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56. Wong, K.C.Y.; Sletten, E.M. “Extending optical chemical tools and technologies to mice by shifting to the shortwave infrared region.” Curr. Opin. Chem. Biol. 2022, 68, 102131.
55. Jaye, J.; Sletten, E.M. “Recent advances in the preparation of semifluorinated polymers.” Polym. Chem. 2021, 12, 6515-6526.
54. Kataki-Anastasakou, A.; Hernandez, S.; Sletten, E.M. “Cell-surface labeling via bioorthogonal host-guest chemistry.” ACS Chem. Biol. 2021, DOI: 10.1021/acschembio.1c00494.
Performing chemistry in living systems, deemed bioorthogonal chemistry, has proven to be
transformational in understanding and manipulating biological processes. Traditional chemistries
rely on the formation of covalent bonds that inside complex organisms may suffer from
incomplete conversions or side-reactivity. Here, we explored the use of molecular recognition or
host-guest chemistry to label cell-surfaces without the need for covalent bond formation. We
introduced unnatural functionality on mammalian cell surfaces and determined how strong the
interaction between guests and a fluorescently-tagged host needs to be to efficiently label cells.
Finally, we were able to metabolically incorporate boron clusters (carboranes) as sialic acid
derivatives onto the cell surface by utilizing the cell’s own biosynthetic machinery. The
carboranes on the cell surface were then non-covalently labelled with a cucurbituril-
fluorescein conjugate. This work contributes to our understanding of the fundamental
requirements and properties that next-generation host-guest systems must possess to be
translated into complex organisms.
53. Pengshung, M.; Cosco, E.D.; Zhang, Z.; Sletten, E.M. “Counterion pairing effects on a flavylium heptamethine dye.” Photochem. Photobiol. 2021, DOI: 10.1111/php.13531.
52. Deshmukh, A.; Geue, N.; Bradbury, N.; Atallah, T.; Chuang, C.; Pengshung, M.; Cao, J.; Sletten, E.; Neuhauser, D.; Caram, J. “Bridging the gap between H- and J-Aggregates: Classification and supramolecular tunability for excitonic band structures in 2-dimensional molecular aggregates.” ChemRxiv 2021, DOI: 10.33774/chemrxiv-2021-ql3b7.
51. Bailey, A.; Deshmukh, A.; Atallah, T.; Barotov, U.; Pengshung, M.; Sletten, E.M.; Caram, J. “Tubular J-aggregates of cyanine dyes in the near-infrared.” ChemRxiv 2021, DOI: 10.33774/chemrxiv-2021-rjmvz.
50. Day, R.A.; Sletten, E.M. “Experimental perspectives on direct visualization of endosomal rupture.” ChemBioChem 2021, DOI: 10.1002/cbic.202100379.
A major limitation of nanomaterials is the inability to efficiently escape the endosome and avoid subsequent degradation. Here, we visualize the disruption of the endosome, separately from the escape of nanomaterials from the endosome. Traditional methods of visualizing endosomal escape focus on the payload. The separation of endosomal membrane disruption from payload release provides insight into this field, with the goal of providing new assays for others working on the problem of endosomal escape.
49. Jia, S.; Sletten, E.M. “Spatiotemporal control of biology: Synthetic photochemistry toolbox with far-red and near-infrared light.” ACS Chem. Biol. 2021, DOI: 10.1021/acschembio.1c00518.
This review was published as part of the Young Investigator issue.
Controlling biological events by light is powerful for the detection and/or alteration of these processes, with wide applications in biological research and strong potential for clinical use. Two of the most widely-studied approaches, reversible photoswitches and irreversible photocages (light-sensitive protection groups), largely rely on photochemistry that occurs under high energy UV or blue light, which exhibits shallow penetration due to the strong absorption and scattering in biological samples. Recently, new chemical designs have expanded these photochemistries to the visible (400-700 nm) and near-infrared (700-1000) regions, with the latter exhibiting deeper penetration depth that enables photochemistries in model animals. This review summarizes current designs of synthetic red and near-infrared photocages and photoswitches with their current and potential biological applications.
48. Lee, G.Y.; Hu, E.; Rheingold, A.L.; Houk, K.N.; Sletten, E.M. “Arene-perfluoroarene interactions in solution.” J. Org. Chem. 2021, 86, 8425-8436.
