Photoreversible prodrugs and protags: Switching the release of maleimides by using light under physiological conditions

Article abstract of DOI:10.1002/chem.201405767

A water-soluble furyl-substituted diarylethene derivative has been prepared that can undergo reversible Diels-Alder reactions with maleimides to yield photoswitchable Diels-Alder adducts. Employing bioorthogonal visible light, the release of therapeutically effective concentrations of maleimide-based reactive inhibitors or labels from these "prodrugs" or "protags" could be photoreversibly triggered in buffered, aqueous solution at body temperature. It is shown how the release properties can be fine-tuned and a thorough investigation of the release dynamics is presented. Our system should allow for spatiotemporal control over the inhibition and labeling of specific protein targets and is ready to be surveyed in living organisms.

Full text of DOI:10.1002/chem.201405767

DOI: 10.1002/chem.201405767
Full Paper
&
Photopharmacology
Photoreversible Prodrugs and Protags: Switching the Release of
Maleimides by Using Light under Physiological Conditions
Robert Gçstl and Stefan Hecht*[a]
Abstract: A water-soluble furyl-substituted diarylethene de-
rivative has been prepared that can undergo reversible
Diels–Alder reactions with maleimides to yield photoswitcha-
ble Diels–Alder adducts. Employing bioorthogonal visible
light, the release of therapeutically effective concentrations
of maleimide-based reactive inhibitors or labels from these
“prodrugs” or “protags” could be photoreversibly triggered
in buffered, aqueous solution at body temperature. It is
shown how the release properties can be fine-tuned and
a thorough investigation of the release dynamics is present-
ed. Our system should allow for spatiotemporal control over
the inhibition and labeling of specific protein targets and is
ready to be surveyed in living organisms.
hibition can evoke cell death.[21,22] Most TOP2 inhibitors that
are employed today are classified as TOP2 poisons that stabi-
lize the so-called “cleaved complex” of TOP2 and DNA thus in-
hibiting enzyme turnover.[21–23] However, as TOP2 poisons can
provoke unwanted secondary malignancies, it is sometimes
necessary to inhibit the formation of stable cleaved complexes
between TOP2 and DNA alongside pharmacotherapy.[24] Re-
cently, the effect of different maleimide derivatives on TOP2
action was assessed and strong inhibiting properties with ef-
fective concentrations showing activity in the micromolar
range could be verified.[25,26] More importantly, these malei-
mide derivatives have been shown to antagonize the toxicity
caused by TOP2 poisons, such as etoposide.[26] Since succini-
mide was not found to have an effect on the TOP2 catalytic
cycle, it was reasoned that the inhibition is caused by thiol-ene
ligation of exposed cysteine residues. The formed covalent
modification is assumed to decrease the overall available con-
centration of catalytically active TOP2 and thus to antagonize
TOP2-related side effects preventing uncontrolled DNA cleav-
age.[26]
Introduction
Today’s drug administration often faces challenges associated
with poor selectivity, resulting in high toxicity and drug resist-
ance, both of which have their origin in the limited spatiotem-
poral control offered by conventional drugs. This means that
there is generally no possibility to control where and when the
drug is active, inside or outside the organism. However, light
as a non-invasive stimulus with its superior spatial, temporal,
as well as energetic resolution in combination with its high or-
thogonality to biological processes, makes for an excellent
gate to control drug activity with higher precision.[1–4] Out-
standing examples have been reported in the literature that
exploit light-gated molecular switches to turn drug-activity
“on” and “off”[5–18] and recently the term “photopharmacology”
has been coined, which describes this entire emerging field.[4]
The implementation of photoswitchability into pharmaco-
logically active chemical entities is only limited by (bio)chem-
ists’ imagination and several clever designs have been report-
ed that incorporate particular azobenzene moieties into
drugs.[2,4] We have selected here a more general approach, ex-
ploring the versatile use of maleimide electrophiles as reactive
inhibitors and labeling agents.
