Understanding the binding properties of phosphorylated glycoluril-derived molecular tweezers and selective nanomolar binding of natural polyamines in aqueous solution

Article abstract of DOI:10.1039/d1ob00379h

A modular synthetic platform for the construction of flexible glycoluril-derived molecular tweezers was developed. The binding properties of four exemplary supramolecular hosts obtained via this approach towards 16 organic amines were investigated by means of 1H NMR titration. In this work, we compare the Ka values obtained this way with those of three structurally related molecular tweezers and provide a computational approach towards an explanation of the observed behavior of those novel hosts. The results showcase that certain structural modifications lead to very potent and selective binders of natural polyamines, with observed binding of spermine below 10 nM. This journal is

Full text of DOI:10.1039/d1ob00379h

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Biomolecular Chemistry
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PAPER
Understanding the binding properties of
phosphorylated glycoluril-derived molecular
tweezers and selective nanomolar binding of
natural polyamines in aqueous solution†
Cite this: Org. Biomol. Chem., 2021,
19, 3628
Michael Heilmann, ‡a Melina Knezevic,a GiovanniMaria Piccini b and
a,c
Konrad Tiefenbacher
*
A modular synthetic platform for the construction of flexible glycoluril-derived molecular tweezers was
developed. The binding properties of four exemplary supramolecular hosts obtained via this approach
towards 16 organic amines were investigated by means of 1H NMR titration. In this work, we compare the
Ka values obtained this way with those of three structurally related molecular tweezers and provide a
computational approach towards an explanation of the observed behavior of those novel hosts. The
results showcase that certain structural modifications lead to very potent and selective binders of natural
polyamines, with observed binding of spermine below 10 nM.
Received 26th February 2021,
Accepted 23rd March 2021
DOI: 10.1039/d1ob00379h
rsc.li/obc
be remarkably selective for lysine and arginine derivatives and
was even successfully employed to tightly bind these moieties in
Introduction
Over the past decades, the growing understanding of inter- oligopeptides and on protein surfaces.7 However, its structural
molecular processes has set the foundation for studying mole- design limits the possibilities of facile derivatization. On the
cular recognition, both in biological and artificial systems, in an other hand, the glycoluril building block is a well-established
increasingly exact fashion.1 Numerous synthetic supramolecular subunit for an entire family of acyclic tweezers of varying size,
host structures with different sizes, shapes and functionalization shape and flexibility that have been utilized as hosts for a broad
patterns have been shown to interact with a multitude of classes range of viable guest molecules.3d One example is host 2, which
of guest molecules.2 Among those are biologically highly relevant is very similar to 1 in size and shape of its cavity, but has a higher
targets, including proteins, drugs or drug-like molecules or bio- level of flexibility due to the lack of rigid bicyclic linkers.6b,9
genic small molecules.3 One class of such constructs called mole- Inspired by these contributions and motivated by our group’s
cular tweezers is defined as U-shaped molecules with aromatic interest in catalysis inside supramolecular containers and within
panels that are connected with rigid linkers.4 Several different molecular tweezers,10 we sought to develop a modular and deriva-
frameworks for such tweezers have been shown suitable to tization-friendly platform for the synthesis of molecular tweezers.
accommodate
a guest molecule within the pre-organized Ultimately, we envision this to enable the selective binding and
cavity.2b,4h,k,5 Importantly, by deliberate decoration of a hydro- modification of biologically relevant targets. We recently showed
phobic core structure with solubilizing groups like phosphates, that the conformationally flexible phosphorylated host 3 binds
phosphonates, or carboxylates, such tweezers can be adapted to very tightly to numerous sterically undemanding diamine
bind organic guests in aqueous solution.6 For instance, the phos- guests.8 Guided by these results, we have designed a streamlined
phate derivative of tweezer 1 (Fig. 1A, R = O−) has been shown to synthetic procedure for tweezers of the general structure 4 with
the goal of understanding host–guest interactions of these hosts
in more detail. Here, we report a comparative study of the
binding properties of four derivatives of the general structure 4
and the previously described tweezers 1, 2 and 3.