Non-covalent interactions involving aromatic rings are responsible for a wide array of phenomena in chemistry and biology. An interesting and yet underexplored non-covalent interaction is arene-perfluoroarene interaction. Here, we report a systematic study of arene-perfluoroarene interactions in solution. Using a combination of NMR titration experiments, X-ray crystallography, and computational analysis, we analyze the effects of fluorination, substituents, ring size, and solvation on the arene-perfluoroarene interaction. We find that fluorination, extension of the π systems, and enhancement of solvent polarity greatly stabilize the stacking energy up to 3 orders of magnitude (Ka = <1 to 6000 M–1), with the highest Ka achieved in buffered D2O (pD = 12). The enhanced understanding of arene-perfluoroarene interactions in aqueous solution sets the stage for the implementation of this abiotic intermolecular interaction in biology and medicine.
47. Jaye, J.A.; Sletten, E.M. “Simple synthesis of fluorinated ene-ynes via in-situ generation of allenes.” Synthesis 2021, 53, A-K.
Fluorination of small molecules is a key route toward modulating reactivity and bioactivity. The 1,3 ene-yne functionality is an important synthon towards complex products, as well as a common functionality in biologically active molecules. Here, we present a new synthetic route towards fluorinated ene-ynes through simple starting materials. We employ gas chromatography-mass spectrometry analysis to probe the sequential eliminations necessary for this transformation and observe an allene intermediate. The ene-yne products are sufficiently fluorous to enable purification via fluorous extraction. This methodology will allow facile access to functional, fluorous ene-ynes.
46. Estabrook, D.A.; Day, R.A.; Sletten, E.M. “Redox‐responsive gene delivery from perfluorocarbon nanoemulsions through cleavable poly(2‐oxazoline) surfactants.” Angew. Chem. Intl. Ed. 2021, 60, 17362-17367.
The clinical utility of emulsions as delivery vehicles is hindered by a dependence on passive release. Stimuli-responsive emulsions overcome this limitation but rely on external triggers or are composed of nanoparticle-stabilized droplets that preclude sizes necessary for biomedical applications. Here, we employ cleavable poly(2-oxazoline) diblock copolymer surfactants to form perfluorocarbon (PFC) nanoemulsions that release cargo upon exposure to glutathione. These surfactants allow for the first example of redox-responsive nanoemulsions in cellulo. A noncovalent fluorous tagging strategy is leveraged to solubilize a GFP plasmid inside the PFC nanoemulsions, whereupon protein expression is achieved selectively when employing a stimuli-responsive surfactant. This work contributes a methodology for non-viral gene delivery and represents a general approach to nanoemulsions that respond to endogenous stimuli.
45. Cosco, E.D.; Lim, I.; Sletten, E.M. “Photophysical properties of indocyanine green in the shortwave infrared region.” ChemPhotoChem 2021, 5, 727-734.
With the growing development of new contrast agents for optical imaging using near‐infrared and shortwave infrared (SWIR) wavelengths, it is essential to have consistent benchmarks for emitters in these regions. Indocyanine green (ICG), a ubiquitous and FDA approved organic dye and optical imaging agent, is commonly employed as a standard for photophysical properties and biological performance for imaging experiments at these wavelengths. Yet, its reported photophysical properties across organic and aqueous solvents vary greatly in the literature, which hinders its ability to be used as a consistent benchmark. Here, we measure photophysical properties in organic and aqueous solvents using InGaAs detection (~950–1700 nm), providing particular relevance for SWIR imaging.
44. Cosco, E.D.; Arus, B.A.; Spearman, A.L.; Atallah, T.L.; Lim, I.; Leland, O.S.; Caram, J.R.; Bischof, T.S. Bruns, O.T.*; Sletten, E.M.* “Bright chromenylium polymethine dyes enable fast, four-color in vivo imaging with shortwave infrared detection.” J. Am. Chem. Soc. 2021, 143, 6836-6846.
Fluorescence imaging in the shortwave infrared (SWIR, 1000–2000 nm) region of the electromagnetic spectrum enables non-invasive, high-resolution and high-contrast in vivo imaging. With orthogonally excited fluorophores, multiplexed imaging allows visualization of multiple biological parameters in real time. Polymethine dyes are optimal probes for SWIR multiplexed imaging, thanks to their high absorption coefficients and narrow absorption spectra. This work improves upon previous multiplexed imaging efforts with the synthesis of bright chromenylium-based polymethine dyes matched to common laser lines. These chromenylium dyes are based on 2-position modifications to the flavylium scaffold and have significantly higher quantum yields due to decreased non-radiative rates. This work has enabled non-invasive single-color imaging at 300 fps and 3-color imaging at 100 fps: the fastest SWIR imaging to date. Finally, in concert with previously reported dyes, we achieved 4-color video-rate in vivo SWIR imaging for the first time. We envision that the development of brighter dyes for SWIR multiplexed imaging will lead to improved medical imaging technologies.
