A General Approach to Biocompatible Branched Fluorous Tags for Increased Solubility in Perfluorocarbon Solvents

Article abstract of DOI:10.1021/acs.orglett.8b02976

A modular, cost-effective route to a library of branched fluorous tags with two short, biocompatible, fluorinated chains (C₆F₁₃) is reported. These branched fluorous tags provide high fluorous content without the use of long-chain linear perfluorocarbons, which have rising health concerns due to their bioaccumulation. By attaching these tags to a porphyrin, it is demonstrated that high solubility can be achieved in fluorous solvents that are readily cleared from mammals. This work enhances the biocompatibility of perfluorocarbon nanoemulsions for photodynamic therapy.

Full text of DOI:10.1021/acs.orglett.8b02976

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A General Approach to Biocompatible Branched Fluorous Tags for
Increased Solubility in Perfluorocarbon Solvents
Margeaux A. Miller and Ellen M. Sletten*
Department of Chemistry and Biochemistry, University of California, Los Angeles, 607 Charles E. Young Drive East, Los Angeles,
California 90095, United States
S
* Supporting Information
ABSTRACT: A modular, cost-effective route to a library of branched fluorous tags with two short, biocompatible, fluorinated
chains (C6F13) is reported. These branched fluorous tags provide high fluorous content without the use of long-chain linear
perfluorocarbons, which have rising health concerns due to their bioaccumulation. By attaching these tags to a porphyrin, it is
demonstrated that high solubility can be achieved in fluorous solvents that are readily cleared from mammals. This work
enhances the biocompatibility of perfluorocarbon nanoemulsions for photodynamic therapy.
erfluorocarbons, molecules where all the hydrogen atoms
are replaced with fluorine atoms, are an unnatural class of
Branched tags are a promising approach to employ short
fluorous segments, yet still obtain high wt % F. Furthermore,
branched alkyl chains have been shown to improve the
solubility of planar aromatic compounds in organic solu-
tion,18,19 indicating that branched tags may impart superior
fluorous solubility at lower wt % F.
Previously reported strategies to access branched C6F13 tags
include malonate alkylation,20,21 Grignard addition,22,23 and
sequential iodo-ene/elimination reactions24,25 (Figure 1A).
P
compounds with distinct characteristics due to the size and
electronegativity of fluorine.1 The inert nature and non-
polarizability of perfluorinated materials have been widely
realized through the success of poly(tetrafluoroethylene) as a
nonstick coating.2,3 The high gas content of perfluorocarbons,
coupled with their low boiling points and metabolic stability,
was exploited for oxygen delivery using perfluorocarbon
nanoemulsions in the 1980s.4 The synthetic chemistry
community was introduced to the orthogonality of perfluor-
ocarbons in 1994 as a means to efficiently recycle catalysts.5
This work coined the term “fluorous” and initiated the field of
fluorous phase chemistry where perfluorinated tags were
appended to organic compounds to facilitate purification by
fluorous extraction. The use of fluorous tags has since been
extended to biological applications to streamline proteomics,6
display bioactive molecules on microarrays,7−9 improve
transport into cells,10,11 and encapsulate chromophores inside
perfluorocarbon nanoemulsions.12,13
Given the broad applications of perfluorinated compounds,
the molecular requirements for obtaining fluorous phase
solubility have been extensively explored. Strategies to
solubilize compounds in perfluorocarbon include increasing
the weight percent fluorine (wt % F, ideally to above 60%)
through the addition of fluorous tags.14 Initially, C8F17 tags
were determined to have the appropriate balance of synthetic
ease and fluorous character.15 However, concerns regarding the
environmental persistence of long-chain perfluorinated com-
pounds (C7 or greater, e.g. perfluorooctanoic acid) prevent the
use of C8F17 chains as fluorous-solubilizing groups.16,17 For the
full potential of the fluorous phase to be realized, methods to
render molecules soluble in perfluorocarbon with C6F13
fluorous tags or shorter are necessary.
Figure 1. Approaches to branched fluorous tags. (A) Existing
approaches. (B) Our approach from ethyl cyanoacetate 1 leading to
multiple functional handles in minimal steps.
Received: September 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02976
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Scheme 1. (A) Synthesis of Modular Building Block 3. (B) Synthesis of a Library of Branched Fluorous Tags from 3
Perfluorinated tert-butyl groups have also been investigated as
biocompatible fluorous tags through the addition of perfluoro-
tert-butoxide.26,27 Collectively, these approaches have validated
the use of short fluorous segments to impart solubility in
perfluorocarbons; yet, there remains no tag that can easily be
appended to compounds with a variety of different chemistries.
Here, we describe the preparation of branched C6F13
fluorous tags from ethyl cyanoacetate 1. The minimal steric
hindrance of 1 facilitates alkylation with readily accessible
(perfluorohexyl)ethyl iodide (<$1/g),28 as opposed to the
expensive ($36/g)29 and difficult to prepare (perfluorohexyl)-
propyl iodide30 that is necessary for similar strategies.21
Additionally, the use of ethyl cyanoacetate allows direct access
to two distinct chemical functionalities, which can be easily
converted to an array of functional groups for tagging
compounds of interest (Figure 1B).
