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Multiwavelength Control of Mixtures Using Visible Light Absorbing Photocages

Julie A. Peterson Iowa State University

Ding Yuan Iowa State University, [email protected]

Arthur H. Winter Iowa State University, [email protected]

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Abstract Selective deprotection of functional groups using different wavelengths of light is attractive for materials synthesis as well as for achieving independent photocontrol over substrates in biological systems. However, wavelength-selective is difficulto t achieve with common UV-absorbing photoremovable protecting groups (PRPGs) because it is difficulto t separate the chromophore absorption profiles. Moreover, deep UV irradiation of photocages can result in cellular phototoxicity. Here, we investigated the ability of recently-developed visible light absorbing BODIPY-derived PRPGs and a coumarin-derived PRPG to undergo wavelength selective activation in order to identify well-behaved pairs of PRPGs that allow independent optical control over a mixture of photocaged substrates using more biologically benign long-wavelength light. The three pairs of PRPGs tested have complete selectivities for cleaving the longerwavelength absorbing photocage first, and fair ot excellent selectivities for releasing the lower-wavelength absorbing PRPG first when mixtures were irradiated in solution. When the PRPGs are attached to the same substrate, irradiating the shorter-wavelength absorbing PRPG results in energy transfer, but the PRPGs can be cleaved in a sequential manner starting by deprotecting the longest wavelength absorbing photocage first and then emor ving the lower-wavelength absorbing PRPG. A mixture of the three photocages could be sequentially reacted using common red, green, and far-UV (365 nm) LED irradiation.

Keywords photochemistry, selective photorelease, photocages, BODIPY, Coumarin

Disciplines Chemistry

Comments This is a pre-print of the article Peterson, Julie A., Ding Yuan, and Arthur H. Winter. "Multiwavelength Control of Mixtures Using Visible Light Absorbing Photocages." ChemRxiv (2020). Posted with permission.

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This article is available at Iowa State University Digital Repository: https://lib.dr.iastate.edu/chem_pubs/1260 Multiwavelength Control of Mixtures Using Visible Light Absorbing Photocages Julie A. Peterson, Ding Yuan, Arthur H. Winter*

