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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: anslyn@austin.utexas.edu
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Figure 2.1 Intermolecular interactions involved in complexation.
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pentaethyleneglycol
dimethylether (EG5)
18-crown-6
O
O
O Me
O
O
[2.2.2]cryptand
O
O
N
O
log K (K+)
MeOH, 25°C
O Me
O
O
O
O
O
O
O
2.3
6.08
Scheme 2.1 Binding affinities of cyclic and acyclic polyethers for K+.
O
O
10.0
N
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O
H
H
O
O
O
O
O
O
O
O
K
O
H
H
O
O
O
O
O
O
Scheme 2.2 Conformational change required for K+ binding in 18-crown-6.
O
O
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Scheme 2.3 Barbital binding by macrocyclic Hamilton receptor and deconstructed acyclic hosts.
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H3C
O
H 3C
N
H
N
O
H
O
N
N
H3C
O
H
N
N
N
RH
O
CH 3
H N
O
N
CH 3
CH3
H
2.5
Scheme 2.4 Adenosine binding by cleft-shaped receptor.
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R
R
R
R
R
R
H
N
H
H
N
N
2.6
R=
NH
HN
N
H
O
O
O P
O P
O
O
OH
HO
O
O
HO
O P
O O
O
Scheme 2.5 Pinwheel host 2.6 with six guanidinium groups binds strongly to inositol-1,4,5-triphosphate.
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R
R
R
N
R
N
N
2.7
R
Br
R
Br
N
N
N
R = -NH2
Scheme 2.6 Inward binding conformation of pinwheel host is induced by the presence of Br - guest.
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kJmol-1
0
100
200
300
400
500
600
covalent bonda
ion-ion interactionsa
ion-dipole interactionsa
dipole-dipole interactions
hydrogen bonding
cation-p interactions
van der Waals forces
Figure 2.2 Strengths of covalent bonds and noncovalent interactions. asingle covalent bond or monovalent interaction.
Figure 2.3 Cation···π interaction.
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unfolded
folded
A
K
9
1
H
R2
R1
H
H
H
R1
R2
unfolded
B
folded
R
R
O
MeO 2C
O
O
K
O
N
N
R1
R2
N
N
R1
unfolded
C
CO 2Me
R2
folded
R2
O
N
O
K
N
O
O
R1
Ph
unfolded
R2
Ph
Ph
O
O O
O
R1
Ph
folded
Figure 2.4 Three types of molecular torsion balances designed by the groups of: A) Ōki, B) Wilcox, and C) Shimizu.
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Figure 2.5 Host guest association in solution.
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© The Royal Society of Chemistry 2015
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.
O
N
N
O
N
3
2.8
pyrene
Scheme 2.7 Structures of cyclophane host 2.8
and pyrene guest.
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Table 2.2 Log K values for complexation of K+ by 18-crown-6 in various solvents that differ in surface tension.
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Table 2.3 Reversible covalent reactions.
Transimination
R1
N
Hydrazone exchange R1
N
Oxime exchange
N
R1
R2
H
N
O
R3
R2
R3
N
R2
R3
N
O
Transamidation
R1
N
H
R1
H
N
O
R1
R3
N
H
O
R3
O
R1
S
R2
R4
R4
Disulfide exchange
Boronate exchange
R1
R1
R2
S
R1 B
S
O
O
R2
R2
R3
4
R5 R
R3
R3
S
protease
or metal
N
R1
SH
H
N
O
S
HO
R6 7
R
HO
R8
R9
R4
R3
N
R4
R3
N
R2
H
N
O
R2
R2
O
N
H
R1
R3
N
H
R2
O
O
R4
R3
O
R2
O
R3
base
R1
base
N
R4
S
S
R3
R2
SH
O
R1
R4
R3
O
base
base
R4
O
R1
O
Conjugate addition
R1
base
SH
R3
N
acid
O
Transthioesterification
R1
R4
O
R2
N
acid
R4
O
R2
O
Transesterification
acid
R4
N
R2
S
S
R4
R3
S
R2
S
R7
HO
R2 3
R
8
R9 R
HO
R4
R5
O
R6
R1 B
O
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HO
OH
B
OH
OH
O
HO
HO
B
HO
OH
O
B
B
O
O
Scheme 2.8 Reversible covalent bonding of diol-containing guest using boronic acids. (Adapted with permission from Org.