To showcase the general utility of these tags, we prepared a
highly fluorous-soluble porphyrin. We compared the porphyrin
containing branched C6F13 chains to one containing linear
C8F17 chains. Leveraging the absorbance and emission of
porphyrins, we determined that the branched fluorous tags
resulted in an increased fluorous partition coefficient, solubility
in an array of perfluorocarbons, and superior retention in
droplets of fluorous solvent (e.g., perfluorocarbon nano-
emulsions). Efficient encapsulation of porphyrins in perfluor-
ocarbon nanoemulsions is of particular interest for applications
in photomedicine. The combination of enhanced solubility
imparted by branched fluorous tags and the removal of
persistent fluorinated chains increases the biocompatibility of
perfluorocarbon (PFC) nanoemulsions for photodynamic
therapy.
multiple functional handles in a few, simple steps. We
envisioned that alkylation chemistry would be the most
efficient to install two fluorous chains in one pot. We targeted
(perfluorohexyl)ethyl iodide 2 as the fluorous starting material
due to its low cost and high wt % F. Previously, malonate esters
have been employed for direct addition of two fluorous chains
via alkylation; however, (perfluoroalkyl)propyl iodides were
necessary (Figure 1A). Our attempts to doubly alkylate
malonate esters with (perfluorohexyl)ethyl iodide resulted in
monoaddition at mild temperatures and elimination at elevated
temperatures (Scheme S1 and Table S1). Looking to increase
the reactivity of the nucleophile, we found that ethyl
cyanoacetate 1 could be successfully dialkylated with 2 to
provide 3 in 90% yield, with less than 1% of fluoride
elimination observed (Scheme 1A).31
The ethyl cyanoacetate provided increased reactivity as well
as two separate functional groups that could be transformed
into branched fluorous tags with different functional handles
(Scheme 1B). In one step from 3, we could access nitrile tag 4
through Krapcho decarboxylation. The nitrile could be
reduced to the primary amine 5 or aldehyde 6, demonstrating
the immediate modularity of this approach. Concurrently,
sequential saponification and decyanation provided branched
carboxylic acid tag 7 in 89% yield. The acid can be readily
reduced to the corresponding alcohol 8. From primary alcohol
8, we prepared tosylate 9, which can be displaced with azide or
thioacetate to give 10 and 11, respectively. Tags 4, 6, 10, and
11 represent popular chemical handles for click chemis-
tries,32,33 facilitating the simple installation of fluorous content.
To evaluate the ability of the branched fluorous tags to
solubilize organic compounds in perfluorocarbon solvents, we
performed a nucleophilic aromatic substitution reaction with
11 and 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin 12 to
yield 13 with 51 wt % F (Figure 2A).34 We compared 13 to
In efforts to develop a general strategy for the preparation of
biocompatible branched fluorous tags, we looked to employ
readily available starting materials that could be converted to
B
DOI: 10.1021/acs.orglett.8b02976
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partitioned against 1-octanol.12 Previously, we have shown that
14 displays some leaching into the 1-octanol.13 When we
performed the identical assay with 13, we found that 50% less
porphyrin escaped the droplets (Figure 2D), corroborating the
partition coefficient results and demonstrating the efficacy of
the branched fluorous tags.
The ability for branched fluorous porphyrin 13 to remain
inside perfluorocarbon nanoemulsions in the presence of
aqueous and lipophilic media is of particular interest for
applications in photodynamic therapy. Photodynamic therapy
is a clinically approved treatment for skin, esophageal, and lung
cancers.38−40 This procedure requires three components: a
photosensitizer, molecular oxygen, and light. We recently
reported that enhanced photodynamic therapy could be
achieved when perfluorocarbon nanoemulsions containing
14, acting as a photosensitizer, were irradiated with light.13
These nanoemulsions were composed of a mixture of 7:3
perfluorodecalin 15/perfluorotripropylamine 16, analogous to
the previously FDA-approved formulation for oxygen delivery.
Thus, with this system we are able to deliver both oxygen and
the photosensitizer simultaneously.
Despite the advantageous dual delivery, concerns regarding
clearance of both the C8F17 chains16 and perfluorotripropyl-
amine (PFTPA, 16)41,42 limit the translation of these materials
to higher organisms. Looking to overcome both these
limitations, we evaluated the solubility of 13 compared to 14
in the readily cleared solvents of perfluorodecalin (PFD, 15),
perfluorooctyl bromide (PFOB, 17), and perfluoro(tert-
butylcyclohexane) (PFt-BuCy, 18).43 We found that 13 was
more soluble than 14 in all cases (Figure 2E), facilitating the
preparation of emulsions for photodynamic therapy from these
solvents.
Finally, we performed photodynamic therapy with more
biocompatible perfluorocarbon nanoemulsions (Figure 3). We
Figure 2. (A) Branched 13 and linear 14 fluorous porphyrins
prepared from 12. (B) Fluorous partition coefficient in toluene (upper
phase) and perfluoro(methylcyclohexane) (lower phase). (C)
Preparation of PFC nanoemulsions containing branched 13 and
linear 14 fluorous porphyrin. Both porphyrins were dissolved in
separate 7:3 mixtures of PFD 15/PFTPA 16 (10 vol %) and
combined with Pluronic F-68 (2.8 wt %) in phosphate buffered saline.
