Article
Reference
Planarizable push-pull probes : overtwisted flipper mechanophores
MACCHIONE, Mariano, et al.
Abstract
Planarizable push–pull fluorescent probes, also referred to as flipper probes, have been introduced as conceptually innovative mechanophores that report on forces in their local environment in lipid bilayer membranes. The best flipper probes respond to a change from liquid disordered to solid ordered membranes with a red shift in excitation of 50–90 nm. A simultaneous increase in fluorescence lifetime and negligible background fluorescence from the aqueous phase qualifies these fluorescent probes for meaningful imaging in live cells.
Here, we report that the replacement of methyl with isobutyl substituents along the scaffold of a dithienothiophene dimer strongly reduces fluorescence intensity but increases solvatochromism slightly. These trends imply that the large substituents in “leucine flippers”
hinder the planarization in the first excited state to result in twisted intramolecular charge transfer (TICT). As a result of this overtwisting, the leucine flippers form interesting fluorescent micelles in water but fail to respond to changes in membrane order. These dramatic changes in function provide one of the [...]
MACCHIONE, Mariano, et al . Planarizable push-pull probes : overtwisted flipper mechanophores. Chempluschem , 2017, vol. 82, no. 7, p. 1062-1066
DOI : 10.1002/cplu.201600634
Available at:
http://archive-ouverte.unige.ch/unige:95494
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Planarizable Push-Pull Probes: Overtwisted Flipper Mechanophores
Mariano Macchione, Nicolas Chuard, Naomi Sakai and Stefan Matile*
Abstract: Planarizable push-pull probes, also referred to as flipper probes, have been introduced as conceptually innovative mechanophores that report on forces in their local environment in lipid bilayer membranes. The best flipper probes respond to a change from liquid disordered to solid ordered membranes with a red shift in excitation of 50–90 nm. A simultaneous increase in fluorescence lifetime and negligible background fluorescence from the aqueous phase qualifies for meaningful imaging in live cells.
Here, we report that substitution of methyl to isobutyl substituents along their scaffold strongly reduces fluorescence intensity but increases solvatochromism slightly. These trends imply that the large substituents in “leucine flippers” hinder the planarization in the first excited state to result in twisted intramolecular charge transfer (TICT). As a result of this overtwising, the leucine flippers form interesting fluorescent micelles in water but fail to respond to changes in membrane order. These dramatic changes in function provide one of the most impressive illustrations for the hypersensitivity of fluorescent membrane probes toward small changes in their structure.
Introduction
The concept of planarizable push-pull probes[1] has been inspired by the change of color of lobsters during cooking.[2] The idea is to combine the planarization and the polarization of twisted fluorophores in the ground state (Figure 1a).[1] Their planarization by mechanical or other forces from the surrounding environment should then result in large shifts in excitation, whereas emission from the planar first excited state[3] should be mechano-insensitive. This mechanism is distinct from and somewhat complementary to solvatochromism, TICT, PET or ESIPT of other membrane probes and related systems, which mostly report in emission.[4]
The currently best flipper probe 1,[5] result of a quite extensive optimization,[5-7] is composed of two dithienothiophene (DTT)[8] monomers (Figure 1b). These “fluorescent flippers” are bright enough to keep emitting when twisted out of conjugation and have a large enough surface to feel the environment really well. The push-pull system is established with accepting “sulfone”
and donating “sulfide” bridges in the DTT[6] and further
Figure 1. a) The concept of planarizable push-pull probes together with b) the structure of the so far best flipper probe 1 and the here introduced “leucine flipper” 2.
supported by cyano acceptors and intriguing chalcogen-bonding thenyl ether donors.[5] The headgroup further contains an essential triazole to prevent elimination[5] and a carboxylate to produce an overall amphiphilic probe. This is essential to deliver and orient flipper probes in membranes.[6]
Deplanarization[9,10] of the DTT dimer 1 is achieved by chalcogen-bond repulsion[5] between methyls and endocyclic sulfur atoms. The deplanarization of conjugated oligomers like 1 in the ground state is reported by a blue shift of the absorption or excitation maxima. The subsequent planarization of the twisted mechanophore in confined space results in the corresponding red shift in excitation.[5-7] Consistent with mechanical planarization in the ground state, increasingly red shifted excitation was found for flipper probe 1 in lipid bilayer membranes of increasing order. Such mechanosensitivity was of interest to image so far invisible forces in biological systems.[11] However, in single crystals, face-to-face π-stacked mechanophores 1 are already fully planarized.[7] This observation suggested that increasing twisting could perhaps further increase the mechanosensitivity of flipper probe 1. Here, we report that this is unlikely. Already the replacement of methyl by isobutyl groups, an overall small change, is shown to afford with “leucine flipper” 2 a fluorophore that has lost all functional relevance. This quite spectacular response, from best to worst, provides a wonderful illustration for the high sensitivity of fluorescent membrane probes, mechanophores and beyond, toward small changes of their structure.