1605 Gilman Hall, Department of Chemistry, Iowa State University, Ames IA 50010

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ABSTRACT: Selective deprotection of functional groups bioactive substrates. Applications for wavelength con- using different wavelengths of light is attractive for ma- trolled release include control of separate processes in bi- terials synthesis as well as for achieving independent pho- ological systems (such as different inhibitors of signaling tocontrol over substrates in biological systems. However, pathways or neurotransmitters),1-4 materials and surface wavelength-selective activation is difficult to achieve patterning,2, 5-9 drug delivery,7, 10 peptide synthesis,11, 12 with common UV-absorbing photoremovable protecting and selective release of different protecting groups on a groups (PRPGs) because it is difficult to separate the substrate with multiple reactive sites.13-15 chromophore absorption profiles. Moreover, deep UV ir- In reality, however, chromophores have overlapping ab- radiation of photocages can result in cellular phototoxi- sorbance bands, which makes selective deprotection dif- city. Here, we investigated the ability of recently-devel- ficult.1, 16-18 Selectivity may be obtained from two chro- oped visible light absorbing BODIPY-derived PRPGs and mophores with overlapping absorbances as long as one of a coumarin-derived PRPG to undergo wavelength selec- them has an absorbance band that extends to a longer tive activation in order to identify well-behaved pairs of wavelength than the other (Figure 1a). In these cases, PRPGs that allow independent optical control over a mix- multiple levels of sequential release is possible if the irra- ture of photocaged substrates using more biologically be- diation source is carefully chosen.2, 12, 18, 19 nign long-wavelength light. The three pairs of PRPGs Assuming that the chromophores do not interact during tested have complete selectivities for cleaving the longer- the lifetime of the excited state (e.g. no electron transfer, wavelength absorbing photocage first, and fair to excel- energy transfer, or exciplex formation occurs), the selec- lent selectivities for releasing the lower-wavelength ab- tivity is governed by the relative quantum yields of pho- sorbing PRPG first when mixtures were irradiated in so- torelease if both chromophores absorb equal amounts of lution. When the PRPGs are attached to the same sub- light. Under conditions of photon scarcity, which is more strate, irradiating the shorter-wavelength absorbing often the case in dilute biological experiments under mod- PRPG results in energy transfer, but the PRPGs can be erate photon fluxes, the selectivity is related instead to the cleaved in a sequential manner starting by deprotecting relative quantum efficiencies (εΦ) of the photocages at the longest wavelength absorbing photocage first and the wavelength of irradiation. The quantum efficiency is then removing the lower-wavelength absorbing PRPG. A defined as the of the quantum yield of photore- mixture of the three photocages could be sequentially re- lease (Φ) and the extinction coefficient at the excitation acted using common red, green, and far-UV (365 nm) wavelength, and takes into account both how strongly the LED irradiation. photocage chromophore absorbs light and the percentage of release events that occur once light is absorbed. It follows, then, that one way to allow for better independ- Biological systems consist of a multitude of systems act- ent selectivity when the absorbances of the PRPGs over- ing in conjunction with each other. Orthogonal control of lap is if the quantum efficiency of the shorter wavelength separate biological processes within the cellular environ- absorbing photocage is much higher than the photocage ment is highly attractive for investigating such complex which has a longer wavelength absorbance (Figure 1b). biological phenomena. Light is an ideal stimulus for In this case there is still complete selectivity for cleaving achieving intracellular controlled activation of biological the longer-wavelength-absorbing PRPG as well as im- targets. It allows spatial and temporal control of activa- proved selectivity for cleaving the shorter wavelength-ab- tion, and it is a noninvasive external control so long as sorbing PRPG, assuming the chromophores do not inter- high wavelengths of light are used that are not absorbed act during the lifetime of the excited state. The extent of by cellular biomolecules. The use of photocaged sub- selectivity with the shorter wavelength PRPG can be strates is a popular way to achieve optical control over tuned based on the quantum efficiencies of the two PRPGs. In addition, sequential release may be obtained Ellis-Davies and coworkers successfully identified a cou- with a single wavelength depending on the rates of release marin derivative with a decreased absorbance in the UV of the chromophores.20, 21 In a classic example, Bochet region that gives excellent selectivity for photodeprotec- and coworkers exploited the kinetic isotope effect on o- tion with a UV absorbing photocage (Figure 1d), allow- nitrobenzyl derivatives to successfully tune their reactiv- ing independent control of cAMP and GABA. Another ity and were able to achieve independent control of two strategy to achieve selectivity is to exploit differences in o-nitrobenzyl PRPGs on a linker with two functional sites the two-photon absorbing cross-sections of the photo- (Figure 1G).15 These cases, however, also require judi- cages. For example, Heckel and coworkers exploited dif- cious selection of the irradiation wavelengths as well as ferential selectivity for a two-photon active PRPG that is the PRPGs. The photocage that absorbs longer wave- surprisingly inactive to one-photon reactivity, which al- length light often cannot be irradiated at its λmax and there- lows selective release by a combination of differential se- fore requires long periods of irradiation (e.g. > 12 h) for lectivity for photorelease of one- and two-photon absorb- full release to occur.13-16 ing cages.22 However, selective photorelease for a mix- True orthogonality between the two photocages could po- ture of photocaged substrates using single photons of vis- tentially occur if there is negligible overlap of the absorb- ible light would be highly desirable for many biological ances at the two wavelengths of irradiation (Figure 1c). experiments.

Figure 1. A) Two separate chromophores with overlapping absorbances that can be activated sequentially, B) Chromophores that have selectivity based on differences in quantum efficiencies. C) Chromophores with separated absorbances that can be released orthogonally. D) A study done by Ellis-Davies et. al. of two PRPGs that were shown to give orthogonal release of GABA and cAMP.1 E) Schematic of a substrate with two reactive functional sites that can be caged and orthogonally released using different chromophores. F) Schematic of a substrate with two functional sites that can be released sequentially. G) An example of orthogonal uncaging of a substrate with two functional sites done by Bochet et. al..15

We envisioned that the narrow absorption bands of BODIPY chromophores at various wavelengths25 (Figure 2) may have the potential to achieve near orthogonality, or multi-layered sequential release with very high selec- tivities using more biologically benign visible light. Here, we show that indeed these PRPGs allow for long-wave- length photocontrol over a mixture of photocaged sub- strates. For our investigation we compared three PRPGs—one, using coumarin PRPG 1, which has a lmax at ~380 nm, and an absorption tail that extends above 400 nm into the blue range of the visible (for notational clar- ity, we color this one blue); a BODIPY-derived PRPG 2, which has a strong absorbance ~520 nm (colored green), and a redshifted BODIPY PRPG 3, which has a strong absorbance in the red to near IR region ~690 nm (colored red). These three PRPGs feature separated λmax values and have lmax values that fall near the emission of common LED wavelengths (See Figure 2). The BODIPY PRPGs 2 and 3 also have the advantage that their quantum efficien- Figure 2. Photocages investigated in this study based on cies can be adjusted based on the substituents attached to coumarin, a green absorbing BODIPY and a red-absorbing the boron (BMe is much more efficient than BF ), BODIPY (top). These three chromophores have well sepa- 2 2 providing another handle with which to achieve selectiv- rated absorbances that match well with available red, green 25, 26 and UV LEDs (solid colored insets). ity. The plots of the absorbance and quantum efficien- cies for each of the three sets of pairs are shown in Figure Recently, our group as well as Weinstain and coworkers 3. As can be seen, all of them have reasonably separated reported that meso-substituted BODIPY derivatives absorbance bands. More importantly, plots of the quan- could act as visible light PRPGs.23, 24 More recently, we tum efficiencies for each pair suggests the possibility for have shown that structural variants of these PRPGs can very high selectivities (Figure 3, Figure S3). release substrates with red to near-infrared (NIR) light.25

