Photoinduced [2+2] and [4+4] Cycloaddition and Cycloreversion Reactions for the Development of Photocontrollable DNA Binders

Abstract

In the current field of photopharmacology, molecular photoswitches are applied whose interactions with DNA can be triggered or controlled by light. And although several photochromic reactions have been shown to serve this purpose well, the reversible photocycloaddition and photocycloreversion reactions have been largely neglected. This absence of research is surprising because especially the photodimerization of a DNA ligand leads to products with significant change of the size and shape which, in turn, leads to strongly diminished or even suppressed DNA association. Therefore, photocycloaddition–cycloreversion sequences have a huge potential for the photoinduced, reversible deactivation and activation of ligand–DNA interactions, as will be shown with selected examples in this Concept Article. Specifically, heterostyryl and ‐stilbene derivatives are presented whose DNA–binding properties are efficiently switched in reversible [2+2] photocycloaddition reactions. In addition, the photocontrolled DNA–binding of anthracene derivatives and their heterocyclic benzo[b]quinolizinium analogues in a [4+4] photocycloaddition, as well as the use of this reaction as part of dual–mode switches in combination with redox‐active functionalities, are highlighted. Furthermore, examples of conjugates are provided, in which the photochromic unit is bound covalently to nucleic acids or proteins, such that the photocycloaddition reaction can be used for reversible photoinduced crosslinking, ligation, or inhibition of gene expression.

Full text

Photoinduced [2 +2] and [4 +4] Cycloaddition and
Cycloreversion Reactions for the Development of
Photocontrollable DNA Binders
Christoph Dohmen[a] and Heiko Ihmels*[a]
In the current field of photopharmacology, molecular photo-
switches are applied whose interactions with DNA can be
triggered or controlled by light. And although several photo-
chromic reactions have been shown to serve this purpose well,
the reversible photocycloaddition and photocycloreversion
reactions have been largely neglected. This absence of research
is surprising because especially the photodimerization of a DNA
ligand leads to products with significant change of the size and
shape which, in turn, leads to strongly diminished or even
suppressed DNA association. Therefore, photocycloaddition–
cycloreversion sequences have a huge potential for the photo-
induced, reversible deactivation and activation of ligand–DNA
interactions, as will be shown with selected examples in this
Concept Article. Specifically, heterostyryl and -stilbene deriva-
tives are presented whose DNA–binding properties are effi-
ciently switched in reversible [2 +2] photocycloaddition reac-
tions. In addition, the photocontrolled DNA–binding of
anthracene derivatives and their heterocyclic benzo[b]-
quinolizinium analogues in a [4 +4] photocycloaddition, as well
as the use of this reaction as part of dual–mode switches in
combination with redox-active functionalities, are highlighted.
Furthermore, examples of conjugates are provided, in which
the photochromic unit is bound covalently to nucleic acids or
proteins, such that the photocycloaddition reaction can be used
for reversible photoinduced crosslinking, ligation, or inhibition
of gene expression.
Introduction
The investigation of DNA–binding compounds is still a highly
topical area of research in interdisciplinary fields between
chemistry, biology, pharmacy, and medicine,[1,2] because upon
association of such ligands the structure of the nucleic acid may
be significantly changed. This property, in turn, can be used to
specifically disturb or prevent the biochemical function of DNA.