43. Friedman, H.C.; Cosco, E.D.; Atallah, T.L.; Jia, S.; Sletten, E.M.; Caram, J.R. “Establishing design principles for emissive organic SWIR chromophores from energy gap laws.” Chem 2021, DOI: 10.1016/j.chempr.2021.09.001.
First posted here: ChemRxiv 2021, DOI: 10.26434/chemrxiv.14374493.v1.
Fluorophores are the key to fluorescence imaging, and one of the key properties is their brightness, which is dependent on the extinction coefficient, describing how strong the fluorophore absorbs light, and the fluorescence quantum yield, evaluating the efficiency of the fluorophore to convert the energy in the light it absorbs to the energy in the light it emits. As researchers design fluorophores with wavelengths as long as 700-1000 nm (near-infrared) and 1000-2000 nm (shortwave infrared) for deep tissue and animal imaging, the fluorescence quantum yield drops precipitously as the wavelength moves longer, limiting the overall brightness of these fluorophores. This phenomenon is explained by the exceeding small energy jump in the excited long-wavelength fluorophore after it absorbs the energy of a photon, or one unit of light. This smaller energy is easier to be lost by the competing pathways of high-frequency molecular vibrations, resulting in heat rather than light being released. Based on experiment and theory, this work establishes an energy gap quantum yield master equation (EQME), which quantifies the limit of fluorescence quantum yield in relationship to the wavelength of a near-infrared or shortwave infrared fluorophore. The equation provides insights in designing brighter near-infrared and shortwave infrared fluorophores and shows the underlying mechanism of quantum yield increase by deuteration or molecular aggregation.
42. Day, R.A.; Sletten, E.M.* “Perfluorocarbon nanomaterials for photodynamic therapy.” Curr. Opin. Colloid Interface Sci. 2021, 54, 101454.
This review was published as part of the Nanobubbles and Nanodroplets issue.
Photodynamic therapy (PDT) is a treatment modality in which a photosensitizer is irradiated with light, producing reactive oxygen species. As it is common for tumors to be hypoxic, methods to deliver photosensitizer and oxygen are desirable. One such approach is the use of perfluorocarbons, molecules in which all C—H bonds are replaced with C—F bonds, to co-deliver oxygen due to the high solubility of gases in perfluorocarbons. This review highlights the benefits and limitations of several fluorinated nanomaterial architectures for use in PDT.
41. Shelton, E.R.; Kim, S.; Gross, B.J.; Wu, R.; Pochitaloff, M.; Lim, I.; Sletten, E.M.; Campàs, O. “Stress-driven tissue fluidization physically segments vertebrate somites.” bioRxiv 2021, DOI: 10.1101/2021.03.27.437325.
Over the course of embryonic development, functional structures are controlled by both genetic and physical factors. In zebrafish, genetic and molecular signals in the presomitic mesoderm (PSM) orchestrate somite formation. However, the mechanical and physical forces are unelucidated. In this work, direct mechanical measurements, live imaging, and computer simulations are used to explain the segmentation process. Direct mechanical measurements and live imaging are accomplished with a fluorous-soluble Cy5 and perfluorocarbon microdroplets. Overall, actomyosin structure drives an anisotropic stress at nascent somite-somite boundaries, and the tension fluctuations are optimized to define boundaries and minimize morphological defects in the PSM.
40. Cosco, E.D.; Spearman, A.L.; Ramakrishnan, S.; Lingg, J.G.P.; Saccomano, M.; Pengshung, M.; Arus, B.A.; Wong, K.C.Y.; Glasl, S.; Ntziachristos, V.; Warmer, M.; McLaughlin, R.R.; Bruns, O.T.*; Sletten, E.M.* “Shortwave infrared polymethine fluorophores matched to excitation lasers enable non-invasive, multicolour in vivo imaging in real time.” Nat. Chem. 2020, 12, 1123-1130.