aUniversity of Basel, Department of Chemistry, Mattenstrasse 24a, 4058 Basel,
Switzerland. E-mail: konrad.tiefenbacher@unibas.ch, tkonrad@ethz.ch
bETH Zurich, Department of Chemistry and Applied Biosciences, c/o USI campus, Via
Guiseppe Buffi 13, 6900 Lugano, Switzerland
cETH Zurich, Department of Biosystems Science and Engineering, Mattenstrasse 26,
4058 Basel, Switzerland
Results and discussion
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob00379h
For this study, we chose to synthesize and investigate the fol-
lowing derivatives (Scheme 1): benzo-tipped tweezer 4a which
‡Current address: Merck Center for Catalysis at Princeton University, Princeton,
NJ 08544, USA.
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Scheme 1 Synthesis of tweezers 4a–d. R = CO2Et. (A) Zn, AcOH,
130 °C, 60 min. (B) NaH, (EtO)2P(O)Cl, DMF, 0 °C, 18 h, 64% (2 steps). (C)
NBS, AIBN, CCl4, 95 °C, 16 h, 87%. (D) 6, 7 (2.0 equiv.), Cs2CO3, TMAI,
35–58% (dr = 1.3/1 … 1.9/1). (E) TMSBr, 0 °C, 24 h then EtOH, rt, 60 min,
82–88%. NBS: N-Bromosuccinimide, AIBN: azobis-iso-butyronitrile,
TMAI: tetramethylammonium iodide, TMS: trimethylsilyl.
Fig. 1 Chemical structures of molecular tweezer 16a and the similarly
sized tweezer 2.6b Tweezer 38 shares the framework with 2 but the
phosphate groups attached to it provide unique binding properties.
Tweezers of the general structure 4 were synthesized with the goal of
having access to a broad range of chimeras via a modular platform.
closely resembles 1; naphtho-tipped tweezer 4b which is sion at room temperature, likely due to the steric congestion of
related to 4a but features a larger cavity due to increased electrophile 6, and resulted in decomposition without for-
angular distortion resulting from repulsion of the larger tips; mation of 8 when heated. The use of differently protected
dimethoxybenzo-tipped tweezer 4c which shares features of derivatives of 6, including several alkyl, acetal, or acyl protect-
both 1 and 2; and hexaphosphorylated tweezer 4d which ing groups, did not resolve the issue. Attempts to use different
serves as a chimera of 3 and 4a. The synthetic strategy of twee- leaving groups instead of bromides as in 6, including readily
zers 4a–d is based on the convergent alkylation of the respect- accessible chlorides and acetates, were not successful either.12
ive glycoluril derivatives 7a–d′ with tetrabromide 6 (Scheme 1). Gratifyingly, trace product formation was observed when we
Tetrabromide 6 is accessible from commercially available duro- subjected 6 and 7a to the weak inorganic base potassium car-
quinone (5) in three steps. After a zinc mediated reduction11 bonate and sodium iodide at 40 °C. Further optimization
and phosphorylation employing sodium hydride and diethyl showed that using catalytic amounts of tetramethylammonium
chlorophosphate, fourfold benzylic bromination delivered 6 in iodide and cesium carbonate smoothly gave the desired com-
good yield (55% over three steps). While the preparation of the pounds in good yields. Unlike in our previously presented syn-
partially substituted glycoluril derivatives 7a–d′ was easily thesis of 38 but also observed in the synthesis of 2,6b mixtures
accomplished by alkylation of the parent unsubstituted glyco- of the “C-shaped” 8a–d′ and their undesired “S-shaped” di-
luril with the corresponding o-xylylene dibromides (see ESI† astereomers were obtained that necessitated separation via
for details), the direct construction of the final frameworks HPLC (see ESI†). Subsequent deprotection of the obtained di-
8a–d′ proved to be a highly challenging transformation. astereopure diethylphosphates by addition of bromotrimethyl-
Numerous attempts of employing different inorganic and silane followed by ethanol furnished the desired phosphate
organic bases in a variety of solvents led to virtually no conver- tweezers 4a–d in excellent yields.