For example, the occupation of DNA binding sites by a ligand
may influence biologically relevant DNA–protein interactions
and, thus, potentially influence gene suppression or even
apoptosis of the affected cells.[1,3] The latter effect is particularly
useful in the treatment of cancer because tumor cells often
evade the naturally occurring cell–death processes, resulting in
uncontrolled tumor growth.[4] Specifically, some approaches of
currently applied DNA–targeting chemotherapy operate accord-
ing to this principle and are still valuable therapeutic tools in
cancer treatment.[1,5] Nevertheless, because of the low selectivity
of the employed DNA ligands chemotherapy is often associated
with severe side effects.[6] Therefore, novel concepts are still
needed that lead to an increased selectivity of the employed
DNA–targeting drugs. In this context, photochromic com-
pounds, often referred to as photoswitches, that is, substances
that transform into another species in a reversible photo-
reaction, have been introduced to this field. Specifically, if the
two interconvertible compounds bind differently to a target
DNA, ideally binding versus non–binding, they may enable the
controlled activation of the DNA–ligand interactions.[7–9] This
approach is particularly attractive because light as an activating
(or deactivating) stimulus provides a high temporal and local
control and can, therefore, be applied directly at the target.[7,8]
Furthermore, by introducing chromophores that absorb in the
near-infrared region (NIR) the light required to induce a
chemical reaction penetrates through the tissue, which provides
an improved spatial effectiveness.[10] Among the most prom-
inent photoswitches, that were investigated along these lines,
are azobenzenes, stilbenes, diarylethenes, spiropyrans and
spirooxazines, and anthracenes,[7,11–14] whose mode of operation
involves photoinduced structural changes by E/Z-isomeriza-
tions, electrocyclization reactions, hetero- or homolytic CO-
bond cleavage, or cycloaddition reactions. In the context of
bioactivity, the structural differences between the two states of
the photochromic equilibrium determine both their binding
modes and binding strength to the respective target.[7,13,14,15] For
example, it was demonstrated that spiropyrans,[16]
spirooxazines[17] and chromenes[18] predominantly intercalate
into DNA in their open form, whereas the sterically demanding
closed forms do not bind. In other representative examples, it
was shown that diarylethenes[19] and azobenzenes[20] exhibit
varying binding modes, including intercalation and groove
binding, in both photochromic states. Moreover, it was
[a] C. Dohmen, Prof. Dr. H. Ihmels
Department of Chemistry and Biology, and Center of Micro-and Nano-
chemistry and (Bio)Technology (Cμ)
University of Siegen
Adolf-Reichwein-Str. 2, 57068 Siegen, Germany
E-mail: ihmels@chemie.uni-siegen.de
© 2024 The Authors. ChemPhotoChem published by Wiley-VCH GmbH. This
is an open access article under the terms of the Creative Commons Attri-
bution Non-Commercial License, which permits use, distribution and re-
production in any medium, provided the original work is properly cited and
is not used for commercial purposes.
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demonstrated that the photoisomerization of azobenzenes can
effectively be used to control peptide–DNA binding.[21–23] In
these examples, only the Z-isomers of azobenzene–peptide
conjugates offer the prerequisites for the peptides to bind to
DNA allowing for a photocontrol of DNA–binding properties
even in living cells.[22,23] Furthermore, additional photolabile
groups were introduced that turn a non–binding peptide into a
DNA–binding one upon the photoinduced release of an
oligodeoxynucleotide (ODN) that initially blocked the DNA–
binding sequence of the peptide.[22,23] Likewise, the photo-
induced activation of DNA–binding ligands may also be
accomplished with metal–ligand complexes.[24] In particular,
according to the general concept of photoinduced fragmenta-
tion reactions to release bioactive fragments[25] the DNA–
binding properties of sterically demanding metal complexes
can be changed by photoinduced exchange or displacement of
the complex ligands.[26] Besides the control of DNA–binding
modes, photoswitchable DNA–ligands were also employed to
regulate the hybridization of oligonucleotides.[27] Furthermore,
photoswitchable ligands were used to control the interconver-
sion of various non–canonical DNA forms, including quadruplex
DNA and the i-motif.[22,28] And although these studies all showed
convincingly that the DNA–binding properties of appropriately
designed photochromic ligands can be switched by light, it
should be noted that in most cases the molecular photo-
switches bind to the DNA in both of their photochromic forms.
But to improve the selectivity of a photo–controllable drug, one
form of the photochromic equilibrium should ideally be
bioinactive, as realized in the prodrug concept.[29] In this regard,
the photoinduced [2+2] and [4+4] cycloaddition–cyclorever-
sion sequences appear to be promising alternatives because
these reactions transform flat aromatic molecules, i. e. potential
DNA intercalators, into sterically demanding dimers, which no
longer fit in the DNA binding sites.[30] To add to that, the
photocycloaddition and cycloreversion reactions of
stilbenes[31,32] and anthracenes,[11,32,33] as well as their hetero-
aromatic analogues,[34] are well established and investigated, so
that a rich source of compounds is available for the design of
DNA–binding photochromes. As a consequence, it was demon-
strated that cycloaddition reactions may, indeed, be used to
switch from a DNA–binding ligand to a non-binding
compound.[35,36] But as this particular approach is somewhat
neglected in this research field, so far,[7] we point out and
discuss in this Concept the scope, the limits, and the potential
of the cycloaddition–cycloreversion sequence in the develop-
ment of photoswitchable DNA binders.
Photoswitchable DNA binding based on [2 +2]
photocycloaddition reactions
The inter- and intramolecular photoinduced formation of cyclo-
butanes is a well–known process.[37] But only a few studies have
explored its application to control ligand binding to biological
targets,[35,38–40] presumably because the cycloaddition is a
bimolecular process that requires the close proximity of the two
alkenes, which is difficult to realize in biological systems.