Learn more about Dr. Maly Cosco’s experience while working on this project: https://chemistrycommunity.nature.com/posts/multiplexing-in-mice-joining-chemistry-and-imaging-across-continents
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Highlighted by Burgess and coworkers in ChemPhotoChem
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High-resolution, in vivo multiplexed imaging has been achieved in cellulo but translation to mammals has been a challenge. Existing fluorophores in the visible (350-700 nm) and near infrared (700-1000 nm) regions can suffer low tissue penetration and high background autofluorescence respectively. The shortwave infrared region (SWIR, 1000-2000 nm) avoids these limitations and is therefore suitable for real-time, multiplexed imaging in animals. Through the elucidation of flavylium polymethine structure-property relationships, we were able to design SWIR fluorophores matched to common laser lines (980 and 1064 nm). We then developed an imaging system with variable near-infrared/SWIR excitation and single-channel detection, allowing for video-rate multicolor SWIR imaging for optically guided surgery and imaging of awake and moving mice with multiplexed detection. This work enables real time monitoring of orthogonal functions in unrestrained moving animals. Additionally, the development of polymethine-based SWIR probes as well as clinical SWIR imaging systems will lead to improved surgical, diagnostic, and biomedical studies.
39. Deshmukh, A.P.; Bailey, A.D.; Forte, L.S.; Shen, X.; Geue, N.; Sletten, E.M.; Caram, J.R.* “Thermodynamic control over molecular aggregate assembly enables tunable excitonic properties across the visible and near-infrared.” J. Phys. Chem. Lett. 2020, 11, 8026-8033.
38. Mu X.; Hopp, M.; Dziedzic, R.M.; Rheingold, A.L.; Sletten, E.M.; Axtell, J.C.; Spokoyny, A.M. “Expanding the scope of palladium-catalyzed B—N cross-coupling chemistry in carboranes.” Organometallics 2020 39(23), 4380-4386.
First posted here: ChemRxiv 2020, DOI: 10.26434/chemrxiv.12844820.v1
Our interest in host-guest chemistry and its potential for introducing new developments in the field of chemical biology has prompted a closer look into promising candidates for both components. Carboranes — polyhedral boron clusters composed of catenated C-H and B-H vertices — exist in various shapes and charges and have increasingly been applied in chemical research due to their topology and electronic properties. We recently identified these molecules as promising guest targets and demonstrated their utility for the recycling of cucurbituril hosts, made possible through new amination chemistry on the carborane cage. In this paper, given the traditional difficulty in forging B-N bonds on certain carborane vertices, we opted to explore the breath of this synthetic strategy with two carborane substrates. We find that several nitrogen-based coupling partners — including phosphoramidates and isocyanates — can be rapidly installed, providing versatile, reactive handles for future chemistry.
37. Kataki-Anastasakou, A.; Axtell, J.C.; Hernandez, S.; Dziedzic, R.M.; Balaich, G.J.; Rheingold, A.L.; Spokoyny, A.M.; Sletten, E.M.* “Carborane guests for cucurbituril facilitate strong binding and on demand removal.” J. Am. Chem. Soc. 2020, 142(49), 20513-20518.
Cucurbituril (CB) has become the host of choice in biomolecule purification, small molecule separation, polymer cross-linking and sensor development. Previously discovered strong binding guests for CB have been difficult to remove from the CB cavity thus limiting widespread adoption of host-guest chemistry applications. In this paper, we introduce a new class of CB guests, namely ortho-carboranes, that can be removed on demand using a mild chemical trigger. Water soluble derivatives of ortho-carborane and their isomers meta-carboranes were synthesized and shown to have high binding affinity to CB as well as orthogonal response to “deboronation” that causes meta-carboranes to be stable against removal. Finally, in a proof-of-concept study a CB-decorated resin was used to isolate a fluorescent payload and amino-ortho-carborane was used to release the payload and recycle the CB-resin through on-demand removal.
36. Lim, I.; Vian, A.; van de Wouw, H.; Day, R.A.; Gomez, C.; Liu, Y.; Rheingold, A.L.; Campàs, O.; Sletten, E.M.* “Fluorous soluble cyanine dyes for visualizing perfluorocarbons in living systems.” J. Am. Chem. Soc. 2020, 142(37), 16072-16081.
