Clickable Nucleic Acids: Sequence-Controlled Periodic Copolymer/Oligomer Synthesis by Orthogonal Thiol-X Reactions

Article abstract of DOI:10.1002/anie.201506711

Synthetic polymer approaches generally lack the ability to control the primary sequence, with sequence control referred to as the holy grail. Two click chemistry reactions were now combined to form nucleobase-containing sequence-controlled polymers in simple polymerization reactions. Two distinct approaches are used to form these click nucleic acid (CNA) polymers. These approaches employ thiol-ene and thiol-Michael reactions to form homopolymers of a single nucleobase (e.g., poly(A)_n) or homopolymers of specific repeating nucleobase sequences (e.g., poly(ATC)_n). Furthermore, the incorporation of monofunctional thiol-terminated polymers into the polymerization system enables the preparation of multiblock copolymers in a single reaction vessel; the length of the diblock copolymer can be tuned by the stoichiometric ratio and/or the monomer functionality. These polymers are also used for organogel formation where complementary CNA-based polymers form reversible crosslinks.

Full text of DOI:10.1002/anie.201506711

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201506711
German Edition: DOI: 10.1002/ange.201506711
Controlled Polymerization Hot Paper
Clickable Nucleic Acids: Sequence-Controlled Periodic Copolymer/
Oligomer Synthesis by Orthogonal Thiol-X Reactions
Weixian Xi, Sankha Pattanayak, Chen Wang, Benjamin Fairbanks, Tao Gong, Justine Wagner,
Christopher J. Kloxin, and Christopher N. Bowman*
Abstract: Synthetic polymer approaches generally lack the
ability to control the primary sequence, with sequence control
referred to as the holy grail. Two click chemistry reactions were
now combined to form nucleobase-containing sequence-con-
trolled polymers in simple polymerization reactions. Two
distinct approaches are used to form these click nucleic acid
specific manner. Similarly, many other polymers formed in
nature (e.g., peptides, proteins, polysaccharides) possess the
shared characteristic of having specific control of and
behavioral dependence on their primary monomer sequence.
[
3]
DNA mimics, such as peptide nucleic acids (PNAs), possess
similar functionality, although they are also generally imprac-
tical for use as functional materials or in other large-scale
applications owing to the difficulties associated with large-
scale solid-phase synthesis. In all cases, the sequence specific-
ity in each of these “polymers” results in the storage of
information, such as genetic material in DNA, but the
primary sequence also dictates the folding of the macro-
molecules, for example, in polypeptides, into secondary and
tertiary structures—all of which makes the materialꢀs behav-
ior strongly dependent on the primary sequence of the
polymer.
(
CNA) polymers. These approaches employ thiol–ene and
thiol-Michael reactions to form homopolymers of a single
nucleobase (e.g., poly(A) ) or homopolymers of specific
n
repeating nucleobase sequences (e.g., poly(ATC) ). Further-
n
more, the incorporation of monofunctional thiol-terminated
polymers into the polymerization system enables the prepara-
tion of multiblock copolymers in a single reaction vessel; the
length of the diblock copolymer can be tuned by the
stoichiometric ratio and/or the monomer functionality. These
polymers are also used for organogel formation where
complementary CNA-based polymers form reversible cross-
links.
In contrast, for most synthetic polymers, we have essen-
tially no sequence control over their primary structures
beyond simple statistical control. Although there have been
many exciting efforts focused on achieving sequence control
D
NA is the most capable and powerful biomolecular
[
4]
structure, functional as genetic material and aptamers,
hybridizing to complementary strands, and active in tran-
scription and translation. Foremost, DNA conveys genetic
information from one generation to the next in living
organisms; however, in the materials science realm, its ability
for sequence-specific hybridization is often used to facilitate
in polymer synthesis, synthetic polymers not produced by
solid-phase synthesis generally do not exhibit primary-
sequence control, particularly in a manner that would lead
[
5]
to sequence-dependent behavior as observed in nature. In
fact, the goal of achieving sequence control in synthetic
polymers has been referred to as the holy grail of synthetic
[1]
[6]
the synthesis of various nanoscale structures and assemblies.
polymer science with significant progress made using living
For example, particles functionalized with complementary
oligonucleotide strands assemble into hierarchical structures
simply through hybridization. DNA folding and double-
strand formation lead to DNA nanostructures of controlled
shape and also to the formation of nanoactuators, nano-
polymerization approaches that consider monomer reactivity
to gain both dispersity control and good sequence selectiv-
[
7]
ity. These approaches have been successfully employed in
making polymers with sequence-ordered blocks or controlling
the sequence distribution in the polymer chain. Whereas the
development of these synthetic approaches is promising,
many still lack both the sequence specificity and functional
similarity observed in nature that leads to the unique
functions of natural polymers.