Specifically, other than in homogeneous solution, the low
accessible concentrations of the substrates in biological media
as well as the heterogeneous nature of the latter multi-
component mixture may hamper the diffusion–controlled
dimerization. In the first reported example, it was discovered
that the irradiation (λex =392 nm) of the DNA–binding arylstil-
bazonium ligand 1 a gave two different cyclobutanes at rather
low concentrations (c=40 μM) (Scheme 1). In fact, the forma-
tion of the cyclobutanes was only observed when 1 a was
irradiated in the presence of DNA. Furthermore, the particular
binding mode of the stilbazonium ligand with the DNA seemed
to determine whether the cycloaddition products are formed
(Scheme 1). Thus, in contrast to the groove binding ligand 1 a,
which dimerizes upon irradiation (Scheme 1, path B),[38] the
intercalating ligands 1 b–cfurnish only the respective E/Z-
isomers in their photostationary states (PSS) (Scheme 1, path A).
It was suggested that pairs of 1 a bind cooperatively to the
minor groove of the DNA either in a head–to–tail (2 a) or head–
to–head (2 b) orientation leading to two different photo-
cycloaddition products. It is reasonable to assume that both the
preferential association and the electrostatic interactions by
backbone association compete and therefore result in the
formation of two isomeric cyclobutanes. However, the dimers
were not isolated and further characterized, and therefore the
structures were only deduced from the above–mentioned
orientations within the binding pocket. It is worth mentioning
that similar to the derivatives 1 b–cthe stilbazonium 1 a also
binds to the DNA by intercalation, however, this binding mode
Christoph Dohmen obtained his Bachelor’s degree in
Chemistry from the University of Siegen in 2016.
During his Master’s studies, he pursued an internship
as DAAD fellow with Prof. Dustin Gross at the Sam
Houston State University, Huntsville, Texas. He com-
pleted his Master’s studies at the University of Siegen
in 2018. In 2019, Christoph was awarded a PhD
fellowship from the House of Young Talents (University
of Siegen) and continued his academic journey in the
group of Prof. Heiko Ihmels, focusing on the develop-
ment of photochromic DNA–targeting drugs. His
research also involves the investigation of (CH)10
valence isomerizations in supramolecular assemblies.
Heiko Ihmels obtained his education at the University
of Göttingen and the University of Padova (ERASMUS)
and received his PhD in 1995 (with J. Belzner and A.
de Meijere). He enjoyed postdoctoral work with J. R.
Scheffer at the University of British Columbia, Vancou-
ver. Thereafter, he joined the University of Würzburg
where he completed his habilitation in 2002. Since
2003, he occupies a Chair of Organic Chemistry at the
University of Siegen. His research interests lie in the field
of organic photochemistry and bioorganic chemistry.
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does not contribute to the formation of photocycloaddition
products because the alkene units are spatially separated.
With the naphthylstilbazonium derivative 1 a it was demon-
strated that the pre–organization of a DNA–ligand within the
minor groove of DNA leads to a topochemical intermolecular
[2+2] photocycloaddition, even at low concentrations
(Scheme 1, path A). This interesting feature was revisited for the
selective photochemical synthesis of cyclobutane–containing
natural products.[41] In particular, aplysinopsins such as 3bind
to DNA by electrostatic interactions or groove binding and form
J-aggregates (head–to–tail orientation) along the DNA–bound
monomers (Scheme 2). Upon irradiation of these complexes,
dictazole alkaloids are formed by a photoinduced [2 +2]
cycloaddition, as shown with the formation of dictazole B (4)
(Scheme 2).[42,43] Control experiments confirmed that the in-
duced aggregation through initial groove binding of aplysinop-
sins is a prerequisite for the photoreaction to occur. In these
experiments, pyrophosphate was used to mimic the electro-
static interactions between the ligand and the DNA backbone.
Thus, when a 2 : 1 complex of an aplysinopsin with pyrophos-
phate was irradiated, it did not result in the formation of
dictazoles.