Highlighted in JACS Spotlights: https://pubs.acs.org/doi/pdf/10.1021/jacs.0c09804
Perfluorocarbon emulsions have been used in biological settings as oxygen delivery vehicles, ultrasound contrast agents, and F-MRI contrast agents. In this paper, we enable the the fluorescence visualization of perfluorocarbon emulsions by synthesizing fluorous-soluble cyanine dyes. These dyes were photophysically characterized in fluorous solvent, which few fluorous-soluble fluorophores have done. We also showed the fluorous solubility of these cyanine dyes were superior to a benchmark rhodamine. We used perfluorocarbon nanoemulsions labelled with a red-shifted cyanine to perform multichannel microscopy in cells. Larger droplets labelled with the same cyanine yielded biophysical force information in zebrafish and multicellular aggregate models.
35. Day, R.D.; Estabrook, D.A.; Wu, C.; Chapman, J.O.; Togle, A.; Sletten, E.M.* “Systematic study of perfluorocarbon nanoemulsions stabilized by polymer amphiphiles.” ACS Appl. Mater. Interfaces 2020, 12(35), 38887-38898.
Perfluorocarbon nanoemulsions, droplets of fluorous solvent stabilized in water through a surfactant are a modular nanomaterial for the treatment and diagnosis of disease. In this work, we systematically vary the structure of the surfactant in order to understand the structure-property relationship. For each surfactant we analyze the size, stability, payload retention, cellular uptake and protein adsorption on perfluorocarbon nanoemulsions. We find the hydrophilic block length and identity, polymer hydrophilic: lipophilic balance, and polymer architecture are important parameters when selecting a surfactant to stabilize emulsions.
34. Pengshung, M.; Li, J.; Mukadum, F.; Lopez, S.A.*; Sletten, E.M.* “Photophysical tuning of shortwave infrared flavylium heptamethine dyes via substituent placement.” Org. Lett. 2020, 15, 6150-6154.
Fluorophores in the shortwave infrared region (SWIR, 1000-2000 nm) of the electromagnetic spectrum have gained a lot of interest recently for fluorescence imaging. However, more often than not these fluorophores are not biocompatible or are very dim. We have previously developed a small molecule dye, Flav7, with acceptable brightness in the SWIR. In this article, we explore structural-property relationship of flavylium heptamethines by changing the position of the dimethylamino substituent around the ring. Through computational and experimental analysis, we explore how these positions effect photophysical properties and gain a deeper understanding on how to design fluorophores for the SWIR.
33. Miller, M.A.; Sletten, E.M.* “Perfluorocarbons in Chemical Biology.” ChemBioChem 2020, 21, 3451-3462.
Chemical biology is a field that uses chemical tools to study and manipulate biology. One way this is done is to introduce unnatural groups that can be detected among all the naturally-occurring small molecules and biomolecules. Perfluorocarbons are carbon chains where all the hydrogen atoms have been replaced with fluorine atoms. These molecules are not found in mammalian tissue and can be considered “orthogonal” to many living systems. In this review, we discuss how perfluorinated unnatural groups have been incorporated into and interact with biomolecules as a way to study biological systems.
32. Pengshung, M.; Neal, P.; Atallah, T.L.; Kwon, J.; Caram, J.R.*; Lopez, S.A.*; Sletten, E.M.* “Silicon incorporation in polymethine dyes.” Chem. Commun. 2020, 56, 6110-6113.
First posted here: ChemRxiv 2019, DOI: 10.26434/chemrxiv.11320064.v1.
Imaging in complex biological systems is difficult due to the limitation of current fluorescent probes. To overcome this, we are focused on developing dyes with red-shifted (longer) absorption and emission wavelengths. Herein we have shown the first example of incorporating silicon into polymethines which red-shifts 100 nm and increases photostability. This showcases how simple structural modifications to molecules can cause significant photophysical changes that can be used in the design of future probes.
31. Jaye, J.A.; Sletten, E.M.* “Vinyl iodide containing polymers directly prepared via an iodo-yne polymerization.” ACS Macro Lett. 2020, 9, 410-415.
The vinyl halide functionality is ubiquitous in small molecule chemistry, but examples of polymer containing vinyl halides are rare. We have synthesized vinyl iodide containing fluorinated polymers through reaction of diynes and diiodoperfluoroalkanes. These polymers could undergo multiple cross-couplings reactions to alter thermal and physical properties. Vinyl iodide could also be eliminated to generate activated alkynes which can undergo cycloaddition chemistry. We expect these polymers to be used for applications which benefit from an array of post-polymerization modifications.
30. Miller, M.A.;# Day, R.D.;# Estabrook, D.A.;# Sletten, E.M.* “A reduction-sensitive fluorous fluorogenic coumarin.” Synlett 2020, 31, 450-454.