[
2]
tweezers, and other nanoscale devices.
All of these enabling functions and applications of DNA
are based on the primary nucleobase sequence and its ability
to hydrogen-bond and ultimately hybridize in a sequence-
Click chemistry has been employed and demonstrated to
be a powerful method in both polymer synthesis and materials
[
*] W. Xi, Dr. S. Pattanayak, C. Wang, Dr. B. Fairbanks, Dr. T. Gong,
J. Wagner, Prof. Dr. C. N. Bowman
Department of Chemical & Biological Engineering
University of Colorado Boulder
[8]
science. The high conversion and other desirable attributes
of click reactions have enabled their widespread implemen-
tation in polymer synthesis and modification. Herein, we
propose various strategies that utilize thiol-X click chemis-
5
96 UCB, Boulder, Colorado 80309-0596 (USA)
E-mail: Christopher.Bowman@Colorado.edu
[9]
try to enable the facile and robust formation of sequence-
Prof. Dr. C. J. Kloxin
controlled polymers (Scheme 1), including those functional-
ized by nucleobases to form mimics of natural oligonucleo-
tides. One particularly versatile thiol-X strategy is the
sequential use of a base/nucleophile-catalyzed thiol-Michael
addition and a radical-mediated thiol–ene reaction to build up
Department of Materials Science & Engineering and
Department of Chemical & Biomolecular Engineering
University of Delaware
1
50 Academy Street, Newark, Delaware 19716 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506711.
[10]
oligomeric sequences.
Herein, we developed a robust
1
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thiol-Michael/thiol–ene combination with just a single thiol
deprotection step for the synthesis of the functionalized
oligomers enables a wide range of sequence-controlled
polymers to be fabricated in a single, robust step from
a library of these functionalized oligomers. Thus, from a single
polymerization step, the outcome of this approach is such that
it is possible to produce sequence-controlled polymers with
repeating periodic sequences of nucleobases. Examples of
simple methods for the synthesis of repeating sequences of
nucleobases are given in Scheme 1.
To demonstrate the capacity of the thiol click reaction for
the preparation of DNA-mimicking oligonucleotides, nucleo-
base-functionalized monomers containing a thiol and an
allylamine functional group and monomers containing a thiol
and an acrylamide functional group were synthesized from
readily available starting materials (Figure 1).
Scheme 1. Thiol-click reaction strategy for sequence-controlled periodic
functional oligomers and polymers. A) General monomer structure
that enables thiol-based click polymerization, R is a functional group
that can be, but not necessarily is limited to a nucleobase (adenine,
thymine, uracil, cytosine, or guanine). B) The type of thiol click
reaction that takes place—a base/nucleophile-catalyzed thiol-Michael
addition or a radical-mediated thiol–ene reaction—is dictated by the
chemical nature of the vinyl group (i.e., electron-poor or electron-rich,
respectively). C) A functionalized thiol-protected acrylamide monomer
is readily coupled to a functionalized thiol–allylamine monomer (1) in
a thiol-Michael addition, followed by deprotection of the thiol (2) to
restore the thiol and allylamine end groups. In this report, the
functional groups, represented by different colors, are nucleobases. At
any stage during the sequential thiol-Michael addition reactions, the
thiol and allylamine functional groups readily polymerize by radical
initiation of the thiol–ene reaction (3). Trt =trityl.
collection of thiol-X approaches for sequence-controlled
polymers that are DNA-like oligonucleotides; however, this
method is readily extendable to other functional polymer
motifs.
These click nucleic acid (CNA) polymers synergistically
combine all of the benefits of sequence-specific nucleobases
with the robust simplicity of click chemistry to enable their
implementation in sequence-specific applications. The two
functional groups on the monomer are independently
selected to enable the desired reaction from within the
thiol-X family of reactions. Specifically, the polymerizable
groups employed here include thiols and protected thiols,
acrylamides, and allylamines. The unprotected thiols react
either with the allylamine in the radical-mediated thiol–ene
reaction or with the acrylamide in the base- or nucleophile-
catalyzed thiol-Michael reaction. As will be shown later,
thoughtful design of the monomer structures enables several
simple divergent approaches to yield complex, sequence-
specific copolymers in a very small number of reaction steps.