Results and Discussion
The synthesis of leucine flipper 2 required strategic [*] M. Macchione, N. Chuard, Dr. N. Sakai, Prof. S. Matile
Department of Organic Chemistry University of Geneva, Geneva, Switzerland E-mail: [email protected]
Homepage: www.unige.ch/sciences/chiorg/matile/
Supporting information for this article is given via a link at the end of the document.
reconsideration because the convenient traditional approach from methylthiophene was not applicable.[6,8]
Tetrabromothiophene 3 was selected as starting point instead (Scheme 1).[12] A cascade condensation with aldehyde 4 and ethyl 2-thioacetate 5 afforded the new DTT core 6 with the two desired isobutyl substituents in good yield.[12,13] Ester hydrolysis followed by decarboxylation liberated the ortho positions in DTT 7 for further elaboration along the routes developed for the original probe 1.[5,6] The first step was a formylation. The resulting aldehyde 8 was reduced, and protection of the resulting thenyl alcohol with a silyl group lead to 9. To access the accepting flipper, the same aldehyde 8 was converted into nitrile 10. Bromination with NBS readily gave DTT 11, which was oxidized with mCPBA to DTT 12 with a sulfone instead of a sulfide bridge. The electron-rich DTT 9 and the electron-poor DTT 12 were then connected by Stille coupling. The resulting twisted dimer 13 was obtained in good yield. Removal of the silyl protecting group and reaction of thenyl alcohol 14 with bromide 15 gave alkyne 16, ready for cycloaddition with azide 17 to yield leucine flipper 2. Detailed procedures and full characterization of all new compounds can be found in the Supporting Information.[14] The here newly realized synthetic approach provides an alternative route to flipper probes in general. It will be of use also to produce probes such as flipper 1 at larger scale because it is more cost effective.
In toluene, the absorption maximum of the hydrophobic precursor 13 of leucine flipper 2, was at λabs = 403 nm (Figure 2a). This was ∆λabs = –10 nm blue shifted compared to 18, the previously reported[5,6] “methyl” homolog of 13. Moreover, the maximum of 13 extended more toward the blue, whereas the maximum of 18 showed a distinct shoulder toward the red. The differences supported that in solution, the ground state of leucine flipper 2 is more deplanarized than that of flipper 1.
Consistent with previous observations,[6] the absorption spectra showed little dependence on solvent polarity, and excitation and absorption spectra were nearly identical.
The emission maximum of the hydrophobic, not amphiphilic pre-leucine flipper 13 in toluene was at λem = 562 nm (Figure 2b, solid, blue). The slight red shift ∆λ = +6 nm compared to the original 18 supported that the blue shift in
absorption of 13 originates from ground-state deplanarization and not from unrelated effects.[3]
Figure 2. Normalized (a) absorption and (b) emission spectra of hydrophobic precursors of 2 (i.e., 13, solid, blue) and 1 (i.e., 18, dashed green)[5] in toluene, and emission of 13 (solid, cyan) and 18 (dotted green)[5] in EtOAc.
Red-shifted emission of 13 compared to the less twisted original 18 was observed also in more polar solvents such as EtOAc (Figure 2b, solid cyan vs dotted green, Figure S1). The spectral shift of emission from hexane to DMSO calculated to 3778 cm–1 for leucine flipper 13 and 3147 cm–1 for original 18.
Quantitative Lippert analysis[6] of their Stokes shifts as a function of solvent polarity gave the apparent difference in dipole moments of the ground and the excited state (Figure S2). The obtained ∆µL = 14.8 D of leucine flipper 13 exceeded the ∆µL = 13.6 D of original 18 clearly (Figure 3).
Using Rhodamine 6G as an established standard, the fluorescence quantum yield φ = 4.4% obtained for leucine flipper 13 in EtOAc was clearly below the φ = 35% of the original 18 (Figure 3). Both decreasing quantum yield and increasing positive solvatochromism with increasing twist of the push-pull fluorophore implied the emergence of twisted excited states.