As Michael acceptors exhibit a high and rather nonselective
alkylation potential, it would be advantageous to introduce
a new level of control over the ability of maleimide to undergo
thiol ligation reactions. The Diels–Alder reaction with furan
seems well-suited for this task as it masks the reactive C=C
double bond of maleimide and can readily be rendered rever-
sible at physiological temperatures.[27,28] Furthermore, diaryle-
thenes (DAEs) with their thermal stability and high fatigue re-
sistance, in combination with large optical changes between
their ring-open (o) and -closed (c) forms, constitute ideal gates
to photocontrol function on the molecular level.[29–31] Conse-
quently, we recently reported on achieving photocontrol over
the reversible Diels–Alder reaction between a furyl-substituted
diarylethene (DAE) and maleimide.[32] Here, we use this proto-
typical system as a phototriggerable release system as concep-
tually depicted in Figure 1.
DNA topoisomerase II (TOP2) is an enzyme that catalyzes
the interconversion of different DNA topoisomers (e.g., super-
coiled or catenated DNA) by religation of the DNA strands
thus promoting chromosome disentanglement.[19,20] Therefore,
TOP2 makes for an ideal target in anticancer therapy as its in-
[a] Dr. R. Gçstl, Prof. S. Hecht
Laboratory of Organic Chemistry and
Functional Materials, Department of Chemistry
Humboldt-Universitꢀt zu Berlin, Brook-Taylor-Str. 2
12489 Berlin (Germany)
E-mail: sh@chemie.hu-berlin.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405767.
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leimide to yield ring-open Diels–Alder adducts 1o and 2o. Ex-
pediently, the fraction of endo and exo stereoisomers produced
in the Diels–Alder reaction of 3 with the two different malei-
mides can be tuned conveniently by varying the reaction tem-
perature. Whereas furan 3 and maleimide were treated at
room temperature for 1 d to yield a mixture consisting of 40%
of the endo and 60% of the exo isomer for adduct 1o, stirring
3 and N-ethylmaleimide at 708C for 6 h almost exclusively
Figure 1. Conceptual depiction of the photoreversible activation of a release
system relying on a subsequent thermal equilibrium.
The locked Diels–Alder adduct
is thereby transformed into its
active state by irradiation with
visible light. A subsequent ther-
mal equilibrium then governs
the released amount of malei-
mide over a given period of
time. The thermal equilibrium
Scheme 1. Photoreversible activation of the release of maleimide or N-ethylmaleimide from their respective ring-
closed Diels–Alder adducts by irradiation with visible light (lirr >400 nm).
enables long-term release of the
active drug, that is, the genera-
tion of a “depot effect”. This is
desirable as conventional drug
administration usually suffers
from an initially high but compa-
ratively short bioavailability of
the drug as the reactive sites are
generally metabolized quickly.
Another important difference
compared to conventional irre-
versible photocaged systems is
that the release can be stopped
at any time by locking the Diels–
Alder adduct with UV light.
Specifically, we report here on
the successful implementation
of water-soluble ring-closed
Scheme 2. Synthesis of target DAEs 1 and 2: a) i) n-BuLi, (THF), RT, 30 min, ii) B(OBu)3, (THF), RT, 1 h, iii) ethyl 4-bro-
Diels–Alder adducts 1c and 2c mobenzoate, [Pd(PPh3)4], Na2CO3, (THF/H2O), 658C, 1 d, 67%; b) NaOH, (EtOH), 658C, 3 h, 75%; c) maleimide,
(EtOH), RT, 1 d, quant. or N-ethylmaleimide, (EtOH), 758C, 6 h, quant.; d) 10À4 m, (PBS), l=313 nm, 258C, 10 min,
quant.
of the furyl-substituted DAE 3
and maleimide or N-ethylmalei-
mide for their release in buffered
aqueous solution at body temperature triggered by visible
light (Scheme 1). To the best of our knowledge, the ring-closed
Diels–Alder adducts 1c and 2c are the first examples of water-
soluble photoreversible protecting groups for maleimides.