In particular, as the allylamine group is unreactive under the
reaction conditions of the thiol-Michael addition, the combi-
nation of monomers that can undergo thiol–ene and thiol-
Michael reactions enables the sequential, self-limiting syn-
thesis of polymerizable oligomers. Furthermore, using the
Figure 1. A) Synthetic route for thymine-containing thiol–allylamine
monomers. B) Synthetic route for adenine-containing thiol–acrylamide
monomers. DIPEA=diisopropylethylamine, EDC=3-(3-dimethylamino-
propyl)-1-ethylcarbodiimide, HOBt=hydroxybenzotriazole, TEA=tri-
ethylamine, TES=triethylsilane, TFA=trifluoroacetic acid.
The results of the synthesis of polythymine (polyT) from
the thiol–ene radical homopolymerization of the thymine
monomer are presented in Figure 2A. MALDI-TOF analysis
[
11]
reveals that the polyT product has a M of 3148 Da, which is
n
equivalent to a degree of polymerization (DP) of 11. The gap
between two molecular peaks in the MALDI-TOF spectrum
is 283 Da, which is the exact molecular weight of the thymine-
functionalized thiol–ene monomer. Furthermore, we moni-
tored the molecular-weight evolution by size-exclusive chro-
matography (SEC) for irradiation times of 20–480 s. The SEC
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analysis of the polyT polymer,
which was found to have a glass
transition temperature (Tg) of
1
(
27 Æ 48C as determined by DSC
Figure S3).
Both the cyclic monomer and
the intermediate-molecular-weight
polymer formed at relatively low
conversions are unexpected for
a canonical step-growth polymeri-
zation. Thus, it is apparent that the
presence of both a thiol and a vinyl
group in a single monomer with
a short distance between them is
capable of inducing relatively facile
intramolecular chain-transfer and
propagation reactions. The intra-
molecular chain-transfer reaction
would tend to extend the chain
beyond that expected for a classical
step-growth
polymerization
whereas the intramolecular propa-
gation reaction would be expected
to lead to cyclic structures.
After the successful prepara-
tion of thymine-containing homo-
polymers, we developed the strat-
egy further to synthesize function-
alized CNAs by incorporation of
Figure 2. The thymine thiol–allylamine monomer (0.1 mmol) is photopolymerized by irradiation with
À2
3
65 nm light (20 mWcm ) for 10 min in the presence of 1 mol% DMPA. A) The MALDI-TOF
spectrum reveals M =3148 Da; the spacing between the peaks corresponds exactly to the monomer
n
molecular weight. B) Overlaid SEC traces (DMSO at 508C) of the thymine thiol–ene polymerization
mixture with various irradiation times. The exposure times in seconds as well as the conversion of the
1
allyl group as determined by H NMR spectroscopy are given.
a
thiol-functionalized monomer
traces indicate that higher-molecular-weight polymers were
generated with increasing polymerization time. However, the
into the polymerization mixture to generate diblock copoly-
mers. We employed poly(ethylene glycol) (PEG) monothiol
peak in the low M region was still present after the
(M ꢀ 2000) as a model monofunctional thiol, then added the
w
n
polymerization with almost full conversion of the functional
groups (Supporting Information, Figure S1). We propose that
this unusual peak whose retention time is almost the same as
that of the starting monomer arises from the thiol–ene
cyclization product of a single monomer. The cyclized product
was removed by washing the crude product with methanol
and isolated in 58% yield; its structure was confirmed by
thymine thiol–ene monomer in a stoichiometric ratio of 1:4 or
1:10 (PEG monothiol/thiol–ene monomer; Table 1). Under
typical thiol–ene photopolymerization conditions, the diblock
polymer PEG–polyT was prepared. SEC trace analysis
indicated that changing the stoichiometric ratio of the starting
materials influenced the length of the diblock copolymer
(Figure 3). With the incorporation of a hydrophilic PEG tail
into the hydrophobic polyT, the solubility of the CNA(polyT)
in aqueous solution increased (Figure S4). We have thus
demonstrated that a simple thiol–ene copolymerization
provides a relatively facile method and general approach to
functionalize our CNAs with different thiols.
1
H NMR spectroscopy and ESI mass spectrometry (Table 1,
Figures S2 and S3). After removal of the cyclized monomer,
1
H NMR spectral analysis of the polyT product indicated that
this polymer still has an allyl group at the end, indicative of
a linear polymer structure. We also performed thermal
Supramolecular gels are soft materials based on non-
covalent interactions, such as hydrogen bonding, host–guest,
[
12]
or electrostatic interactions. They have emerged as a broad
class of smart materials as their multiresponsive properties
Table 1: Molecular-weight distributions and product yields for nucleo-
base-functionalized homopolymers and copolymers/oligomers.
