Mechanical activations of synthetic and biological systems

textPolymer mechanochemistry, wherein exogenous forces are harnessed to drive chemical processes within polymeric matrices, has afforded access to an astounding array of otherwise kinetically prohibitive reactivity. These multifarious mechanochemical transformations include formally symmetry forbidden electrocyclic processes, thermodynamically disfavored isomerizations, and thermally inaccessible cycloreversions of both carbocyclic and heterocyclic functionalities. The fundamental principles that govern mechanochemistry, however, remain elusive. To address this deficiency, we report a series of experimental and computational efforts that probe chemical reactivity under the action of mechanical force. Specifically, we have explored the formal 1,3-dipolar cycloreversion of 1,2,3-triazole moieties in an effort to understand the interplay between kinetic stability and mechanical perturbation. Briefly, 1,4-disubstituted 1,2,3-triazoles were embedded within high molecular weight poly(methyl acrylate) chains and reverted into their azide and terminal alkyne precursors sonochemically. The liberated azide and alkyne moieties were identified by orthogonal chemical ligation to chromophores, and the reactive azido- and alkynyl-polymer fragments could be recoupled through a copper-mediated cycloaddition. Inspired by this result, we developed a computational model to rapidly discover qualitative trends in mechanochemical reactivity. Application of this model to the cycloreversion of 1,2,3-triazoles revealed an intriguing result: the 1,5-disubstitued regioisomer was predicted to exhibit enhanced susceptibility to mechanical cycloreversion in comparison to the 1,4-disubstituted congener. This trend was experimentally verified upon embedding 1,5-disubstituted 1,2,3-triazoles into high molecular weight poly(methyl acrylate) chains and subjecting them to ultrasonication. Specifically, the observed rate constant for chain scission of a poly(methyl acrylate) material containing the 1,5-disubstituted isomer was 20% larger than that of an analogous material containing the 1,4-disubstituted congener. Having established confidence in the predictive capabilities of our model, we undertook an exhaustive evaluation of regiochemical effects on the activation of six previously reported mechanically labile scaffolds. Our theoretical work suggested that all of the evaluated scaffolds could exhibit suppressed reactivity under stress (an underexplored phenomenon), and this result was supported by experimental investigation. Moreover, our theoretical considerations predicted that anti-Hammond effects (i.e., increased structural dissimilarity between reactant and transition state geometries as the two approach energetically) could be predominant in mechanochemical processes. Finally, we endeavored to expand the scope of polymer mechanochemistry beyond traditional chemical systems to biologically relevant species. We found that the photophysical properties of fluorescent protein variants could be modulated by embedding the proteins within poly(methyl methacrylate) matrices and compressing the resulting composites.Chemistr

Alkoxyamine Polymers: Versatile Materials for Surface Ligation Applications

Immobilization of biomolecules (i.e., proteins, carbohydrates), on polymeric surfaces has been an area of intense research. The resultant bioconjugates often display increased stability, bioavailability and activity. Our research program seeks to explore the utility of the alkoxyamine (RONH2) functional group in new materials as versatile ligating sites for the immobilization of various compounds. The ease with which alkoxyamines (RONH2) condense with aldehydes or ketones has prompted their widespread use in labelling liposome, bacterial and mammalian cell surfaces as well as chemoselectively ligating small molecule ‘recognition elements\u27 onto polyfunctional substrates. These condensation reactions proceed in aqueous media to afford the robust oxime ethers in near quantitative yields, making these conjugations ideal for a variety of applications. Thus, alkoxyamines are excellent ‘molecular anchors\u27 to immobilize aldehyde/ketone compounds on a surface. We have installed alkoxyamines on polymer surfaces to tether a variety of compounds through the covalent oxime ether bond to the polymer backbone. Our synthetic efforts towards these novel alkoxyamine polymers as well as initial aldehyde/ketone immobilization studies will be discussed