The DNA–binding properties of stilbenes and their deriva-
tives are well investigated,[38,42] especially in the form of styryl
dyes that are employed for fluorimetric DNA detection.[44] But
their use as photoswitchable DNA ligands has been mostly
neglected. As one of the few examples along these lines, the
photoswitching and DNA–binding properties of E-styrylquinoli-
zinium ions 5 a–dwere investigated in aqueous solutions
(Scheme 3).[35] These compounds intercalate into DNA with
binding constants of Kb=4.826×104M1, which was shown in
detail by photometric and fluorimetric titrations and by circular
(CD) and linear dichroism (LD) spectroscopy. Upon irradiation
with λex =520535 nm (5 a), λex =420470 nm (5 b–c), or λex =
395 nm (5 d) for 1–5 h the styrylquinolizinium derivatives were
converted into the cyclobutanes 6 a–d(Scheme 3). It was
exemplarily shown by photometric and polarimetric DNA
titrations that cyclobutane 6 b only binds to DNA by a weak
outside–edge binding (Scheme 3). Upon irradiation with λex =
315 nm for 30 min, the cyclobutane 6 b was converted back to
the DNA–binding monomer 5 b. Notably, this reversible photo-
switching takes place even in the presence of DNA with only
low photobleaching after four cycles. However, the photo-
cycloreversion is not quantitative and eventually reaches a
photostationary state (PSS). The photorelease of the monomer
5 b may be initiated from the loosely DNA–bound or free dimer
6 b, whereas the photocycloaddition requires 5 b to be outside
the intercalation binding side. At this point, it is worth
mentioning that all ligand–DNA interactions are dynamic
equilibrium processes and that at least for a short period of
time the ligand always exists in its unbound form in solution.
Overall, it was demonstrated that the functionalization of styryl
derivatives with DNA–binding subunits proved useful in the
development of a new concept to a switchable DNA–targeting
substrate.
Scheme 1. Photochemical reactions of DNA–bound arylstilbazonium ions.
Scheme 2. Photochemical reaction of an DNA–bound aplysinopsin deriva-
tive.
Scheme 3. Photoinduced switching of the DNA–binding properties of
styrylquinolizinium E-5 b (red) to its dimer 6b (blue). Adapted from Ref. [35]
CC by 4.0 DEED.
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[2 +2] Photocycloadditions of photoswitchable
ligands for targets other than DNA
Complementary to the quest for photoswitchable DNA ligands,
it was shown in resembling studies that other biological
activities of suitable substrates can be switched by [2 +2]
photocycloaddition reactions. And although these examples do
not have DNA as a target, they are briefly mentioned herein
because it is the same general concept regarding the photo-
chemical reaction. Specifically, it was shown that the activity of
already established drugs or drug candidates with alkene units
may change upon photodimerization. Thus, the approved
protein kinase inhibitor axitinib (E-7) (Inlyta©, Pfizer)[45] carries a
styryl–substituent and is, therefore, potentially photoreactive
with respect to the reversible E/Zisomerization and [2 +2]
cycloaddition (Scheme 4). It was demonstrated that this intrinsic
photoreactivity of the drug can be used to switch its biological
activity by light.[39] In particular, irradiation of the E-isomer E-7
with λex =365 nm leads to the [2+2] photodimer 8as the main
product, whereas no Z-isomer Z-7is formed (Scheme 4).
Notably, irradiation of the Z-isomer with λex =385 nm almost
quantitatively afforded E-7. Hence, to determine whether light–
induced modulation of E-7or Z-7allows the control of their
kinase–inhibiting properties, their individual performance was
assessed in a kinase assay. Thus, the kinase inhibitory efficacy of
E-7(IC50 =19 nM) was ca. 43 times higher than the one of the
respective isomer Z-7(IC50 =817 nM) (Scheme 4). In contrast,
the dimer 8essentially had no activity in the employed in vitro
kinase assay, which clearly showed a complete shut–down of
the inhibitory properties under these conditions. Although, the
release of the bioactive axitinib monomer 7by a photo-
cycloreversion of the dimer 8was not investigated, this study
demonstrated the large potential of the [2 +2] photocycloaddi-
tion as efficient tool to manipulate the biological activity of an
approved drug by light. More importantly, a broader application
of this concept should allow the discovery of even more drugs
whose biological activity can be controlled by light. For that
purpose, it may be worthwhile to screen approved drugs for
candidates that carry styryl functionalities, such as, for example,
Cinnarizine, Flunarizine, or Tamoxifen, and investigate their
photoactivity accordingly.
In a recent study, a norbornadiene derivative was identified
as a possible photoswitchable fluorescence probe for amyloid
beta plaque, that is, the hallmark of Altzheimer’s disease
(Scheme 5).[40] Thus, the fluorescent norbornadiene 9can be
transformed into its non–fluorescent quadricyclane 10 by an
intramolecular [2+2] photocycloaddition with excitation at
λex =405 nm and converted back upon irradiation at λex =
305 nm or thermally under physiological conditions at 37°C in
cells (Scheme 5). The binding itself, however, remained un-
affected in this example. But noteworthy, in comparison with
the [2+2] photocycloaddition of stilbene–type derivatives the
photoreaction of the norbornadiene does not compete with
other isomerization reactions.