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With the desired tweezers in hand, we started investigating ger ionic interactions facilitated by the six phosphate moieties
their binding properties by means of 1H NMR titration in in 4d as compared to two in 1 and 4a-c. Interestingly, the
buffered D2O (70 mM phosphate buffer, pD = 7.2), and deter- binding properties of tweezers 3 and 4a–d did not change sub-
mining the equilibrium constants via non-linear regression.13 stantially when we investigated the same equilibrium in
We found that 4a and 4d undergo weak dimerization (Kdim
=
unbuffered D2O, although we observed diminished solubility
32.7 M−1 and 35.0 M−1, respectively), while this process is con- of 4a–d, likely due to stronger self-aggregation in this sol-
siderably more pronounced in 4b (773 M−1) and 4c (624 M−1), vent.6b As expected, we were not able to observe any binding in
with the orders of magnitude in good agreement with compar- control titration experiments of the exemplary S-shaped depro-
able systems.6a,7a,9b Job plots indicated that these tweezers tected construct dia-4c; in agreement with the exclusive accom-
bind their guests in a 1 : 1 fashion (see ESI†). Next, the guest modation of the aliphatic chains of the guests in the tweezers’
scope was explored in detail. Table 1 summarizes the binding C-shaped cavity.
constants (Ka) of complexes of 16 guests and the four tweezers
We next investigated the dependency of aliphatic diamine
4a–d as well as available literature values of tweezers 1–3 for guest binding on the length of their methylene linkers. As
comparison. Similar to previous findings with 2 and 3, 4a and expected, we found moderate-length guests to be optimal, the
4c bind short aliphatic monoamine compounds like propyl- size of which suit the tweezers’ cavities most closely (C7-di-
ammonium chloride (9) relatively weakly, and 4b did not show ammonium chloride 13 for 4a and 4c, C8-diammonium chlor-
significant uptake of such short-chained diammonium guests. ide 14 for the larger host 4b). However, the binding of di-
The stronger affinity of 4d to 9 is in agreement with the stron- ammonium guests in 4a–c is weak compared to the derivatives
Table 1 Guest molecules investigated and binding constants Ka (M−1) of their complexes with molecular tweezers 4a–d, determined via 1H NMR
titration, and comparison to related systems. Titrations performed at 100 µM host in 70 mM phosphate buffer (pD 7.2). The precision of the measure-
ments is discussed in detail in the ESI;† the error for 95% confidence is generally below 5% (see ESI† for exact values)
Related tweezers
f
Guest
Schrader 1 (Ka/M−1 c
)
Isaacs 2 (Ka/M−1 e
)
Our prev. work 3 (Ka/M−1
)
9
138
208
35.8
247
569
838
517
240
<10
88.0
32.1
14.3
26.2
144
147
200
815
<10
<10
<10
83.5
354
870
1200
831
<10
<10
<10
<10.0
103
1750
585
45
88.7
275
<10
3310
4260
105
345
295
9a
890d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
26 100
287 000
148 000
49 600
14 300
3150
28.3
1430
30.8
1260
724
10 700
122 000
133 000
155 000
179 000
36 300
<10
4220
57.1
253
33 800
21 600
54.0
388 000
7 920 000
377
5960
15 200
6460
7060
1170
2580
1900
861
<10
23.0
<10
14.8
99.2
130.4
175
94.4
325
58 800
47 600
18 800
27 100
<10
496
2060
2 370 000b
148 000 000b
<10
a Titration performed in unbuffered D2O. b Determined via competitive displacement titration at 100 μM 4d and 10 mM or 200 mM 21 as a com-
petitor. c Values for the phosphate derivative of tweezer 1 as determined by Klärner & Schrader.6a d Value for the methylphosphonate derivative of
tweezer 1 as determined by Klärner & Schrader.14 e Values for tweezer 2 as determined by Isaacs.6b f Values for tweezer 3 as determined in our pre-
vious work.8
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4d and 3.8 Interestingly, the values for 10–14@4c and 23@4d and 1.48 × 108 M−1 for 24@4) than the tetraphosphory-
10–14@2 suggest that the phosphates present in 4c but lated host 3 whereas 4a–c interact only weakly with those