Methods for activating and characterizing mechanically responsive polymers

Mechanically responsive polymers harness mechanical energy to facilitate unique chemical transformations and bestow materials with force sensing (e.g., mechanochromism) or self-healing capabilities. A variety of solution- and solid-state techniques, covering a spectrum of forces and strain rates, can be used to activate mechanically responsive polymers. Moreover, many of these methods have been combined with optical spectroscopy or chemical labeling techniques to characterize the products formed via mechanical activation of appropriate precursors in situ. In this tutorial review, we discuss the methods and techniques that have been used to supply mechanical force to macromolecular systems, and highlight the advantages and challenges associated with each

Isolation and Reactivity of Trifluoromethyl Iodonium Salts.

The strategic incorporation of the trifluoromethyl (CF3) functionality within therapeutic or agrochemical agents is a proven strategy for altering their associated physicochemical properties (e.g., metabolic stability, lipophilicity, and bioavailability). Electrophilic trifluoromethylation has emerged as an important methodology for installing the CF3 moiety onto an array of molecular architectures, and, in particular, CF3 λ(3)-iodanes have garnered significant interest because of their unique reactivity and ease of handling. Trifluoromethylations mediated by these hypervalent iodine reagents often require activation through an exogenous Lewis or Brønsted acid; thus, putative intermediates invoked in these transformations are cationic CF3 iodoniums. These iodoniums have, thus far, eluded isolation and investigation of their innate reactivity (which has encouraged speculation that such species cannot be accessed). A more complete understanding of the mechanistic relevance of CF3 iodoniums is paramount for the development of new trifluoromethylative strategies involving λ(3)-iodanes. Here, we demonstrate that CF3 iodonium salts are readily prepared from common λ(3)-iodane precursors and exhibit remarkable persistence under ambient conditions. These reagents are competent electrophiles for a variety of trifluoromethylation reactions, and their reactivity is reminiscent of that observed when CF3 iodanes are activated using Lewis acids. As such, our results suggest the mechanistic relevance of CF3 iodonium intermediates in trifluoromethylative processes mediated by λ(3)-iodanes. The isolation of CF3 iodonium salts also presents the unique opportunity to employ them more generally as mechanistic probes

Unclicking the Click: Mechanically Facilitated 1,3-Dipolar Cycloreversions

The specific targeting of covalent bonds in a local, anisotropic fashion using mechanical methods offers useful opportunities to direct chemical reactivity down otherwise prohibitive pathways. Here, we report that embedding the highly inert 1,2,3-triazole moiety (which is often prepared using the canonical "click" coupling of azides and alkynes) within a poly(methyl acrylate) chain renders it susceptible to ultrasound-induced cycloreversion, as confirmed by comprehensive spectroscopic and chemical analyses. Such reactivity offers the opportunity to develop triazoles as mechanically labile protecting groups or for use in readily accessible materials that respond to mechanical force

Cariporide Prodrugs: Targeting Brain Cancer Cells through Sodium-Proton Exchange Inhibition

More than 200,000 people in the United States are diagnosed with a primary or metastatic brain tumor annually. The life expectancy for these individuals is approximately 9-12 months from the time of diagnosis. This poor prognosis is due to the ineffectiveness of existing therapies (i.e., chemotherapy and radiotherapy) against brain cancer, where the primary problem is the inability to differentiate cancer cells from healthy brain cells. Relative to healthy brain tissue, the heightened metabolism of cancer cells increases their reliance on the ion transport proteins NHE (sodium-proton exchanger) and NCX (sodium-calcium exchanger). Inhibition of these proteins disrupts the intricate pH and ion balances within cancer cells to a much greater extent than in normal cells, and this leads to cancer cell death. In contrast, healthy brain cells are less affected by this targeted approach because they are far less reliant on NHE and NCX due to their normal (and lower) metabolic activity. Consequently, NHE and NCX are excellent molecular targets for a new, selective brain cancer therapy. Although potent NHE/NCX inhibitors are available, a fundamental impediment to the field is the delivery of these compounds to poorly vascularized tissues. As part of our target-specific approach to treating brain cancer, we have synthesized analogs of cariporide, a potent (e.g., nanomolar IC50 activity) NHE inhibitor, to address the drug delivery challenge. The preparation and biological activities of our cariporide analogs will be discusse