Published as part of the Special Section for the 11th EuCheMS Organic Division Young Investigator Workshop.
Dyes sensitive to their environment are useful tools for sensing chemical changes and probing biological systems. Traditionally, these probes have been developed for use in organic solvents, aqueous buffers, or the gas phase, with little attention paid to their utility in the fluorous phase. Herein, we synthesized a fluorous-soluble dye that lights up when exposed to a biologically relevant reducing agent. We expect that these types of dyes will find use in the expanding fluorous drug delivery community.
29. Chen, W.#; Cheng, C.-A.#; Cosco, E.D.#; Ramakrishnan, S.; Lingg, J.G.P.; Bruns, O.T.*; Zink, J.I.*; Sletten, E.M.* “Shortwave infrared imaging with J-aggregates stabilized in hollow mesoporous silica nanoparticles.” J. Am. Chem. Soc. 2019, 141, 12475–12480.
First posted here: ChemRxiv 2018, DOI: 10.26434/chemrxiv.7503506.v1.
Organic chromophores are known to be bright and biocompatible agents for optical imaging using visible and near-infrared light. Recently, we and others have focused on tuning molecular structure of polymethine dyes to red-shift monomer absorption wavelengths into the shortwave infrared (SWIR), where tissue properties are more favorable for imaging in mammals. However, this pursuit comes with challenges in brightness and stability for long-wavelength absorbing monomers. Here, we explore J-aggregation as a new strategy to create biocompatible polymethine-loaded nanoparticle imaging agents which absorb and emit SWIR light.
28. Jaye, J.A.; Sletten, E.M.* “Modular and processable fluoropolymers prepared via a safe, mild, iodo-ene polymerization.” ACS Cent. Sci. 2019, 5, 982–991.
Commercial fluorinated polymers are developed for many applications but can suffer from processability issues and are difficult to derivatize. We have developed new methodology to generate high molecular weight fluoropolymers with a modular backbone dependent on diene functionality. We also demonstrate multiple post-polymerization modifications to place azide, thiol, and allyl functionalities across the polymer. Irradiation with UV light and an initiator allowed facile cross-linking into fluorinated gels. We expect these polymers to lead to new commercial applications.
27. Estabrook, D.A.; Ennis, A.F.; Day, R.A.; Sletten, E.M.* “Controlling nanoemulsion surface chemistry with poly(2-oxazoline) amphiphiles.” Chem. Sci. 2019, 10, 3994–4003.
First posted here: ChemRxiv 2018, DOI: 10.26434/chemrxiv.7052027.
Emulsions are liquid-in-liquid droplets that are found in the pharmaceutical, food and cosmetic industries. However, use of these droplets is limited by challenges in controlling their properties, like size, charge or surface chemistry. In this paper, we make functional macromolecules (i.e. polymers) that self-assemble at the surface of these droplets; thus, by controlling the polymer, we can control resulting droplet properties on the nanoscale. Further, we show that particular properties dictate how these droplets behave in biological environments, demonstrating the importance of these parameters in real-world applications.
26. Rodrigues, R.M.; Guan, X.; Iniguez, J.A.; Estabrook, D.A.; Chapman, J.O.; Huang, S.; Sletten, E.M.; Liu, C.* “Perfluorocarbon nanoemulsion promotes the delivery of reducing equivalents for electricitry-driven microbial CO2 reduction.” Nature Catalysis 2019, 2, 4017–4014.
The reduction of CO2 into chemicals and fuels is a promising way to transform and store renewable energies while removing greenhouse gases. Previously, Prof. Chong Liu has integrated inorganic electrochemical catalysts with CO2-fixing microorganisms in order to convert CO2 gas into acetic acid, a high-value chemical. However, the maximum throughput was limited by the solubility and transfer kinetics of H2 gas involved within the pathway. In this collaboration, we demonstrated that perfluorocarbon nanoemulsions–known gas carriers–can work to promote microbial CO2 reduction through efficient H2 delivery. The design principles described herein show how fluorous nanocarriers can impact the way we approach converting greenhouse gases into commodity chemicals, and are expected to be applicable to other processes (e.g. N2 fixation and CH4 functionalization).
25. Cao, W.; Sletten, E.M.* “Fluorescent cyanine dye J-aggregates in the fluorous phase.” J. Am. Chem. Soc. 2018, 140, 2727–2730.