Photoswitchable DNA binding based on [4 +4]
photocycloaddition reactions
In the context of cycloaddition reactions, the reversible photo-
dimerization of anthracene is a prominent example
(Scheme 6).[11,12,46] This [4+4] cycloaddition is induced by light,
whereas the cycloreversion is initiated either by light or heat.
Along with this photochemical reactivity, anthracene also has
some structural features of a typical DNA intercalator, namely a
planar structure and an extended π-system.[1,47] As a result,
several anthracene derivatives have been reported that bind to
DNA by intercalation.[47,48] In most cases, however, the water
solubility and DNA affinity had to be improved by the attach-
ment of amino functionalities that are protonated under
physiological conditions.[48] Despite this relatively large number
of studies with anthracenes, only one example has been
reported, so far, in which the photochromism of anthracene has
been employed for the controlled photoswitching between
DNA–binding modes (Scheme 6).[36] Namely, the 9-aminoalkyl-
substituted anthracene 11 intercalates into calf thymus DNA (ct
DNA) with a binding constant of Kb=4.7×104M1. However, in
contrast to the monomer 11, the dimer 112, which is obtained
by irradiation of 11 in the solid state or in solution, does not
bind to DNA (Scheme 6).[36,49] These particular photochemical
and DNA–binding properties can be used for the photoinduced
release of a DNA ligand. Specifically, when 112is irradiated in
Scheme 4. Photoswitchable kinase inhibition of axtinib (7).
Scheme 5. Reversible photoswitching of a fluorescent norbornadiene deriva-
tive 9to the non–fluorescent quadricyclane 10.
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an aqueous solution in the presence of DNA the monomer 11 is
released by cycloreversion and subsequently binds to the DNA
(Scheme 6). As one drawback of this approach, however, high–
energy light (λex =275 nm) has to be employed for the photo-
cycloreversion, which may, in turn, lead to direct or indirect
DNA damage.[50] Furthermore, the photostationary state of the
photocycloaddition–cycloreversion sequence lies in favor of the
photodimer under these conditions, which may be explained
by the poor water solubility of 11 and the resulting aggrega-
tion. However, as a proof of concept it was demonstrated that
the DNA–binding properties of an anthracene derivative can
indeed be reversibly turned on or off by light.
In contrast to anthracene, the structurally resembling
annelated quinolizinium derivatives 12,13 a and 13 b carry a
permanent positive charge (Scheme 6), which provides better
water solubility and also increases the affinity towards DNA.[51]
Hence, the quinolizinium derivatives 12,13 a, and 13 b exhibit
high binding affinities towards DNA with Kb=1.2×105M1
(12),[52] 2.0×104M1(13 a),[53] and Kb=6.2×104M1(13 b).[54] Most
notably, these polycylic azoniahetarenes have essentially the
same photophysical and photochemical properties as the
corresponding anthracene derivatives, that is, they also dimer-
ize in a [4+4] photocycloaddition reaction.[34] Specifically, upon
irradiation the annelated quinolizinium derivatives 12,[55] 13 a,[56]
and 13 b,[56,57] are converted to their respective dimers 122,13 a2
and 13 b2(Scheme 6). As the only outlier the dibenzoquinolizi-
nium derivative 122can be also converted into its dimer in a
thermally–induced cycloaddition.[55] While the dimers 13 a2and
13 b2only bind to DNA by a weak backbone association the
dimer 122still binds to DNA with one quinolizinium unit weakly
intercalating between DNA base pairs.[36] Upon irradiation with
λex =315 nm the monomers 12,13 a, and 13 b are generated
from their respective dimers, even in the presence of DNA
(Scheme 6). In the case of the dibenzoquinolizinium 122it was
demonstrated that the DNA even catalyzes the cleavage to the
monomer, presumably in the course of a photoinduced electron
transfer (PET) reaction.[52] Moreover, in contrast to the release of
the anthracene monomer 11 (Scheme 6), the quinolizinium
derivatives are unleashed with a significantly higher efficiency.
Hence, the concept of the photoinduced in situ release of DNA–
binding quinolizinium derivatives from their respective non–
binding dimers was realized. It should be noted that the water
solubility of the polycyclic azoniahetarenes is much better than
the one of anthracene derivatives, so that these cationic
hetarenes are better suited for this particular purpose. And
among the linearly benzo–annelated quinolizinium derivatives,
the benzo[b]quinolizinium has the optimal prerequisites for the
development of photoswitchable DNA–binding ligands because
in contrast to 12 its dimers only interact with DNA by a very
weak backbone association (Scheme 6).