[7d,13]
[b]
have been widely used in materials science.
gels, in particular, have been used in drug delivery and cell-
free protein production, for example. Nucleobase interac-
tions are often used as a sequence-specific physical crosslink
within a polymer gel; this type of gel is responsive to the
presence of other sequences, temperature, and various other
molecular stimuli.
To demonstrate the capacity of CNA polymers to serve as
reversible physical crosslinks, we synthesized a gel structure
that utilizes self-complementary pairs of nucleobases [poly(T-
DNA-based
Entry
Polymer
M [Da]
n
M [Da]
w
PDI
Yield [%]
1
2
3
4
polyT
poly(T-alt-A)
poly(TAA)
9700
3200
2100
14000
4000
2400
1.42
1.20
1.14
1.36
42
83
85
87
[14]
[
a]
PEG–polyT
10000
14000
[
a] Polymerization conditions: PEG-SH/monomer=1:10. M , M , and
n w
PDI values were determined by SEC using poly(methyl methacrylate)
standards (DMF at 508C). [b] Polymerization/oligomerization yield. The
polymerization yield is reduced primarily by the formation of low-
molecular-weight cyclic structures.
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Figure 3. A) Synthesis of the diblock polymer PEG–polyT in a one-pot
copolymerization of PEG-SH and the thymine thiol–allyl monomer.
B) Overlaid SEC traces (DMSO at 508C) of PEG–polyT with different
polyT molecular weights and PEG-SH (M =2000). PolyT homopoly-
n
mers were removed by precipitation in MeOH prior to dialysis.
Figure 4. A) Thiol-Michael coupling of thymine and adenine monomers
5 mol% DBU in DCM, 1 h), yielding a thymine–adenine dimer that is
photopolymerized using 20 mWcm of 365 nm light for 10 min in the
presence of 1 mol% DMPA. B) Thiol–ene photocoupling of hybridized
poly(T-alt-A) with tetrathiol-PEG (20 kDa) leads to the formation of
a supramolecular organogel (20 wt% in DMSO). C) Rheological mon-
alt-A); Table 1]. This self-complementary polymer is formed
in a single homopolymerization step using a thymine-and
adenine-functionalized thiol/allylamine-terminated dimer,
which was prepared from the thiol-Michael coupling reaction
between the thiol of the thymine and the acrylamide of the
(
À2
1
adenine monomers, (Figure 4A). The H NMR spectrum of
itoring of the polymerization before irradiation and after irradiation
À2
(
365 nm, 20 mWcm ) reveals the formation of an organogel with
the thymine–adenine dimer, which is soluble in chloroform,
indicated hydrogen bonding between the thymine and the
adenine (Figure S6). After thiol–allyl polymerization, the
cyclized product was also observed, but in a lower relative
yield (ca. 17%) owing to the increase in the minimum cycle
size compared to polyT. MALDI-TOF analysis indicates
a 577 Da spacing, which corresponds to the molecular weight
of the TA dimer (Figure 4A). Although MALDI-TOF
accurately determines repeat-unit molecular weights, the
molecular-weight averages and distributions determined by
this method do not accurately reflect the degree of polymer-
ization because of insufficient ionization in the spectrometer.
a modulus of 1 kPa and a crossover point of 20 s of irradiation. All
rheological tests were performed at fixed frequency (10 Hz) and strain
(500%) at 258C.
found to be thermoreversible as heating and cooling cycles
resulted in obvious viscosity changes (Figure S5). A strain
sweep of the organogel revealed a sharp decrease in the
modulus at high strains associated with disruption of the
CNA(poly(T-alt-A)) crosslinks, elimination of the large strain
leads to recovery of the higher modulus associated with
reforming of the CNA(poly(T-alt-A)) physical crosslinks.
(Figure S7). Both reversibility tests and control experiments
indicated a non-covalent and sequence-specific interaction
that was necessary for organogel formation. For comparison,
we also covalently crosslinked an organogel using tetra-PEG-
SH and tetra-PEG-maleimide, which exhibited a slightly
larger elastic modulus than our CNA(poly(T-alt-A)) organo-
gel (ca. 6000 Pa vs. 1000 Pa), likely owing to the reversible
nature of the hybridization in the CNA(poly(T-alt-A)) gel as
compared with the permanent, covalent crosslinks formed in
this type of control gel.
As demonstrated by the CNA(poly(T-alt-A)) synthesis,
our approach to forming periodically repeating sequences is
based on using sequential thiol-Michael addition reactions to
form monomers of a desired sequence and subsequently
employing the thiol–ene reaction in a single polymerization
step to form polymers of controlled, periodic sequences. The
DNA analogues of these repeating sequences are also
ubiquitous in nature. In fact, completion of the human
genome project revealed that nearly half of the genome
Furthermore, the T of the poly(T-alt-A) polymer was found
g
to be 133 Æ 68C by DSC. Upon mixing of hybridized CNA-
(
poly(T-alt-A)) with tetra-PEG-thiol (20 kD) and photoini-
tiator in DMSO, the specimen remained in a liquid state.
