The synthesis and characterization of thermoresponsive, water-soluble poly-N -isopropyl acrylamide (PNIPAM) derived macroligands displaying cyclosporin A (CsA) and dexamethasone (Dex) for use as novel affinity resins is described. Characterization of these soluble macroligands, including ligand loading and integrity was determined by 1 H NMR spectroscopy. One of the CsA-macroligands was used in a protein affinity experiment to capture known binding proteins of CsA, the cyclophilins, from Jurkat T-cell lysates.Organisms utilize biopolymers in the form of DNA for information storage and in the form of proteins for cellular structure and machinery. Most functional biopolymers respond to external stimuli such as heat and pH in an all-or-nothing, or at least a highly non-linear mode. 1 Most common among such biopolymers are proteins that precipitate or denature on heating. Recently, progress has been made toward the synthesis of synthetic functional polymers that mimic biopolymers by responding in a desired way to external environmental stimuli such as temperature, pH, and either electric or magnetic fields. 2 These highly nonlinear responses of synthetic polymers occur primarily in water, but also in organic solvents 3 or polymer blends. 4 When this stimulus-responsive behavior occurs in aqueous solution, these polymers have potential as useful tools for biotechnological and medicinal research. Among the synthetic stimulus-responsive polymers, temperature responsive polymers have been the most extensively studied. 5 This kind of polymer is soluble below its lower critical solution romo@mail.chem.tamu.edu. Supporting Information Available: General experimental procedures and characterization data for compounds 3a-b and 7−9. Representative 1 H NMR spectra for macroligands 4a-4d and 10a-e and procedure for the affinity experiment. Copolymers of poly(N-isopropylacrylamide) (PNIPAM) and derived functionalized polymers have been shown to be thermoresponsive, exhibiting quantitative inverse temperaturedependent solubility in water. 8,9 These and other thermo-responsive polymers have enabled the design of smart chemical catalysts having activities that can be switched off and on by precipitation and redissolution based on reaction temperature. 8,9 In addition, these polymers are useful in syntheses using biological catalysts. 10 Most pertinent to the described studies herein are previous uses of PNIPAM-derived thermoresponsive polymers to purify known proteins. An imidazole-PNIPAM thermoresponsive polymer loaded with Cu(II) ions was used for the affinity purification of proteins from cereals ( Figure 1). 11 PNIPAM coupled to an iminobiotin affinity ligand was used to isolate lysozyme from fetal calf sera. 12 In connection with our interest in coupling natural products to their cellular receptors, 13 we considered the attachment of natural products to PNIPAM polymers to facilitate characterization of the immobilized natural product. 14 Affinity chromatography is based on the principle of specific protein-ligand inter...

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