In a recent study, the photochromic and DNA–binding
properties of the benzo[b]quinolizinium ion were further
combined with the redox activity of disulfides to generate a
dual–mode switch (Scheme 7).[58] As an additional feature, the
disulfide group was also used to connect to benzoquinolizinium
units such that a more efficient intramolecular cycloaddition
reaction is supported. The dialkyl disulfide–linked bisbenzo[b]-
quinolizinium 14 was shown to bind to DNA in a mixed binding
mode of intercalation and groove binding with an affinity of
Kb=3.2×105M1(Scheme 7).[59] Upon irradiation with λex =
365 nm 14 is converted into a mixture of three photoproducts,
namely the syn–head–to–tail photocyclomer c 14sht (18 %), the
syn-head-to-head photocyclomer c 14shh (74%), and the photo-
reduced syn–head–to–head product 152(8%) (Scheme 7).
Notably, the intramolecular photocycloaddtion of 14 is
240 times faster than the intermolecular photodimerization of
the unsubstituted benzo[b]quinolizinium.[59] The photoproducts
only interact with DNA by a weak, unspecific backbone
association, but they can be converted into the DNA–intercalat-
ing 9-(sulfanylmethyl)benzo[b]quinolizinium (15) (Kb=
4.0×103M1) by the reaction with dithiothreitol (DTT)
(Scheme 7). Notably, this sequence of the initial photodeactiva-
tion of DNA–binding properties and subsequent reactivation by
a reduction to the thiol 15 also proceeded in the presence of
DNA. The irradiation of the photocyclomers c 14sht,c 14shh and
152at λex =270 nm led to a photoinduced cycloreversion to the
initial DNA ligand 14. But the photometric analysis also
indicated photobleaching, presumably initiated by the forma-
Scheme 6. Photoinduced release of DNA–binding anthracene and benzoquinolizinium derivatives (red) from their respective dimers (blue).
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tion of thiyl radicals by photoinduced disulfide cleavage.[60]
Nevertheless, for the first time a cyclomer of a benzo[b]-
quinolizinium derivative was thermally converted into a DNA–
binding monomer at temperatures (37°C) that are compatible
with physiological conditions. Furthermore, as the conversion of
c 14sht,c 14shh and 152to 15 only proceeds under hypoxic
conditions[59] this concept may be employed for further
development of DNA–targeting drugs for cancer cells, which
provide a hypoxic medium.[61]
In a follow–up study the initial photoinduced deactivation
of benzoquinolizinium dimers was improved by reduced
complexity of the photoproducts, and the entire sequence was
extended by an additional molecule that acts as a shut–off
switch (Scheme 7). Thus, in analogy to 14 the disulfide 16 binds
in a mixed binding mode of intercalation and groove binding
with a binding constant of Kb=6.1×105M1.[58] Upon irradiation
with λex =365 nm, the disulfide 16 is converted into a mixture
of the head–to–head isomers c 16shh (46 %) and c 16ahh (54 %)
that only interact with DNA by a weak backbone association
(Scheme 7). The photocycloaddition of 16 is slower than the
one of 14 but still 44 times faster than that of the unsubstituted
benzo[b]quinolizinium. Upon addition of DTT to the photo-
cyclomers c 16shh and c 16ahh the thiol–substituted monomer 17
was formed and intercalated into DNA like its isomer 15. But
contrary to the latter, the thiol 17 is more reactive and was
subsequently converted to the benzothiophene 18 in an
intramolecular cyclization–ring opening sequence (Scheme 7).
Interestingly, the benzothiophene 18 does not bind to DNA, so
that its formation from 16 may be regarded as an intrinsic
shut–off function. Overall, it was demonstrated with the
disulfides 14 and 16 that the introduction of redox–active
functionalities to the benzo[b]quinolizinium accelerates the rate
of the photocycloaddition and further leads to non–binding
dimers. And the latter can be transformed to active DNA
intercalators again under mild, physiologically compatible
conditions.
