chapter 2. design and synthesis of synthetic receptors for biomolecule recognition katharine l....

Chapter 2. Design and Synthesis of Synthetic Receptors for Biomolecule Recognition

Katharine L. Diehl, James L. Bachman, Brette M. Chapin, Ramakrishna Edupuganti, P. Rogelio Escamilla, Alexandra M. Gade, Erik T. Hernandez, Hyun Hwa Jo, Amber M. Johnson, Igor V. Kolesnichenko, Jaebum Lim, Chung-Yon Lin, Margaret K. Meadows, Helen M. Seifert, Diana

Zamora-Olivares, Eric V. Anslyn*

Department of Chemistry and Biochemistry

1 University Station A1590

Austin, TX 78712

*Email: [email protected]

Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications© The Royal Society of Chemistry 2015

Figure 2.1 Intermolecular interactions involved in complexation.


Scheme 2.1 Binding affinities of cyclic and acyclic polyethers for K+.


Scheme 2.2 Conformational change required for K+ binding in 18-crown-6.


Scheme 2.3 Barbital binding by macrocyclic Hamilton receptor and deconstructed acyclic hosts.


Scheme 2.4 Adenosine binding by cleft-shaped receptor.


Scheme 2.5 Pinwheel host 2.6 with six guanidinium groups binds strongly to inositol-1,4,5-triphosphate.


Scheme 2.6 Inward binding conformation of pinwheel host is induced by the presence of Br - guest.


Figure 2.2 Strengths of covalent bonds and noncovalent interactions. asingle covalent bond or monovalent interaction.


Figure 2.3 Cation···π interaction.

Figure 2.4 Three types of molecular torsion balances designed by the groups of: A) Ōki, B) Wilcox, and C) Shimizu.


Figure 2.5 Host guest association in solution.


Table 2.1 Log K and ΔG° values for complexation of pyrene by cyclophane host 2.8 in various solvents that differ in polarity as expressed by ET(30) values, T = 303 K.

Scheme 2.7 Structures of cyclophane host 2.8 and pyrene guest.


Table 2.2 Log K values for complexation of K+ by 18-crown-6 in various solvents that differ in surface tension.


Table 2.3 Reversible covalent reactions.


Scheme 2.9 Reversible nucleophilic attack on a boronic acid.


Table 2.4 Common carbonyl-based indicators and associated analytes.


Scheme 2.10 Nucleophilic attack by a thiolate on a disulfide.


Scheme 2.11 Design of a glucopyranose receptor using CAVEAT.


Scheme 2.12 Structure designed using CAVEAT.


Scheme 2.13 Dopamine binding by Wang's receptor.


Figure 2.7 Example of the scoring method from HostDesigner's LINKER algorithm. The degree of overlap of the oxoanion guests of the two original fragments determines the score. The top left structure with a RMSD=0.29 is the highest scoring candidate, the bottom right structure with RMSD=3.21 is the lowest scoring. (Reproduced with permission from J. Am. Chem. Soc., 2006, 128, 2035, © 2006 American Chemical Society)


Figure 2.8 Input fragments for generating a host for oxygen mustard. Arrows indicate where new bonds will be formed. (Reproduced with permission from Comput. Theor. Chem., 2014, 1028, 72, © 2014 Elsevier)


Scheme 2.15 Common scaffolds for synthetic organic receptors.


Scheme 2.16 Water soluble crown ether host for NAD+.


Scheme 2.17 Structures showing receptor 2.15 (a calixcrown linked to a calixpyrrole), receptors 2.16 and 2.17 immobilized on silica gel, and calixpyrrole 2.18 delivering Pt(II) drug to AMP.


Scheme 2.18 A) Schematic representation of the synthesis of CB8 under acidic conditions. B) CB8 forms ternary complexes with electron-deficient methyl viologen (2.19) and a second electron-rich partner (2.20). (Adapted with permission Angew. Chem. Int. Ed., 2001, 113, 1574, © 2001 Wiley)


Scheme 2.19 Three most common cyclodextrins.