J-aggregates are a unique fluorophore formation that allows for enhanced photophysical properties, such as red-shifted absorption/emission and increased brightness. Thus, it is of interest to be able to utilize these aggregates for a wide variety of different applications. Traditionally J-aggregates are formed by cyanines in aqueous solutions which severely limits their processability. Herein, we develop a perfluorocarbon-hydrocarbon amphiphilic cyanine dye that J-aggregates in nonaqueous media. This fluorous J-aggregate showcases enhanced photostability and ease of fabrication in comparison to traditional cyanine aggregates, making them more readily applicable to future technologies.
24. Miller, M.A.; Sletten, E.M.* “A general approach to biocompatible branched fluorous tags for increased solubility in perfluorocarbon solvents.” Org. Lett. 2018, 20, 6850–6854.
Highlighted in Synfacts
Molecules with many C-F bonds are referred to as perfluorocarbons. These compounds have many useful properties, however long-chain, linear perfluorocarbons (ex. perfluorooctanoic acid, PFOA) persist in the environment and are not readily broken down in the body. In this paper, we have developed a simple method to synthesize branched, short-chain fluorinated tags. These tags retain the properties of highly fluorinated compounds so that perfluorocarbons can be applied in a more biocompatible manner.
23. Day, R.A.; Estabrook, D.A.; Logan, J.K.; Sletten, E.M.* “Fluorous photosensitizers enhance photodynamic therapy with perfluorocarbon nanoemulsions.” Chem. Commun. 2017, 53, 13043–13046.
Photodynamic therapy – a treatment that uses light, oxygen, and a small molecule photosensitizer to produce toxic reactive oxygen species – has been utilized successfully to treat actinic keratosis, small cell carcinoma, pleural mesothelioma, oesophageal, non-small cell lung and skin cancer. Previous efforts to increase photodynamic efficiency have focused on the development of new photosensitizers. In this work, we delivered the photosensitizer and oxygen simultaneously to increase the amount of reactive oxygen species produced when irradiated with light. Through the co-delivery of oxygen, photodynamic therapy can now be a viable treatment method for diseases (such as solid tumors) that are often lacking sufficient oxygen.
22. Cosco, E.D.; Caram, J.R.; Bruns, O.T.; Franke, D.; Day, R.A.; Farr, E.P.; Bawendi, M.G.; Sletten, E.M.* “Flavylium polymethine fluorophores for near- and shortwave infrared imaging.” Angew. Chem. Int. Ed. 2017, 56, 13126–13129.
Optical imaging with shortwave infrared detection (SWIR, 1000–2000 nm) offers superior contrast, resolution and depth penetration compared with near infrared or visible light detection. While the first contrast agents used for SWIR imaging included carbon nanotubes, rare-earth metal composites, and quantum dots, bright small molecule fluorophores would enable increased biocompatibility and translation of this technology to the clinic. Creating bright molecules which absorb and emit light in SWIR region of the electromagnetic spectrum is a challenging problem for organic chemists. In this study, we designed long wavelength analogues of a molecular scaffold of fluorescent dyes, called cyanine dyes, which are commonly employed with visible and near-infrared wavelengths of light. The result was a series of polymethine dyes which were about 200 nm red shifted from the traditional cyanine dyes. The compound containing 7 methine units in its linker absorbs and emits SWIR light and became the first polymethine dye designed for SWIR imaging. Notably, it also represented the brightest SWIR-light absorbing small molecule dye reported so far. We applied this dye to image deep vasculature in mice.
21. Sletten, E.M.; Swager, T.M. “Readily accessible multifunctional fluorous emulsions.” Chem. Sci. 2016, 7, 5091-5097.
20. Niroui, F.; Wang, A.I.; Sletten, E.M.; Song, Y.; Kong, J.; Yablonovitch, E.; Swager, T.M.; Lang, J.H.; Bulovic, V. “Tunneling nanoelectromechanical switches based on compressible molecular thin films.” ACS Nano 2015, 9, 7886-7894.
19. Zarzar, L.D.; Sresht, V.; Sletten, E.M.; Kalow, J.A.; Blankschtein, D.; Swager, T.M. “Dynamically reconfigurable complex emulsions via tunable interfacial tensions.” Nature 2015, 518, 520-524.
18. Koo, B.; Sletten, E.M.; Swager, T.M. “Efficient synthesis of functionalized poly(3-hexylthiophenes)s via lithium-bromine exchange.” Macromolecules 2015, 48, 229-235.