Sonication (35% amp, 90 s, 0 °C) of the mixture provided PFC
nanoemulsions. (D) Leaching of porphyrin 13 (red, diamond) or 14
(blue, circle) from the fluorous interior of PFC nanoemulsions into 1-
octanol over time. Error bars represent the standard deviation of 3
replicates. (E) Structures of fluorous solvents previously employed as
the core of PFC nanoemulsions and solubility of porphyrins 13 and
14 in each solvent.
previously reported 14,35 which contained linear C8F17 tags
and 46 wt % F (Figure 2B). We determined the fluorous
partition coefficient (P)14,36 of 13 and 14 by subjecting each to
a 1:1 mixture of perfluoro(methylcyclohexane) (C7F14)/
toluene (PhMe) and quantifying the amount in each layer by
UV−vis spectroscopy.37 Branched fluorous porphyrin 13 had a
P = 24 (96:4 in C7F14/PhMe) whereas porphyrin 14 has a P =
1.7 (63:37 in C7F14/PhMe). This striking difference suggests
that branching and increased wt % F are acting synergistically
to enhance fluorous solubility. Another avenue to assay the
fluorous character of the tagged molecules is to evaluate their
tendency to remain in the core of PFC nanoemulsions (Figure
2C) as the aqueous suspension of droplets is continually
Figure 3. (A) Photodynamic therapy with perfluorocarbon nano-
emulsions containing 13 (0.5 mM). Cells were incubated with PFC
emulsions containing 13, washed via centrifugation, and irradiated
(420 nm, 8.5 mW/cm2) for 0 min (gray), 10 min (light blue), or 30
min (dark blue). (B) Flow cytometry analysis after light treatment.
After incubation, washing, and light treatment, cells were stained with
propidium iodide and analyzed by flow cytometry to determine the
degree of cell death. Dead cells were characterized as exhibiting
fluorescence >102 (Figure S4). Error bars represent the standard
deviation of 3 replicate samples.
C
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prepared droplets of PFD 15, PFOB 17, PFt-BuCy 18, and 7:3
PFD 15/PFTPA 16 (20 wt % fluorous solvent) containing 13
stabilized by Pluronic F-68 (2.8 wt %) in phosphate buffered
saline (PBS) (Scheme S2). As a control, we also prepared
droplets without 13 (Figures S1 and S2) and droplets
containing 14 for efficiency comparison (Figure S3). All
emulsions were 160−190 nm in size with polydispersities of
0.06−0.07 (Figure S1). We incubated each of the emulsions
with A375 melanoma cells for 3 h, at which point excess
emulsions were washed away and the cells underwent light
treatment for 0, 10, or 30 min. The degree of cell death was
quantified by immediate treatment with propidium iodide and
analysis by flow cytometry. We found that all emulsions
containing branched porphyrin 13 displayed no dark toxicity
and equivalent levels of cell death, greatly expanding the
fluorous solvents that can be employed for photodynamic
therapy with perfluorocarbon nanoemulsions. Ultimately, we
envision that optimized versions of these nanomaterials can be
systemically administered and accumulate at disease sites for
light-mediated therapies.
In summary, we have developed a route to a library of
biocompatible branched fluorous tags with two C6F13 chains.
These tags are derived from ethyl cyanoacetate 1 and
(perfluorohexyl)ethyl iodide 2 to provide modular building
block 3 with two functional handles and high fluorous content.
We converted 3 to eight branched fluorous tags with distinct
functionalities, including azides, aldehydes, and thiols for
standard click chemistries. We employed the thiol tag for
nucleophilic aromatic substitution to prepare fluorous
porphyrin 13. We demonstrate that 13 is more soluble in
fluorous solvent than its linear counterpart 14, facilitating the
incorporation of 13 into stable perfluorocarbon nanoemul-
sions. The high solubility of 13 in readily cleared, volatile
fluorous solvents allowed for photodynamic therapy to be
carried out with PFC nanoemulsions composed of clinically
relevant fluorous solvents. Looking forward, the simple,
modular synthesis of branched fluorous tags from readily
available starting materials will provide the community with
biocompatible methods to impart fluorous content to
molecules and materials, allowing the unique properties of
perfluorocarbons to continue to be exploited.
ACKNOWLEDGMENTS
■
M.A.M. is supported by the Chemistry-Biology Interface
Training Program (5T32GM008496). This work was
supported by shared instrumentation grants from the NSF
(CHE-1048804) and the NIH (1S10OD016387-01). Further
funding was provided by UCLA start-up funds and ACS-PRF
57379-DNI4.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02976.
Schemes S1 and S2, Table S1, Figures S1−S4, syntheses,
characterization, and experimental procedures for all
new compounds (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sletten@chem.ucla.edu.
ORCID
Margeaux A. Miller: 0000-0003-2301-8572
Ellen M. Sletten: 0000-0002-0049-7278
Notes
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