2-ylmethyl) maleate (CTA 1), bis(oxetane-2-ylmethyl) maleate (CTA 2), or bis(oxetane-2-ylmethyl) (E)-hex-3-enedioate (CTA 3), well-defined α,ω-di(epoxide or oxetane) telechelic PCOEs, P(COE-co-NB or -NBCOOMe)s, and P(NB-co-CDT)s were isolated under mild operating conditions (40 or 60 °C, 24 h). The oxetane CTA 3 and the epoxide CTA 1 were revealed to be significantly more efficient in the CM step than CTA 2, which apparently inhibits the reaction. Quantitative dithiocarbonatation (CS2/LiBr, 40 °C, THF) of an α,ω-di(epoxide) telechelic P(NB-co-CDT) afforded a convenient approach to the analogous α,ω-bis(dithiocarbonate) telechelic P(NB-co-CDT). The nature of the end-capping function of the epoxide/oxetane/dithiocarbonate telechelic P(NB-co-CDT)s did not impact their thermal signature, as measured by DSC. These copolymers also displayed a low viscosity liquid-like behavior and a shear thinning rheological behavior. [ABSTRACT FROM AUTHOR]

Protein has been widely applied in biotechnology and biomedicine thanks to its unique properties of high catalytic activity, outstanding receptor-ligand specificity, and controllable sequence mutability. Owing to the easily induced structural variation and thus the inactivation of protein, there has been much effort to improve the structural stability and biological activity of proteins by the use of polymers to modify protein to construct protein-polymer conjugates. However, during the conjugation of polymer to protein active center, the great loss in the original biological activity of the protein is still a serious and so far unsolved question. Here, for the purpose of preparing site-directed and highly structurally stable protein-polymer conjugate, which would possess at least a substantially similar level of biological activity as the original unmodified protein, we proposed a new strategy by using a pyridine chain-transfer agent (CTA-Py) with a soft pyridine-terminated chain for visible-light-induced reversible addition-fragmentation chain transfer (RAFT) polymerization specifically on a number of sites close to the protein active center. The results showed that all the intermediate conjugates PPa-CTA-Py at different modification sites could retain full enzymatic activities (about 110-130% of the unmodified PPa). It was demonstrated by dynamic computer simulation that introducing of CTA-Py had little interference to the protein spatial structure as compared to the popular maleimide chain-transfer agent (CTA-Ma) with rigid maleimide-terminated. Moreover, intermediate conjugates PPa-CTA-Py is facile and ready for further light polymerization under mild conditions. Final PPa-PNIPAAm conjugate produced from CTA-Py exhibited excellent temperature responsiveness and maintained its enzymatic activity even at high temperature. These highly stable and responsive protein-polymer conjugates have great potential and could be widely used in various industrial, chemical, biological, and pharmaceutical applications.