Photocycloadditions of chromophore–DNA
conjugates
The [2+2] photocycloaddition of pyrimidine bases in DNA
upon exposure to UV-light is an important photodimerization
reaction within the human body (Scheme 8A).[62] In particular,
the dimerization of adjacent thymine/thymine pairs prevents
enzymes, such as polymerase, to bind to these regions and
therefore interferes with the transcription process.[63] For
example, if the dimerization occurs in the region of the p53
gene, which is responsible for the repair of UV-induced DNA
damage and apoptosis, it can lead to skin cancer.[64] However, it
was demonstrated that the artificial crosslinking of DNA–strands
can also lead to the controlled inhibition of gene expression[65]
or DNA damage.[66] In the same manner, the artificial nucleobase
3-cyanovinylcarbazole 21 has proven to be a highly promising
DNA–photo–crosslinking tool as it reacts rapidly in a [2 +2]
photocycloaddition (λex =366 nm) with a pyrimidine base in a
complementary sequence (Scheme 8B–C).[67,68] The photocyclo-
Scheme 7. Dual–mode photo- and redox-switching of DNA–binding properties of bis(benzoquinolizinium) derivatives 14 and 16.
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reversion was achieved upon irradiation with λex =312 nm. This
reversible crosslinking reaction has biological applications such
as the detection of single nucleotide polymorphism in double–
stranded DNA,[68] the stabilization of triplex DNA,[69] the labeling
of plasmid DNA,[70] the editing of DNA–encoded information,[71]
and the photoregulation of a DNA enzyme activity.[72] For
example, a 3-cyanovinylcarbazole (21) unit was attached
synthetically as part of a nucleotide to a ODN strand that is
complementary to the mRNA. The latter is responsible for the
expression of a green–fluorescent protein in HeLa cells.[73] Upon
irradiation of these cells that were incubated with the ODN, the
unit 21 formed a cycloadduct with a neighboring thymine base
in the mRNA (Scheme 8D). The formation of his crosslink leads
to the inhibition of the gene expression within the living cell
and, as a consequence, to the disappearance of the green
fluorescence (Scheme 8D). Besides the photo–crosslinking be-
tween two complementary strands, it was demonstrated that
the terminal attachment of 21 at two DNA strands can be used
for their photoinduced ligation (Scheme 8E).[74] By variation of
the position of this crosslinking unit, even more complex
covalently–bound DNA assemblies can be constructed. The
pyranocarbozole 22 is a complementary reagent, which can be
photo–crosslinked upon excitation at λex =400 nm.[75] It was
demonstrated that a D-threoninol linker instead of a ribose unit
in the phosphate backbone leads to a higher photoreactivity
and photo–crosslinking rate. By irradiation with λex =450 nm,
crosslinks were formed between complementary DNA–
strands[76] and between serinol nucleic acid and RNA based on
the cycloaddition reactions of the pyrene derivative 23.[77]
Recently, a styrylquinoxaline–modified ODN, which was labeled
with an ATTO520 dye, was incubated in living HeLa cells and
irradiated at λex =450 nm in the presence of another ATTO665-
labeled styrylquinoxaline. This [2 +2] photocycloaddition of the
two styrylquinoxaline units was fluorimetrically detected by
monitoring the Förster resonance energy transfer (FRET)
between the dyes, which demonstrates the large potential of
this crosslinking approach in fluorimetric cell imaging.[78]
The incorporation of styryl or alkyne spacers at thymidine
residues in ODNs can lead to the formation of DNA structures in
which the neighboring bases of the chemically modified
thymidine unit are displaced (“flipped out”) from their regular
position in the DNA helix because of favorable dispersion
interactions of the aromatic units within the DNA
(Scheme 9A).[79] Recently, it was demonstrated that such a
modified DNA can form a complex with helicase. But upon
irradiation, the photoinduced crosslink between both styryl
units prohibited the unwinding of the DNA (Scheme 9A).[80]
The photochromic properties of anthracene were also
employed for the control of DNA and peptide–DNA
binding.[81–85] In some cases, it was demonstrated that ligation
of two anthracene–functionalized ODNs can be induced by the
[4+4] photocycloaddition of the anthracene units.[82,83] In
another study, an ODN that carries two anthracene groups at
each end forms a triplex DNA structure upon association with a
complementary ODN (Scheme 10). Upon irradiation of the
triplex structure, the ODN was reversibly and covalently
attached to the duplex, as shown by DNA melting temperature
analysis (Scheme 10).[84] In a similar approach, it was shown that
the duplex DNA formation of ODNs with two anthracenes,
separated by 1–3 bases, can be controlled and switched by the
intramolecular [4+4] photocycloaddition between the neigh-
boring anthracenes.[85] With a different concept, the affinity of a
sequence–specific DNA–binding peptide was controlled photo-
chemically by the incorporation of two anthracene units
(Scheme 9B).[86] More precisely, upon irradiation of the modified
peptide in the presence of the DNA the anthracene photo-
dimerization leads to a covalent crosslink of the peptides and,
therefore, a favored preorganization for DNA binding (Sche-
me 9B). Likewise, by the introduction of an anthracene unit in a
modified G-quadruplex DNA structure from a thrombin–binding
aptamer, the thrombin association was reversibly switched off
upon irradiation with light.[87]
In an approach focused on bioimaging, a photoinduced
[4+2] cycloaddition was reported in which 9,10-phenanthrene-
quinone was converted to its corresponding diether upon
irradiation in the presence of a vinyl ether–conjugated bovine
Scheme 8. Natural and artificial [2 +2] photo–crosslinking reactions in DNA–
structures. The reactive alkene functionalities in A and B are depicted in red.