missing in 2 do not increase but even decrease binding.6b This guests. This particularly strong interaction is consistent with
observation was surprising as the added phosphates were our observation that the additional phosphate moieties in 4d
expected to increase binding substantially due to strong ion– compared to 3 were most advantageous for binding of di-
ion interactions. We interpret these results as an indication amines with relatively short aliphatic linkers. Given that the
that the central phosphate moieties destabilize the desired polyamine metabolism and homeostasis is strongly regulated
tweezer conformation, potentially favouring more open confor- in humans and elevated levels are linked to excessive cell pro-
mations. The conformational flexibility of the related host 2 liferation and also neurodegenerative diseases, these are
was described by Isaacs and co-workers previously.6b While 4d viewed as potential handle for future treatments.15 Therefore,
proved to be a much stronger binder than 4a–c, a similar the nanomolar binding of these guests (422 nM for spermi-
observation was made: the additional phosphate moieties in dine and 6.76 nM for spermine) in aqueous buffer is remark-
4d compared to 3 appeared to offer a limited contribution to able. Furthermore, while comparable affinities to spermidine
the binding of diamine guests 10–15, although a stronger pre- and spermine have been reported for synthetic supramolecular
ference for shorter methylene linkers and reduced affinity for hosts before,9a,16 the level of selectivity for spermidine (23)
longer-chained guests was observed (maximum with C5-di- and especially spermine (24) over their parent biosynthetic pre-
ammonium chloride 11 for 4d and maximum with C8-di- cursor putrescine (10) is substantially higher for 4d compared
ammonium chloride 14 for 3).8
to previously reported hosts.
We were also interested in the formation of complexes of
In order to better understand the guest binding capabilities
the novel tweezers and basic amino acid derivatives. Very little of the new hosts 4a–d, we performed MD simulations of the
interaction was observed between tweezer 4a and the investi- conformational space of hosts 2 and 4c in water (Fig. 2B and
gated lysine derivatives Ac-Lys-OMe (16, Ka < 10 M−1), H-Lys- C, for detailed methodology see ESI†). The conformational
OMe (17, 88.0 M−1) and H-Lys-OH (18, 32.1 M−1) as well as changes in molecular tweezers are similar to those encoun-
arginine derivative H-Arg-OMe (19, 14.3 M−1). These results tered in the folding process of small proteins.17 However, the
were surprising, since the size and shape of the cavity of 4a is symmetric structure of the tweezers as well as their well-
very similar to that of 1, which binds lysine derivatives very defined local conformations allows
a simpler yet more
tightly,6a but are in good agreement with the previous obser- efficient definition of their overall conformational state. In this
vation of comparably poor binding in 3. It is important to note case, ten different conformers are possible with regard to the
that 4a has a much more flexible framework than 1 and that it four pairs of methylene bridges in these hosts, defining the
can populate different non-active conformations besides the correlation between the units that are linked by the methylene
desired “tweezer-like” conformation by means of rotation bridges either as syn (s, when the substituent at the glycoluril
around the methylene bridges (vide infra). Similar to 4a, inter- backbone and the aromatic unit are oriented towards each
actions between amino acid-derived guests 16–19 and hosts 4b other) or anti (a, when they are oriented away from each
and 4c are weak. The binding properties of 4d towards these other).18 We found that while in both 2 and 4c the s,a,a,s con-
guests are very similar to those of 3, which is in good agree- formation is the most favored one, the free energy difference
ment with the finding that the central phosphate moieties do between this state and the “active” a,a,a,a conformation is
not contribute to binding.