Figure 3. Structures of the photocages dissolved in a 1:1 ratio in 50:50 DMSO:MeOH for irradiation (top), Normalized ab- sorbance, quantum efficiencies of photocages based on similar structures (middle), and reactivity over time of the mixtures irradiated with red, green, or UV LEDs. (A) Irradiation of a 0.02 mM mixture of 1-Succ and 2-Succ, (B) irradiation of (c) irradiation of a 0.05 mixture of 2-Me-OAc and 3-OAc with green and red LEDs.

Figure 4. A) 0.02 mM mixture of 1-Succ and 2-Succ dissolved in 50:50 DMSO:MeOH intermittently irradiated with a 520 nm LED and a 365 nm LED. B) 0.01 mM mixture of 2-Me-OAc and 3-OAc intermittently irradiated with a 520 nm LED and a 640 nm LED. C) Irradiation of a 1:1:1 mixture (0.02 mM) of 1-Succ, 2-Me-Succ, and 3-Me-Succ dissolved in 50:50 DMSO:MeOH. Samples were taken at time intervals and run through LC/MS. Solution was irradiated for 0-600 s with red light, followed by 50 s with green light and 60 s with UV light. Percent reacted was calculated by looking at the disappearance of the starting materials. Indeed, when a mixture of 2-Succ and 1-Succ were irra- We then chose the two pairs that had the best selectivity diated with green light, 2-Succ reacted with no evidence in order to demonstrate alternating activation upon irradi- of reaction of 1-Succ. When the mixture was irradiated ation of different wavelengths of light. Figure 4a shows with an LED centered around 365 nm, 1-Succ reacted the relative reactivity of the 1-Succ with 2-Succ by alter- quickly with only a small amount of 2-Succ reacted. Se- nating between irradiating with the 360 nm LED and the lectivity is nearly perfect at short irradiation times, but di- 520 nm LED. Similarly, Figure 4b shows the reactivity minishes as irradiation times increase because the ratio of of a mixture of 2-Me-OAc with 3-OAc (Figure 4a-b) by the absorbances of the unreacted photocages changes in alternating irradiation with the 520 nm LED and the 620 favor of the longer-wavelength absorbing photocage as nm LED. In both cases, selective reactivity is observed, more of the shorter-wavelength absorbing photocage is and demonstrates that the two photocages can be con- consumed. This pair has excellent selectivity with both trolled independently. long and short wavelengths (Figure 3a). While mixtures of these photocages in solution do not For 2-Me-Succ with 3-Me-Succ (Figure 3b), the meth- demonstrate complete orthogonality, they all show per- ylation of the boron on the BODIPY chromophores has fect selectivity when irradiating the longer wavelength been shown to increase quantum yields of release.25, 26 We absorbing photocage first. In order to demonstrate their envisioned that selectivity could be obtained based on the viability to be sequentially cleaved, compounds 1-Succ, much higher quantum efficiency of 2-Me-Succ compared 2-Me-Succ, and 3-Me-Succ were irradiated together in a to that of 3-Me-Succ. This mixture had a good selectivity cuvette with red, green, and UV LEDs to show that they from red to green irradiation; however, 2:1 selectivity for show sequential selectivity (Figure 4c). As expected, 3- 2-Me-Succ over 3-Me-Succ was achieved at full comple- Me-Succ selectively reacted with red light, green light se- tion of 2-Me-Succ when irradiated with an LED centered lectively cleaved 2-Me-Succ, and UV light cleaved the around 520 nm. We then tested a mixture of 2-Me-OAc remaining 1-Succ. with 3-OAc (Figure 3c). Since the fluorinated derivative After observing selectivity with irradiation of a mixture has an even lower quantum efficiency compared to the in solution, we asked whether we could protect two dif- methylated derivative, the mixture should give better se- ferent functional groups on the same substrate to achieve lectivity. Indeed, this pair does give better selectivity wavelength-selective release (Figure 1e). Orthogonal (~4:1 selectivity after completion of 2-Me-OAc). How- protecting groups have a wide variety of applications for ever, in both of these cases, the selectivity is lower than synthesis on single molecules27 including small , that predicted based on the quantum efficiencies at the carbohydrate,28-30 and peptide synthesis.31, 32 Photore- wavelengths of irradiation, suggesting that there may be movable protecting groups are interaction of the chromophores during the lifetime of the excited state (e.g. energy transfer between the chromo- phores of 2 and 3).