Here, we show how the release properties can be fine-tuned
and we provide a thorough investigation of the release dy-
namics.
(97%) led to the exo stereoisomer of 2o. Though the endo/exo
ratio can be fine-tuned regardless of the maleimide derivative
employed, these two combinations were chosen to gain in-
sight into their different release kinetics, because the retro-
Diels–Alder reaction of the endo stereoisomer is expected to
take place at an increased rate compared to the exo isomer.
Ring-closed forms 1c and 2c were generated in situ and on
demand just before the release experiment by using 313 nm
wavelength light to irradiate a 10À4 m solution of the ring-open
forms 1o or 2o until they reached the photostationary state
(PSS).
Results and Discussion
Synthesis
The pathway towards Diels–Alder adducts 1c and 2c started
with the synthesis of ethyl benzoate 4 from the established
chloro precursor 5 by Pd-catalyzed cross-coupling after in situ
halogen–metal exchange and borylation (Scheme 2).[32,33] Sub-
sequent saponification of ester 4 yielded the sodium carboxyl-
ate 3, which was treated with either maleimide or N-ethylma-
Photochemical properties
The molar absorptivities and absorption maxima of adducts
1 and 2, and their composition at the PSS are summarized in
Table 1. Importantly, all irradiation experiments were per-
formed in phosphate-buffered saline (PBS), successfully verify-
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inactive ring-closed forms 1c and 2c through in situ irradiation
of a 10À4 m solution of the corresponding ring-open forms
until the PSS was reached (gray lines in Figure 3).
Table 1. Molar absorptivities, absorption maxima, and composition of the
PSS of adducts 1 and 2 in phosphate-buffered saline.
e [LmolÀ1 cmÀ1
Adduct ring-open ring-closed ring-open ring-closed
]
lmax [nm]
PSS313 nm [%]
[a]
1
2
16700
18500
11500
12600
316
316
412
412
97
98
[a] Amount of ring-closed isomer in the PSS upon irradiation with UV
light as determined by UPLC.
ing that switches 1 and 2 are applicable under in vitro and po-
tentially in vivo conditions. Both derivatives almost quantita-
tively convert to their respective ring-closed forms 1c and 2c
at the PSS after irradiation with UV light. This can be observed
in Figure 2 and is indicated by the appearance of the charac-
Figure 3. UPLC-MS DAD traces at 280 nm of the ring-closed Diels–Alder ad-
ducts in PBS at the PSS, the ring-open Diels–Alder adducts after irradiation
with visible light (lirr >400 nm, 20 min), and the successful release of a) mal-
eimide after 3 h at 808C for 1c and 1o and b) N-ethylmaleimide after 5 h at
808C for 2c and 2o.
The ring-closed derivatives were then irradiated with visible
light (lirr >400 nm) to regenerate the corresponding active
ring-open forms 1o and 2o (dotted lines in Figure 3) and sub-
sequently heated at 808C to release maleimide or N-ethylma-
leimide over time (black lines in Figure 3). Hence, the release
of maleimide derivatives can be carried out quantitatively in
phosphate-buffered saline at elevated temperatures.
Figure 2. UV/Vis absorption spectra for a) Compound 1 (cꢀ7ꢁ10À5 m) and
b) Compound 2 (cꢀ10À4 m) in phosphate-buffered saline at 258C upon irra-
diation with UV light (lirr =313 nm, 9 min). Insets show respective subse-
quent irradiations with visible light (lirr >400 nm, 20 min).
