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39. 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.
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.
First posted here: ChemRxiv, 2020, DOI: 10.26434/chemrxiv.12844820.v1
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.
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(24), 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(5), 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.