17. Sletten, E.M.; Swager, T.M. “Fluorofluorophores: fluorescent fluorous chemical tools spanning the visible spectrum.” J. Am. Chem. Soc. 2014, 136, 13574-13577.
16. Tomlin, F.M.; Gordon, C.G.; Han, Y.; Wu, T.S.; Slettem, E.M.; Bertozzi, C.R. “Site specific incorporation of quadricyclane into a protein and photocleavage of the quadricyclane ligation adduct.” Bioorg. Med. Chem. Lett. 2018, 26, 5280-5290.
15. Sletten, E.M.; de Almeida, G.; Bertozzi, C.R. “A homologation approach to the synthesis of difluorinated cycloalkynes.” Org. Lett. 2014, 16, 1634-1637.
14. Agarwal, P.; van der Weijden, J.; Sletten, E.M.; Rabuka, D.; Bertozzi, C.R. “A Pictet-Spengler ligation for protein chemical modification.” Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 46-51.
13. Gordon, C.G.; Mackey, J.; Jewett, J.C.; Sletten, E.M.; Houk, K.N.; Bertozzi, C.R. “Reactivity of biarylazacyclooctynones in copper-free click chemistry.” J. Am. Chem. Soc. 2012, 134, 9199-9208.
12. Yao, J.Z.; Uttamapinant, C.; Poloukhtine, A.; Baskin, J.M.; Codelli, J.A.; Sletten, E.M.; Bertozzi, C.R.; Popik, V.V.; Ting, A,Y. “Fluorophore targeting to cellular proteins via enzyme-mediated azide ligation and strain-promoted cycloaddition.” J. Am. Chem. Soc. 2012, 134, 3720-3728.
11. de Almeida, G.; Sletten, E.M.; Nakamura, H.; Palaniappan, K.K.; Bertozzi, C.R. “Thiacycloalkynes for Cu-free click chemistry.” Angew. Chem. Int. Ed. 2012, 51, 2443-2447.
10. Sletten, E.M.; Bertozzi, C.R. “A bioorthogonal quadricyclane ligation.” J. Am. Chem. Soc. 2011, 133, 17570-17573.
9. Sletten, E.M.; Bertozzi, C.R. “From mechanism to mouse: a tale of two bioorthogonal reactions.” Acc. Chem. Res. 2011, 44, 666-676.
8. Sletten, E.M.; Nakamura, H.; Jewett, J.C.; Bertozzi, C.R. “Difluorobenzocyclooctyne: synthesis, characterization, and stabilization by beta-cyclodextrin.” J. Am. Chem. Soc. 2010,132, 11799-11805.
7. Chang, P.V.; Dube, D.H.; Sletten, E.M.; Bertozzi, C.R. “A strategy for the selective imaging of glycans using caged metabolic precursors.” J. Am. Chem. Soc. 2010,132, 9516-9518.
6. Jewett, J.C.; Sletten, E.M.; Bertozzi, C.R. “Rapid Cu-free click chemistry with readily synthesized biarylazacyclooctynones.” J. Am. Chem. Soc. 2010, 132, 3688-3690.
5. Chang, P.V.*; Prescher, J.A.*; Sletten, E.M.; Baskin, J.M.; Miller, I.A.; Agard, N.J.; Lo, A.; Bertozzi, C.R. “Copper-free click chemistry in living animals.” Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 1821-1826.
4. Sletten, E.M.; Bertozzi, C.R. “Bioorthogonal chemistry: fishing for selectivity in a sea of functionality.” Angew. Chem. Int. Ed. 2009, 48, 6974-6998.
3. Sletten, E.M.; Bertozzi, C.R. “A hydrophilic azacyclooctyne for Cu-free click chemistry.” Org. Lett. 2008, 10, 3097-3099.
2. Kelly, C.B.; Colthart, A.M.; Constant, B.D.; Corning, S.R.; Dubois, L.N.; Genovese, J.T.; Radziewicz, J.L.; Sletten, E.M.; Whitaker, K.R.; Tilley, L.J. “Enabling the synthesis of perfluoroalkyl bicyclobutanes via 1,3 g-silyl elimination.” Org. Lett. 2011, 13, 1646-1649.
1. Sletten, E.M.; Liotta, L.J. “A flexible stereospecific synthesis of polyhydroxyated pyrrolizidines from commercially available pyranosides.” J. Org. Chem. 2006, 71, 1335-1343.