Lett., 2010, 12, 4804, © 2010 American Chemical Society)
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OH
R
Nuc
B
OH
R
OH
Nuc
B
Nuc
OH
Scheme 2.9 Reversible nucleophilic attack on a boronic acid.
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Table 2.4 Common carbonyl-based indicators and associated analytes.
Receptor
Analyte
Complex
R
O
RNH2,R 2NH
R
CF3
HO
R
ROH
O
SO3
R
H-
H
RHNNH2
H(R)
CF 3
HO
R
RSH
N
OR
CF 3
HO
SR
R
CF 3
HO
SO3-
R
H
HO
NHNHR
R
H
HO
CN
R
H
HCN
(R)H
CN
CN
R
N
R
RNH2, R2NH
CN
R
CN
CN
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R1
S-
R2
S
S
R3
R2
S
S
Scheme 2.10 Nucleophilic attack by a thiolate on a disulfide.
R1
R3
S-
Supplementary information for Synthetic Receptors for Biomolecules: Design Principles and Applications
© The Royal Society of Chemistry 2015
Figure 2.6 CPK models of α-cyclodextrin showing toluene outside (left) and inside (right) the cavity. (Reproduced with
permission from Adv. Chem. Ser., 1971, 100, 21, © 1971 American Chemical Society)
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HO
O
B
O
HO
O
O
B
O
Definition of
vector pair
CAVEAT
OH
H3C
2.9
H 3C
B(OH)2
H
B(OH)2
H
H
H
Scheme 2.11 Design of a glucopyranose receptor using CAVEAT.
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B(OH)2
B(OH)2
O
O
HO
CH3
H
2.10
Scheme 2.12 Structure designed using CAVEAT.
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© The Royal Society of Chemistry 2015
H
N
O
O
π-π
stacking
NH
B
HO
O
O
O
NH3
ionic
interaction
O
covalent
bonding
Scheme 2.13 Dopamine binding by Wang's receptor.
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© The Royal Society of Chemistry 2015
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)
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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)
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Scheme 2.14 Top five synthetically accessible host structures for oxygen mustard generated using
HostDesigner. (Reproduced with permission from Comput. Theor. Chem., 2014, 1028, 72, © 2014
Elsevier)
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Scheme 2.15 Common scaffolds for synthetic organic receptors.
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SO 3-
O
O
O
O
SO 3-
4 Na+
SO3O
O
SO 3O
O
2.11
Scheme 2.16 Water soluble crown ether host for NAD+.
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© The Royal Society of Chemistry 2015
O
O
O
O
O
O
O
H 3C
OH OH HO
OH
O
O
O
O
O
O
O
O
O
CH 3
O
R
O
R
R
SH
HS
R
R
2.13
2.12
2.14
Protein
H 3C
O
S
O
NH 4
O
O
O
O
O
S
CH3
H 3C
O
S
O
NH 4
O
O
O
O
O
CH3
S
Figure 2.9 Protein immobilization on glass slides with calix[4]crown-5 derivative 2.14. (Adapted with permission from
Proteomics, 2003, 3, 2289, © 2003 Wiley)
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O
O
O
N
H
O
O
O
O
H
N
SiO2
N
H
O
O
H
N
O
HN
NH
2.16
O
H
N
H H
N N
NH
HN
NH
HN
O
N
H
SiO 2
2.15
2.17
DMSO
Cl
NH2
Pt Cl
N
N
HN
O
-O
P
N
O
ON
H
OH
HN
NH
N
O
OH
AMP
H
N
2.18
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.
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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)
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OH
OH
OH
O
HO
O
OH
HO
O
HO
HO
O
OH
O
HO
O
OH
HO
OH
a-cyclodextrin
O
O
HO
OH
OH
O
HO
OH
O HO
O
O
HO
OH
O
HO
O
OH
O
O
O
O
OH HO
O
O
OH HO
O
OH
OH
HO
O
OH
HO
HO
HO
O
O HO
OH
O
OH
O
OH
HO
HO
O
HO
O
b-cyclodextrin
OH
O
OH
HO
O
OH
g-cyclodextrin
HO
O
OH
O
HO
OH O
OH
O HO
O
HO
O
Scheme 2.19 Three most common cyclodextrins.