After irradiation, which induced the coupling of CNA(poly-
(
T-alt-A)) to the four-armed PEG core, a CNA-hybridized
crosslinked gel was formed as evident from the significant
change in viscosity and, ultimately, solidification (Figure 4B).
The organogel formation was monitored using photorheom-
etry (Figure 4C). From the rheological trace, we determined
that gelation occurred after 20 s of UV light irradiation. We
also performed a control experiment in which a polyT
polymer that is not capable of self-complementary binding
was coupled to a PEG core with four tetrathiol arms. Whereas
there was a change in the mechanical properties upon
irradiation, likely owing to hydrophobic interactions after
conjugation, the material did not gel (G’ < G’’), and the elastic
modulus was much less than for the CNA(poly(T-alt-A))
crosslinked material (Table S1). The organogel was also
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consists of repetitive sequen-
ces, and in many cases, their
roles are not yet fully under-
[
15]
stood.
Whereas many of
these repeating structures are
non-functional, studies have
shown that repetitive DNA is
essential for genome function,
and many of these sequences
have critical roles in aging and
[
16]
disease.
For example, at
least 16 human-inherited neu-
rological diseases are caused
by simple trinucleotide repeat
expansions (e.g., CAG, CUG)
that are known as trinucleo-
tide repeat disorders and
affect hundreds of thousands
Scheme 2. Thiol-Michael coupling of the thymine–adenine dimer and adenine monomers (5 mol% DBU in
CH Cl , 1 h), yielding a thymine–adenine–adenine trimer that is photopolymerized by irradiation with
2
2
[
17]
À2
of individuals worldwide.
365 nm light (20 mWcm ) for 10 min in the presence of 1 mol% DMPA (DMPA=2,2-dimethoxy-2-
This class of diseases includes phenylacetophenone). Inset: MALDI spectrum of this polymer, showing the 867 Da spacing associated with
the TAA trimer.
Huntington disease (caused
by a CAG repeat), myotonic
dystrophy type 1 (caused by
a CUG repeat), the fragile X syndrome (caused by a CGG
repeat), and several types of ataxia. Thus, the robust
formation of polymers based on nucleotide-repeating sequen-
ces has significant potential in genetic diagnostics and even
approach can be used to create new classes of synthetic
polymeric materials.
controlling disease expression as well as in sequence-directed Acknowledgements
self-assembly. Herein, a CNA monomer consisting of the
trimer TAA was synthesized by reacting the TA allylamine–
thiol dimer with the adenine-functionalized protected thiol–
acrylamide monomer. Following deprotection to yield a TAA
trimer with allylamine/thiol function groups, CNA polymer
strands with a TAA repeating sequence [CNA(polyTAA)]
were formed in a single-step polymerization in similar yield
We gratefully acknowledge financial support from NSF–
MRSEC (DMR 1420736), the NSF (CHE-1214109), DARPA/
US Army (W911NF-14-1-0605), and the NIH R21
(CA174479).
Keywords: block copolymers · click chemistry · polymerization ·
(
ca. 17%) as the cyclized side product by the same general
thiols
strategy used to form CNA(poly(T-alt-A)) (see Scheme 2 and
Table 1).
How to cite: Angew. Chem. Int. Ed. 2015, 54, 14462–14467
Angew. Chem. 2015, 127, 14670–14675
In summary, the utilization of click chemistry provides
a route to sequence-controlled periodic copolymer/oligomer
synthesis that, when combined with functional side groups in
general and nucleobases in particular, enables the creation of
novel, highly functional materials in a robust, simple, and
scalable manner. CNA polymers possessing nucleobase side
groups mimic the functional aspects of DNA and can be used
for the formation of organogels in a sequence-specific
manner. This approach is the first demonstration of nucleo-
base-functionalized sequence-controlled periodic copoly-
mers/oligomers and polymers synthesized without the use of
a solid support. As the nucleobase represents a very small
subset of the possible functional side groups, the extension of
the click conjugation strategy for a wide range of functional
backbones (e.g., amino acid side chains or sugars) can be
readily envisioned. Moreover, hybrid materials present a new
canvas of molecular design where nature-inspired structures
are readily combined with the hope of synergistic properties.
Indeed, the simple materials and concepts outlined herein
provide a powerful framework from which the click chemistry
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