with UV irradiation (Figure S1). When irradiated with green

Figure 5. Predicted reactivity of 4 with different wave- lengths of light (top left); normalized absorbance of 1-Succ, 2-Succ, and 4 (top right); percent of 1-Succ, 2-Succ grown Figure 6. Predicted reactivity of 5 with different wave- in in after irradiation of a 0.03 mM solution of 4 dissolved lengths of light (top left); normalized absorbance of 2-Me- in 50:50 methanol:DMSO with a rayonet equipped with 360 Succ, 3-Me-Succ, and 5 (top right); percent of 2-Me-Succ nm bulbs (bottom left) and a 532 nm Nd:YAG laser (bottom and 3-Me-Succ grown in in after irradiation of a 0.025 mM middle); percent of 1-Succ and succinic acid grown in after solution of 5 dissolved in 50:50 methanol:DMSO with green irradiation of a 0.03 mM solution of 4 dissolved in 50:50 (bottom left) and red (bottom middle) LEDs; percent of 2- methanol:DMSO sequentially irradiated with green fol- Me-Succ and succinic acid grown in after irradiation of a lowed by UV LEDs (bottom right). 0.025 mM solution of 5 dissolved in 50:50 methanol:DMSO particularly attractive in solid phase synthesis as they can sequentially with red followed by green LEDs (bottom give excellent spatial and temporal control in order to cre- right). 33 ate microarrays. Some examples have been published light, however, there was good selectivity. The green with sequential deprotection of substrates including in 12, 19 light-absorbing BODIPY chromophore was able to react liquid and solid phase peptide synthesis. Bochet and and release 1-Succ nearly quantitatively. Furthermore, coworkers identified pairs that undergo orthogonal depro- although 4 is not able to be selectively cleaved first with tection on a linked compound, including an example that 365 nm light, it can be activated sequentially, first with takes advantage of isotope rate changes to achieve selec- the activation of BODIPY photocage with green light, and tivity with two different o-nitrobenzyl derivatives (Fig- 13-15 then with the activation of coumarin with UV light to re- ure 1g). We envisioned that the systems in this study lease succinic acid. may be candidates for selective release of two functional groups on a single substrate but using longer-wavelength We also synthesized 5, which has 2-Me green-absorbing light. BODIPY photocage linked with the read-absorbing 3-Me photocage (Figure 6). We chose 3-Me over the fluori- We chose to investigate the pairs of 1 and 2 (compound nated 3 because it has a much higher quantum yield, lead- 4) as well as 2-Me and 3-Me (compound 5), using suc- ing to shorter irradiation times. However, when irradiat- cinic acid as the linking substrate, as both pairs had fair ing 5 with green light no selectivity was observed. In fact, to excellent selectivity and reasonable rates of photore- we observed growth of 2-Me-Succ without a measurable lease. When irradiating 4 with green light, the BODIPY amount of3-Me-Succ, suggesting that energy transfer fol- photocage was selectively cleaved to release 1-Succ (Fig- lowed by cleavage of the longer-wavelength protecting ure 5). Interestingly, when irradiating 4 with UV light, group was occurring. However, selectivity was obtained much slower photoreactivity was observed. 2-Succ was when first using red light to cleave 3-Me. As was the case observed and 1-Succ was never observed; however, the for 4, we were able to sequentially cleave 5 by first irra- percent of conversion was less than 10% over a much diating with red light followed by green light to release longer time period than 1-Succ had reacted in a mixture. succinic acid. In both cases of 4 and 5 there was selectiv- Likely, energy transfer from coumarin to BODIPY caused ity when the chromophores were separated, but not when the reactivity of the coumarin derivative in 4 to be dimin- linked together, presumably due to the higher efficiency ished (plots of the absorption of 2-Succ and the emission of intramolecular energy transfer that leads to loss of se- of 1-Succ show good overlap, indicating the possibility lectivity. for efficient energy transfer (Figure S2). At the same time, 1-Succ may have been formed, but was not ob- In conclusion, we have demonstrated that BODIPY served because it was able to react much faster than it was PRPGs along with a coumarin photocage can be used for formed. Indeed, succinic acid increased steadily over time selective release with longer wavelength LEDs. While excellent selectivity was obtained in mixed solutions, the Selective Cell Release. 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