Scheme 2.20 Structures of pinwheel hosts.


Figure 2.10 A) Parallel synthesis method of combinatorial library generation, B) Split-mix method of combinatorial library generation, also called split-and-pool, C) Combinatorial library generated through coupling of mixtures.


Scheme 2.21 Guanidiniocarbonyl-pyrrole receptors generated using parallel synthesis. All of the R groups are directly attached to the amide nitrogen.


Scheme 2.22 Peptide substituted-TAC generated by split-mix synthesis. The library consists of amino acids at the specified positions, resulting in 66 = 46,456 members.


Figure 2.11 SELEX protocol for artificial evolution of a complex biopolymer library.


Figure 2.12 Cartoon depiction of building blocks assembling in a dynamic system, with their respective concentrations dependent upon the depth of the thermodynamic wells. Persistent template binding produces a new low-energy library member, and the equilibrium shifts towards the amplified member. (Adapted with permission from Dynamic Combinatorial Chemistry, Wiley-VCH: Weinheim, 2010, © 2010 Wiley-VCH Verlag GmbH & Co. KGaA)


Scheme 2.23 Cyclic monomeric host 2.23 and dimeric host 2.24 where X is one of the disulfide linkages a to f.


Scheme 2.24 Dimeric host with two covalent linkers (X) incorporating the disulfide linkages a to d.


Figure 2.13 General illustrations of systems utilizing cooperativity: A) oxygen binding to hemoglobin and, B) folding of DNA/RNA. (Reproduced with permission from Angew. Chem. Int. Ed., 2009, 48, 7488. © 2009 Wiley)


Figure 2.14 Speciation profile of a system exhibiting positive cooperativity. Note the sharp transition and the low build-up of intermediates. (Reproduced with permission from Angew. Chem. Int. Ed., 2009, 48, 7488. © 2009 Wiley)


Scheme 2.25 Monovalent and divalent β-cyclodextrin receptors and guest.


Figure 2.15 Model of binding interaction caused by tethering, with the bottom two images showing complete and incomplete binding interaction, respectively. (Reproduced with permission from Proc. Natl. Acad. Sci. USA, 2007, 104, 6538, © 2007 National Academy of Sciences, U.S.A.)


Figure 2.16 Example of an entropy-enthalpy compensation plot.


Figure 2.17 Compensation behavior exhibited by a variety of guests to p-sulfonatocalix[n]arenes in water. (Reproduced with permission J. Chem. Soc., Perkin Trans. 2, 2002, 2, 524, © 2002 Royal Society of Chemistry)


Figure 2.18 Di erential sensing using a hypothetical array-based sensor. To a 16-element array, A), analyte 1 (later ffidentified as a beer) and analyte 2 (whisky) are applied. The response patterns B, E are used directly, or the pattern A is subtracted to obtain di erential patterns C, F. (Reproduced with permission from ff Chem. Soc. Rev., 2010, 39, 3954, © 2010 Royal Society of Chemistry)


Figure 2.19 Array-based sensor utilizing analyte binding by differential receptors. Regardless of whether the analyte is a single- or multi-component analyte, receptors bind a number of analytes, but each receptor binds the analytes differently thus providing a differential response. (Reproduced with permission from Chem. Soc. Rev., 2010, 39, 3954, © 2010 Royal Society of Chemistry)


Figure 2.20 Schematic presentation of a cell detection assay and the interactions between polymers (ribbons) and cell types (surface). Fluorescence of the polymer is quenched upon binding to the cell surface. (Reproduced with permission from J. Am. Chem. Soc., 2010, 132, 1018, © 2010 American Chemical Society)


Scheme 2.27 Calixpyrrole scaffold used to create carboxylate indicators.


Scheme 2.28 Cucurbituril hosts used to target nitrosamines.


chapter 2. design and synthesis of synthetic receptors for biomolecule recognition katharine l....

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