However, 808C is nowhere near physiological temperatures
and thus the release of maleimide from 1o was investigated in
detail at lower temperatures ranging from 408C to 808C (see
the Supporting Information, Figure S1). As expected, the retro-
Diels–Alder reaction becomes increasingly slower with decreas-
ing temperatures. Nevertheless, a continuous release of malei-
mide takes place even at 408C to an extent of about 50%
after 92 h.
teristic bands at 412 nm. Consequently, employing light of
a wavelength higher than 400 nm induces the cycloreversion
reaction from 1c to 1o and from 2c to 2o, respectively, there-
by regenerating the ring-open isomers (insets in Figure 2).
Although the almost quantitative character of these ring-
opening processes was confirmed by UPLC measurements, the
absorption bands at 316 nm are not completely regenerated in
the ring-open forms. We attribute this phenomenon to the
presence of (kinetically trapped) aggregates of the initial ring-
open form that are associated with altered spectral signatures
and cannot fully be restored after a complete switching cycle.
To gain further insight into the release kinetics, the individu-
al evolution of the endo and exo adducts of 1o (60% exo, 40%
endo) and 2o (97% exo, 3% endo) in 10À4 m phosphate-buf-
fered saline solution was followed over time by integrating the
diode array detection (DAD) signal of the corresponding ultra-
performance liquid chromatography (UPLC) traces at l=
280 nm in which the Diels–Alder adducts as well as DAE 3 ex-
hibit approximately the same molar absorptivities (Figure 4).
A number of expected features can be extracted from this
set of Figures: 1) The release of maleimide is only slightly
slower at 378C than it is at 408C, and 2) the release of malei-
mide from the endo stereoisomer is clearly faster than from
the corresponding exo stereoisomer. As the retro Diels–Alder
reaction is a unimolecular process, it was furthermore reasoned
Photoinduced release of maleimide derivatives
The conceptual validity of triggering the release of maleimide
derivatives from their respective adducts 1o and 2o was
proven by generation of their presumably pharmacologically
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Diels–Alder reaction apparently is not the rate-determining
step. Thus, it becomes necessary to compare the released
amounts of the respective maleimide derivatives directly. From
the data presented in Figure 4, the overall respective concen-
trations of released maleimide and N-ethylmaleimide can be
calculated at any point of the reaction and the resulting
graphs are shown in Figure 5.
Figure 4. Retro-Diels–Alder reaction at 378C and 408C in PBS (c=1ꢁ10À4 m)
visualized by the evolution of the molar fraction x of the endo and exo
adduct over time as determined by UPLC measurements of a) 1o to 3 and
maleimide and b) 2o to 3 and N-ethylmaleimide. Ratios recorded at t=0 h
slightly deviate from the ratios determined directly after synthesis as the
retro-Diels–Alder reaction had already started.
that at low concentrations the bimolecular forward Diels–Alder
reaction can be neglected and the release should therefore
follow first-order kinetics. However, from Figure 4 it can be
shown that the evolution of the individual concentrations does
not follow the exponential decay expected for a first-order re-
action. Instead, for the retro-Diels–Alder reaction of 1o to 3,
a slight intermediate increase in the amount of exo stereoiso-
mer present was observed.
Figure 5. Retro-Diels–Alder reactions at 37 and 408C, respectively, in PBS
(c=1ꢁ10À4 m) visualized by the evolution of the concentration c of a) malei-
mide released from 1o and b) N-ethylmaleimide released from 2o over time
compared to the release from the respective closed form adducts 1c and
2c.
As the direct interconversion of the stereoisomers is not
possible without performing both the forward and backward
Diels–Alder reaction,[27] it is reasonable to assume that an addi-
tional reaction step is involved. One way to rationalize the in-
termediate formation of exo-1o is to assume aggregation in
aqueous solution, in which released maleimide is trapped
inside an aggregate and its effective concentration in the vicin-
ity of unreacted 3 is increased such that the forward Diels–
Alder reaction becomes relevant and not negligible. To find
out whether the observed phenomenon is indeed related to
aggregation, the release of maleimide from 1o (60% exo, 40%
endo) in a deaggregating solvent mixture (H2O/THF/MeCN=
2:1:1) was followed at 408C by UPLC measurements (the Sup-
porting Information, Figure S2). As opposed to the experi-
ments carried out in PBS, the amount of exo-1o is not increas-
ing in the deaggregating solvent mixture but conversely fol-
lows the initially expected exponential rate law, strongly sug-
gesting the existence of aggregates in phosphate-buffered
saline solution.