lower in 2 (≈−9 kJ mol−1) than in 4c (≈−12 kJ mol−1). This
When we investigated (hetero-)aromatic guests, we found indicates that the active tweezer conformation is more accessi-
that the association constants for the complexes of 4d with ble in solution for tweezer 2 than for 4c. Furthermore, the
p-xylylenediammonium chloride (20, Ka = 1.88 × 104 M−1) and energy barriers between the different conformations are much
methyl viologen chloride (21, 2.71 × 104 M−1) are similar to the higher in 4c than in 2, indicating that interconversion between
values for 20@3 and 21@3 (3.88 × 104 M−1 and 2.16 × 104 M−1
,
different conformers happens at lower rates in 4c than in 2. As
respectively). Additionally, both 4d and 3 show no or very a result, and in agreement with our observations in the
weak interaction with the sterically more demanding binding studies with hosts 4a–d, installation of phosphate
Thioflavin T (22). This further showcases that the installation groups at the central aromatic unit apparently destabilizes the
of additional phosphate moieties at the central aromatic unit desired tweezer conformation in favor of more open confor-
does not generally increase binding. Given this observation, mations that do not bind guest molecules efficiently. These
we were not surprised to see relatively weak binding of 20 and results clarify the surprising finding that central phosphate
21 with 4a–c. Interestingly, especially 20 and 21, both compar- groups do not generally increase binding although additional
ably large aromatic cations, showed stronger binding to ion–ion interactions with cationic guests would become avail-
naphtho-tipped host 4b (Ka = 1.75 × 103 M−1 and 5.85 × 102 able. The binding of spermidine (23) and particularly sper-
M−1, respectively) which displays larger aromatic surfaces than mine (24) to the hexaphosphate tweezer 4d is the exception
4a and 4c.
identified. We assume that the increased ion–ion interactions
We did, however, observe significantly stronger binding of between the triply/quadruply charged guest and the hexapho-
the natural polyamines spermidine (23) and spermine (24) by sphate tweezer 4d are overriding other factors in these two
the hexaphosphorylated host 4d (Ka = 2.37 × 106 M−1 for cases.
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Fig. 2 (A) Schematic depiction of five of the ten possible conformers of a tweezer with the general framework of 2, 3, and 4 by rotation around the
four pairs of methylene bridges using the nomenclature defined by Nolte.18 (B) Metadynamics estimation of the free energy surface (kJ mol−1) for
the conformers of 2 in water reveal a global minimum for the s,a,a,s state. (C) Metadynamics estimation of the free energy surface (kJ mol−1) for the
conformers of 4c in water also reveal a global minimum for the s,a,a,s state, but a much less favored “active” a,a,a,a state as well as higher energy
barriers between the different conformations. Values given in the surface plots are relative to the a,a,a,a conformer.
Conclusions
Acknowledgements
In summary, we have developed a modular synthetic platform for This work was supported by the Swiss National Science
phosphorylated molecular tweezers based on glycoluril linker units Foundation as part of the NCCR Molecular Systems
of the general structure 4 and were able to showcase the synthetic Engineering program. M. H. acknowledges Dr Michael Pfeffer
versatility by synthesizing the four derivatives 4a–d with diverse for HR-MS analysis and Dr Daniel Häussinger for support in
tips. The comparative study of those and related tweezers shows NMR titration experiments. Dr GiovanniMaria Piccini per-
that the installation of phosphate groups at the central aromatic formed the MD simulation on the ETH Euler cluster.
unit of the tweezers did not generally improve binding of
ammonium guests. Comparison of the binding properties of 4a
and 1, 4c and 2 as well as 4d and 3 together with MD simulations
of the conformational space of 4c and 2 suggest that these central
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Org. Biomol. Chem., 2021, 19, 3628–3633 | 3633