With original flipper probe 1, planarization of the excited state upon intramolecular charge transfer (ICT) has been confirmed experimentally by time-resolved fluorescence emission spectroscopy.[3] This planar first excited state of push-pull chromophores is characterized by bright fluorescence, this is high quantum yields and long fluorescence lifetimes. However, Scheme 1. a) 1. 4, BuLi, THF, –78 °C, 2 h, 68%; 2. Na2Cr2O7, H2SO4, H2O, acetone, rt, 16 h, 72%; 3. 5, NaOEt, EtOH, reflux, 2 h, 86%;[10] b) 1. LiOH, EtOH, reflux, 16 h, 95%; 2. Ag2CO3, AcOH, DMSO, 120 °C, 16 h, 73%;[10] c) POCl3, DMF, 0 ºC to 50 ºC, 2 h, 91%; d) 1. NaBH4, DMF, 70 ºC, 2 h; 2. TBDPSCl, imidazole, DMF, rt, 12 h, 87%; e) NaN3, TfOH, MeCN, 70 ºC, 1 h, 86%; f) NBS, CH2Cl2, rt, 12 h, 94%; g) mCPBA, CDCl3, rt, 24 h, 66%; h) 1. LDA, Bu3SnCl, THF, -78 ºC to rt, 1 h; 2. Pd(Ph3)4, toluene, 70 ºC, 24 h, 82%; i) TBAF, AcOH, THF, rt, 30 min, 94%; j) NaH, THF, 0 ºC to rt, 16 h, 36%; k) CuSO4.
5H2O, sodium ascorbate, TBTA, CH2Cl2/H2O 4:1, rt, 4 h, 97%.
413
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450 λ (nm) 400
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a) 403 b) 556 562
Br Br S
Br Br
3
5 a) S
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S S S R
S R O
O N TBDPSO
13: R = iBu Br
S S OS
O N 12 S S
S TBDPSO
9 Br
S S S
N 11 S S
S O
8
S S S
N 10 S S
S
7 S
S S
4 O
O O O O HS
O O
6
b) c) d)
e)
f) g) h)
i)
j) k)
17
(18: R = Me)
several twistable push-pull chromophores have been shown not to relax into planar ICT but into twisted excited states with fully decoupled aromatic rings that are perpendicular to each other.[4,10] These TICT states are characterized by strong solvatochromism due to full charge separation and poor fluorescence due to non-radiative decay. The here identified trends with flipper probes thus suggest that with increasing “pre- twisting” in the ground state, exited state relaxation into planar ICT states becomes increasingly unfavorable and TICT states start to dominate (Figure 3). This interpretation that “pre-twisting”
in the ground state enables TICT is consistent with previously reported results with simpler model systems.[10]
Figure 3. Decreasing fluorescence quantum yield φ in EtOAc and increasing positive solvatochromism ∆µL suggests that the “pre-twisting” of flipper probes in the ground state increasingly favors twisted and disfavors planar excited states.
One of the hallmarks of the mechanosensitive membrane probe 1 is complete fluorescence quenching in water (Figure 4a, solid).[5,6] This is essential for measurements in cells and model membranes without disturbance of background fluorescence. In sharp contrast, leucine flipper 2 showed intense fluorescence in water (Figure 4b, solid). In water, both amphiphiles are expected to self-assemble into micelles. In micellar 1, fluorescence quenching presumably originates from face-to-face π stacking[7] of the mechanophores. The preserved fluorescence of micellar 2 suggested that the bulky isobutyl groups along the scaffold prevent π stacking.
Fluorescence quenching upon self-assembly as with mechanophore 1 is a general phenomenon. Fluorescent micelles, other nanoparticles and also solids have attracted recent attention for this reason.[15,16] For the fluorescent micelles formed by the twisted push-pull amphiphile 2 in water, a fluorescent quantum yield of φ = 4.2% was measured. Using Rhodamine 6G as an established standard, an unchanged φ = 4.4% was found for 13 in EtOAc.
A standard experiment to determine aggregation induced emission (AIE)[16] was used to elaborate on the formation of fluorescent micelles. As expected, the fluorescence intensity of 2 increased non-linearly with increasing percentage of water in MeOH/water mixtures (Figure 5a ). The formation of fluorescent micelles around 60% water in MeOH coincided with a blue shift of the excitation maximum by ∆λex = –8 nm (Figure 5a ). Although the precise origin of this small shift will remain
unknown, it certainly demonstrated that the micelle formation does not cause planarization of the overtwisted leucine flippers 2.
The concentration dependence in buffer was linear, suggesting that the critical micelle concentration (cmc) is below 250 nM (Figure 5b). Fluorescent micelles of 2 could be observed directly as small (at resolution limit), fairly homogenous spheres in fluorescent micrographs (Figure 5c).
Figure 4. In-scale, not normalized fluorescence emission spectra of 1[5](a) and 2 (b) in buffer (solid) and in Ld DPPC LUVs (dashed; 55 ºC), and excitation spectra of 1[5](c) and 2 (d) in So DPPC LUVs (solid; 25 ºC) and Ld
DPPC LUVs (dashed; 55 ºC, 10 mM Tris, 100 mM NaCl, pH 7.4).