HO
OH O
O
HO
O
OH
OH
OH
OH
HO
OH O
HO
O
OH
O
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NH2
H 2N
H2N
HN
NH
N
H
NH
HN
HN
HN
HN
O
O
NH2
HN
H 2N
NH
NH2
HN
HN
N
H
NH
HN
NH
O
O
HN
H
N
O
O
2.21
2.22
Scheme 2.20 Structures of pinwheel hosts.
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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.
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O
O
NH
R
N
H
HN
NH2
NH2
CO2Me
R=
CO2Me
CO2Me
O
N
H
CO2Me
CO 2Me
CO2Me
CO2Me
CO 2Me
CO2Me
CO 2Me
CO2Me
CO 2Me
CO 2Me
Ph
CO2Me
CONH 2
O
CO 2Me
CO2Me
CONH2
SH
N
N
H
CO2Me
NH
CO2Me
CO2Me
N
N
N
Boc
N
Trt
Scheme 2.21 Guanidiniocarbonyl-pyrrole receptors generated using parallel synthesis. All of the R groups are
directly attached to the amide nitrogen.
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O
AA2-AA 1
NH
N
Lys, Glu, Val, Phe, Gly, Ser
N
AA 5-AA6
Arg, Asp, Ile, Trp, Thr, Gln
N
AA 3-AA4
His, Ala, Leu, Pro, Tyr, Asn
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.
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Random ssDNA
or RNA library
isolation of
ssDNA or RNA
Library binding to target
PCR amplification
Washing of
unbound sequences
Elution of
bound sequences
Figure 2.11 SELEX protocol for artificial evolution of a complex biopolymer library.
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Template
Library
Building Blocks
Virtual Library
Templated 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)
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O H
N
O H
N
N
O
N
O
O
N
N
N
N
N
NH
O
O
NH
N
N
N
N
O
N
HN
HN
O
N
O
N
H O
N
N
N
X
O
O
NH
HN
N
O
O
O
N
O
O
2.24
2.23
COOH
SO3Na
X=
-S-S
S-S-
OH
-S-S
S-Sb
a
-S-S
-S-S
S-Sc
S-Sd
COOH
HOOC
O
-S-S
H
N
N
H
e
S-S-
S-SO
-S-S
f
Scheme 2.23 Cyclic monomeric host 2.23 and dimeric host 2.24 where X is one of the disulfide linkages a to f.
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© The Royal Society of Chemistry 2015
X
O
O
N
N
N
O
O
N
HN
O
NH
NH
N
O
HN
N
N
N
O
N
N
O
O
N
N
H
O
O
X
O
N
N
H
2.25
OH
-S
Sa
S-S-
-S-S
b
S-S-
-S-S
c
-S-S
S-Sd
Scheme 2.24 Dimeric host with two covalent linkers (X) incorporating the disulfide linkages a to d.
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A
B
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)
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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)
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OH
O
HO
HO
O
7
Monovalent b-CD
S
S
Divalent b-CD
O
O P
HO
O
guest
Scheme 2.25 Monovalent and divalent β-cyclodextrin receptors and guest.
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© The Royal Society of Chemistry 2015
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.)
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Figure 2.16 Example of an entropy-enthalpy compensation plot.
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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)
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Scheme 2.26 Structure of cucurbit[7]uril host and ferrocence guests. (Reproduced with permission from Proc. Nat.
Acad. Sci. USA, 2007, 104, 20737, © 2007 National Academy of Sciences, U.S.A.)
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Figure 2.18 Differential sensing using a hypothetical array-based sensor. To a 16-element array, A), analyte 1 (later identified
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 differential patterns C, F. (Reproduced with permission from Chem. Soc. Rev., 2010, 39, 3954, © 2010 Royal Society
of Chemistry)
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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)
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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)
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CN
O
NC
CN
NC
NC
CN
NO 2
N
H
R
O
HN
NH
H
N
N
N
O
NC
CN
NC
2.26
O
NC
CN
Scheme 2.27 Calixpyrrole scaffold used to create carboxylate indicators.
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O
O
O
O
N N
N
N
N
N N
N
N
N
O
O
O
N
N
N
N
N
N
N
N N
N
N
N
N N
O
O
O
O
O
2.27
OR
O
N
N
O
O
N
OR
O
N
N
N
N
N
O
O
N
N
N
N
H
HH
H
N
N
N
N
RO
O
O
RO
R = (CH2)3SO3Na
2.28
Scheme 2.28 Cucurbituril hosts used to target nitrosamines.