The cyclobutane units are depicted in blue. A: Photodimerization of thymine.
B: Artificial DNA photo–crosslinking agents. C: Photo–crosslinking between
two single DNA strands, red: photoactive alkene unit in 21 (red). The
structure of the dimer of 21 is depicted in blue D: Photoinduced gene
suppression of a green fluorescent protein in HeLa cells through crosslink
formation of 21 (red) and thymine (grey). The photo–crosslink is depicted in
blue. E: Ligation of double stranded DNA by photoinduced [2 +2] cyclo-
addition of 21 (red).
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serum albumin.[88] The biorthogonality was confirmed through
fluorescence of a dye–labeled quinone derivative that was
attached to a vinyl ether–conjugated cetuximab, that is, an
antibody which targets the cell–surface epidermal growth factor
receptor (EGFR) in EGFR–positive cancer cell lines.
Summary and Outlook
In conclusion, this Concept Article highlights the relevance and
potential of reversible [2 +2] and [4 +4] photocycloaddition
reactions in the field of photocontrollable DNA binders. The
ability to modulate DNA–binding properties through reversible
light–induced transformations offers the control over bioactiv-
ity, presenting a promising strategy to enhance the selectivity
of DNA–targeting compounds. And with suitable substrates the
photocycloaddition/photocycloreversion offers a promising tool
to accomplish this task. Nevertheless, most examples reported,
so far, still have some intrinsic drawbacks that need to be
addressed in the development of the next generation of DNA–
binding photoswitches. First and foremost, sufficient water
solubility is still an issue as it is a main requirement for the
application in biological media. In this regard, ionic compounds,
such as the stilbazonium or benzoquinolizinium derivatives,
seem to have the potential to provide this property. From a
photochemical point of view, the excitation wavelength has to
be shifted to lower energy such that bio(macro)molecules do
not absorb. This effect may be achieved with increasing size of
the πsystem of the chromophore or by the attachment of
auxochromic substituents. Likewise, competing side–reactions
of the chromophores have to be suppressed, for example like in
the case of styryl derivatives, that undergo selective photo-
dimerization reactions in DNA–bound aggregates (Scheme 1
and 2). In this context, the integration of redox–active
functionalities and the development of dual–mode switches
offer new opportunities because they also allow to change the
ligand activity depending on the physiological conditions.
Likewise, the photocycloaddition can be used for photoinduced
crosslinking and applied to control gene expression, DNA
damage, and bioimaging, which further demonstrates the
versatility of photochromic scaffolds as functional units in
diverse biological contexts.
As a future perspective, this brief overview of current trends
in this research field should encourage further exploration and
application of photocycloaddition reactions in lead structures of
efficient DNA–targeting drugs.
Acknowledgements
Financial support was provided by the University of Siegen and
the Deutsche Forschungsgemeinschaft. C. D. is grateful to the
House of Young Talents (University of Siegen) for a PhD
Scheme 9. Photoregulation of peptide–DNA binding. A: Controlling the binding of helicase with a “flipped out” DNA structure modified with a styrene
derivative (red);blue: cyclobutane. B: Photocontrolled DNA binding of anthracene–peptide conjugates; red: anthracene, green: peptide.
Scheme 10. Photoinduced triplex–DNA stabilization by formation of an
anthracene dimer at two oligodeoxynucleotides (ODNs).
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fellowship. Open Access funding enabled and organized by
Projekt DEAL.
Conflict of Interests
The authors declare no conflict of interest.
Keywords: Bioorganic chemistry ·DNA recognition ·
photochromism ·photochemistry ·prodrug
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Manuscript received: November 29, 2023
Revised manuscript received: January 24, 2024
Accepted manuscript online: February 12, 2024
Version of record online: March 1, 2024
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