Because the release from the endo adduct is expected to be
considerably faster than that from the exo adduct, the release
of maleimide from 1o (consisting of 40% endo isomer) was
found to be 46 mmdÀ1 at 378C (59 mmdÀ1 at 408C), not surpris-
ingly much higher than the release of N-ethylmaleimide from
2o (consisting of 3% endo isomer) of 5 mmdÀ1 at 378C
(6 mmdÀ1 at 408C). These daily concentrations are estimated
from the release that was monitored over 12 h and most im-
portantly lie in the range suitable for therapeutic in vitro and
in vivo applications.[26] Furthermore, these results show the
possibility to conveniently fine-tune the amount of the re-
leased maleimide derivative over time by synthesizing Diels–
Alder adducts with varying endo/exo stereoisomer composi-
tions: Whereas a higher endo fraction ensures a larger initial re-
lease of maleimide, a higher exo fraction leads to a slower re-
lease creating a more pronounced “depot effect”.
In addition, the data in Figure 5 show that the release from
the deactivated ring-closed form is negligible and can be disre-
garded. Another advantageous feature potentially useful for in
vivo application is the increased release rate at 408C compared
Inconveniently, the determination of the actual rate con-
stants for the retro-Diels–Alder reaction in PBS thus yields no
noteworthy insight into the release dynamics as the retro-
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to 378C. As tumor tissue tends to exhibit higher metabolic ac-
tivity than unaffected tissue, the release of maleimide deriva-
tives could potentially be preferentially stimulated and hence
localized in these areas.
To verify that the released species in fact corresponds to the
reactive maleimide and not to some potentially pharmacologi-
cally inactive hydrolysis products, the release of the malei-
1
mides from 1o and 2o was monitored by H NMR spectrosco-
py (see example shown for 1o in Figure 6).
Figure 7. Switching the release of maleimide in situ “off” from 1o to 1c
(lirr =313 nm for 9 min) and “on” again from 1c to 1o (lirr >400 nm for
20 min) at 408C in PBS (c=1ꢁ10À4 m) as visualized by the evolution of the
concentration of maleimide cMI over time.
Conclusion
We have successfully demonstrated the use of a photoswitch
to control the release of a reactive chemical entity (drug or
tag) with light under physiological conditions. For this pur-
pose, a water-soluble furyl-substituted DAE (3), which can un-
dergo reversible Diels–Alder reactions with maleimide and N-
ethylmaleimide to the corresponding adducts (1o and 2o),
was designed and synthesized. These Diels–Alder adducts ex-
hibit outstanding photochromic properties and could almost
be quantitatively transformed to their ring-closed forms (1c
and 2c). These “locked” adducts were shown to efficiently
impede the retro-Diels–Alder reaction back to the starting ma-
terials yet readily regenerate their active, ring-open forms (1o
and 2o) upon irradiation with highly bioorthogonal visible
light. The unlocked ring-open adducts (1o and 2o) were
shown to release their respective maleimide under physiologi-
cal conditions (phosphate-buffered saline solution, body tem-
perature) with time, achieving calculated daily concentrations
in the mm range that clearly lie in the reported therapeutic
window of these drugs. Not only could the extent of the
“depot effect”, that is, delayed release, conveniently be tuned
through the adjustment of the endo/exo stereoisomer ratio in
the syntheses of the Diels–Alder adducts, it could also be
shown that after a certain release time residual Diels–Alder
adduct could be reversibly deactivated by irradiation with UV
light in situ through ring-closing remaining 1o or 2o to 1c or
2c. This combination of reversibly toggling a release system
between its inactive “locked” to its active “unlocked” state,
from which a specific chemical reagent can be released
through a thermal equilibration, is best described as photo-
switchable “prodrug” or “protag”. Eventually, the presented
system could prove to be a potent photoswitchable prodrug
for maleimide-based reactive inhibitors, for example, showing
a light-dependent pharmacological effect on TOP2 action, as
well as becoming a powerful tool in chemical biology in which
photoswitchable protags could allow for control over the label-
ing of specific proteins at specific locations and precise times
in living cells.