Arterial supply to the colon

The strategic incorporation of the trifluoromethyl (CF₃) functionality within therapeutic or agrochemical agents is a proven strategy for altering their associated physicochemical properties (e.g., metabolic stability, lipophilicity, and bioavailability). Electrophilic trifluoromethylation has emerged as an important methodology for installing the CF₃ moiety onto an array of molecular architectures, and, in particular, CF₃ λ³-iodanes have garnered significant interest because of their unique reactivity and ease of handling. Trifluoromethylations mediated by these hypervalent iodine reagents often require activation through an exogenous Lewis or Brønsted acid; thus, putative intermediates invoked in these transformations are cationic CF₃ iodoniums. These iodoniums have, thus far, eluded isolation and investigation of their innate reactivity (which has encouraged speculation that such species cannot be accessed). A more complete understanding of the mechanistic relevance of CF₃ iodoniums is paramount for the development of new trifluoromethylative strategies involving λ³-iodanes. Here, we demonstrate that CF₃ iodonium salts are readily prepared from common λ³-iodane precursors and exhibit remarkable persistence under ambient conditions. These reagents are competent electrophiles for a variety of trifluoromethylation reactions, and their reactivity is reminiscent of that observed when CF₃ iodanes are activated using Lewis acids. As such, our results suggest the mechanistic relevance of CF₃ iodonium intermediates in trifluoromethylative processes mediated by λ³-iodanes. The isolation of CF₃ iodonium salts also presents the unique opportunity to employ them more generally as mechanistic probes

Chemical reactions modulated by mechanical stress: Extended Bell theory

A number of recent studies have shown that mechanical stress can significantly lower or raise the activation barrier of a chemical reaction. Within a common approximation due to Bell [Science 200, 618 (1978)], this barrier is linearly dependent on the applied force. A simple extension of Bell's theory that includes higher order corrections in the force predicts that the force-induced change in the activation energy will be given by -F Delta R - Delta chi F-2/2. Here, Delta R is the change of the distance between the atoms, at which the force F is applied, from the reactant to the transition state, and Delta chi is the corresponding change in the mechanical compliance of the molecule. Application of this formula to the electrocyclic ring-opening of cis and trans 1,2-dimethylbenzocyclobutene shows that this extension of Bell's theory essentially recovers the force dependence of the barrier, while the original Bell formula exhibits significant errors. Because the extended Bell theory avoids explicit inclusion of the mechanical stress or strain in electronic structure calculations, it allows a computationally efficient characterization of the effect of mechanical forces on chemical processes. That is, the mechanical susceptibility of any reaction pathway is described in terms of two parameters, Delta R and Delta chi, both readily computable at zero force. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3656367

Regiochemical Effects on Molecular Stability: A Mechanochemical Evaluation of 1,4-and 1,5-Disubstituted Triazoles

Poly(methyl acrylate) chains of varying molecular weight were grown from 1,4- as well as 1,5-disubstituted 1,2,3-triazoles. Irradiating acetonitrile solutions of these polymers with ultrasound resulted in the formal cycloreversion of the triazole units, as determined by a variety of spectroscopic and chemical labeling techniques. The aforementioned reactions were monitored over time, and the rate constant for the cycloreversion of the 1,5-disubstituted triazole was measured to be 1.2 times larger than that of the 1,4-disubstituted congener. The difference was attributed to the increased mechanical deformability of the 1,5-regioisomer as compared to the 1,4-isomer. This interpretation was further supported by computational studies, which employed extended Bell theory to predict the force dependence of the activation barriers for the cycloreversions of both isomers