Figure 5. a) Fluorescence intensity ( ) and excitation maximum ( ) of 2 as a function of the percentage of water (xx mM Tris, pH 7.4) in MeOH. b) Fluorescence intensity as a function of the concentration of 1 ( ) and 2 ( ) in xx mM Tris, pH 7.4. c) Confocal laser scanning microscopy image of 200 µM 2 in PBS buffer with 3% paraformaldehyde.
Partitioning into membranes was measured with large unilamellar vesicles (LUVs) composed of DPPC at 55 ºC, i.e., well above the transition into liquid-disordered (Ld) phase at 41 ºC. Not emitting in water, the partitioning of the original probe 1 into Ld DPPC membranes caused the known dramatic fluorescence recovery (Figure 4a, from solid to dashed).[5] Once
ISo/ILd
∆λex
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H2O (%) 100
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c (µM) 2
c)
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again, the behavior of leucine flipper 2 could not be more different: The strong emission in water did not change much in the presence of Ld DPPC membranes except for general contributions from scattering (Figure 4b, from solid to dashed).
Red shift in excitation ∆λ plus intensity ISo/ILd > 1 in response to cooling from Ld into solid-ordered (So) DPPC membranes are the characteristics of operational flipper probes (Figure 4c).[5,6] Flipper 1, the current best, features ∆λ = + 50- 90 nm and ISo/ILd = 2.7, the latter being also reflected in an increase in fluorescence lifetime τLo/τLd = 2.1,τLo = 5.8 ns
The new leucine flipper 2 simply did not respond to phase transition from Ld into So DPPC membranes (Figure 4d). The contrast between the two could not be stronger, the properties of 2 could not be worse, all mechanosensitivity of 1 was completely lost. With fluorescence being unresponsive also to partitioning (Figure 4b), the possibility that leucine flipper 2 did not enter the Ld DPPC membranes and remained in micellar form in water instead could not be excluded. However, the preparation of DPPC LUVs in the presence of leucine flipper 2 gave the same result. Similar, but clearly less pronounced loss in mechanosensitivity upon overtwisting has been observed previously during twistome screening in the quaterthiophene series.[17]
Conclusions
In summary, we report that the replacement of methyls by isobutyls along the scaffold completely destroys the activity of fluorescent flipper probes. The best flipper probes a) show a red shift in excitation and an increase in intensity and lifetime upon transition from Ld to So membranes and b) do not fluoresce in water (Figure 4a, c). Presumably due to overtwisting of the push-pull fluorophore (Figure 2), the new “leucine flippers” a) do not respond to the transition from Ld to So membranes and b) fluoresce strongly in water (Figure 4b, d). The found formation of small, spherical and quite homogenous fluorescent nanoparticles with overtwisted push-pull amphiphiles 2 (Figure 5) is of interest because the self-assembly of fluorescent amphiphiles in water usually results in complete quenching.
With regard to spectroscopic properties in solution, the consequence of overtwisting the flipper probe 2 in the ground state are reduced quantum yields and increased solvatochromism, that is an increasing preference for twisted rather than planar ICT excited states (Figure 3).
This quite spectacular response in function to an overall small change in structure nicely illustrates that the discovery of operational mechanosensitive membrane probes that operate by a combination of planarization and polarization in the ground state, i.e. flipper 1, is everything else than trivial. In other words, the here reported results testify for the importance of molecular precision in probe design and generate appreciation for the excellent performance of flipper probe 1 by contrast. Moreover, besides producing a completely useless twisted push-pull probe, we also introduce a new synthetic approach to fluorescent flippers that, being more cost effective, will be essential for the production of operational flipper probes 1 at larger scale.
Experimental Section
See Supporting Information.
Acknowledgements
We thank S. Soleimanpour for contributions to synthesis, the NMR, the Mass Spectrometry and the Bioimaging platforms for services, and the University of Geneva, the Swiss National Centre of Competence in Research (NCCR) Chemical Biology, the Swiss NCCR Molecular Systems Engineering and the Swiss NSF for financial support.
Keywords: Fluorescent probes • lipid bilayer membranes • mechanophores • push-pull chromophores • deplanarization •
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FULL PAPER
Appreciation by Contrast: We report that small structural changes related to fluorophore deplanarization cause a complete loss of mechanosensitivity in lipid bilayer membranes but afford fluorescent nanoparticles in water and a cost- effective synthetic route to operational mechanosensitive fluorescent probes.
Mariano Macchione, Nicolas Chuard, Naomi Sakai and Stefan Matile
Page No. – Page No.
Planarizable Push-Pull Probes:
Overtwisted Flipper Mechanophores