1
Figure 6. Details of the H NMR spectra of 1o (cꢀ1ꢁ10À2 m, D2O/
CD3CN=1:1) before and after heating for 3 h at 808C compared to the male-
imide reference. (+)=Thienyl-H of 3, (*)=CH of MI, (#)=furyl-H of 3. For
1o, a minor retro-Diels–Alder reaction already started before the NMR spec-
trum could be recorded.
Most importantly, the signal of the reactive C=C double
bond of maleimide can be clearly retrieved after heating when
compared to the reference sample, proving the release of the
active maleimide species. However, only about 50% of the ex-
pected released amount of maleimide can be detected when
the corresponding signals are integrated and compared to the
likewise released diene 3. This can be attributed to partial hy-
drolysis of the reactive maleimide moiety to diverse byprod-
ucts and is a common phenomenon at elevated temperatures
and high concentrations (compare area around d=6 ppm in
Figure 6).[34] Yet, we found that heating pure maleimide at
physiological temperatures in aqueous solution over multiple
days does not induce degradation (see Figure S3 in the Sup-
porting Information) and thus we reason that the calculated
daily concentrations from Figure 5 are valid nonetheless.
In addition to the irreversible release of the maleimides, the
reversibility of the switching process in DAEs in combination
with the slow thermal release allows for the “on” and “off”
switching of the maleimide liberation in situ (Figure 7). Besides
the activation of the retro-Diels–Alder reaction by ring-opening
1c to 1o with visible light, the release of maleimide could sub-
sequently be inhibited to a large extent by ring-closing un-
reacted 1o back to 1c at the PSS by UV light in situ rendering
this system potentially useful in the context of photopharma-
cology in which the prodrug could be switched “off” after the
desired therapeutic effect has been observed. The system then
remains inactive for the chosen time and can subsequently be
reactivated on demand allowing for the release of maleimide
again.
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Acknowledgements
Generous support by the German Research Foundation (DFG
through SFB 658) and the European Research Council through
ERC-2012-STG_308117 (Light4Function) is gratefully acknowl-
edged. BASF AG, Bayer Industry Services, and Sasol Germany
are thanked for generous donations of chemicals.
Keywords: drug delivery · inhibitors · pericyclic reactions ·
photochemistry · prodrugs
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Received: October 21, 2014
Published online on && &&, 2015
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
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Photopharmacology
R. Gçstl, S. Hecht*
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Photoreversible Prodrugs and
Protags: Switching the Release of
Maleimides by Using Light under
Physiological Conditions
Light release: The use of a photoswitch
to control the release of a reactive
ing bioorthogonal visible light, the re-
lease of therapeutically effective con-
centrations of maleimide-based reactive
inhibitors or labels from these “pro-
drugs” or “protags” could be photore-
versibly triggered (see figure). A thor-
ough investigation of the release dy-
namics is also presented.
chemical entity (drug or tag) with light
under physiological conditions has been
demonstrated. A water-soluble furyl-
substituted diarylethene derivative was
used in the reversible Diels–Alder reac-
tions with maleimides to yield photo-
switchable Diels–Alder adducts. Employ-
Chem. Eur. J. 2015, 21, 1 – 7
www.chemeurj.org
7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