An uncharged oxetanyl sulfoxide as a covalent modifier for improving aqueous solubility

Article abstract of DOI:10.1021/ml5001504

Low aqueous solubility is a common challenge in drug discovery and development and can lead to inconclusive biological assay results. Attaching small, polar groups that do not interfere with the bioactivity of the pharmacophore often improves solubility, but there is a dearth of viable neutral moieties available for this purpose. We have modified several poorly soluble drugs or drug candidates with the oxetanyl sulfoxide moiety of the DMSO analog MMS-350 and noted in most cases a moderate to large improvement of aqueous solubility. Furthermore, the membrane permeability of a test sample was enhanced compared to the parent compound.

Full text of DOI:10.1021/ml5001504

Letter
pubs.acs.org/acsmedchemlett
An Uncharged Oxetanyl Sulfoxide as a Covalent Modifier for
Improving Aqueous Solubility
Erin M. Skoda, Joshua R. Sacher, Mustafa Z. Kazancioglu,‡ Jaideep Saha,‡ and Peter Wipf*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: Low aqueous solubility is a common challenge
in drug discovery and development and can lead to
inconclusive biological assay results. Attaching small, polar
groups that do not interfere with the bioactivity of the
pharmacophore often improves solubility, but there is a dearth
of viable neutral moieties available for this purpose. We have
modified several poorly soluble drugs or drug candidates with
the oxetanyl sulfoxide moiety of the DMSO analog MMS-350
and noted in most cases a moderate to large improvement of aqueous solubility. Furthermore, the membrane permeability of a
test sample was enhanced compared to the parent compound.
KEYWORDS: Aqueous solubility, MMS-350, oxetane, sulfoxide, JP4-039
steric bulk to potentially protect adjacent sites of chemical or
metabolic instability.11,14−16
mproving the low aqueous solubility of many organic
Imolecules remains a considerable challenge in drug
discovery and development. The addition of ionizable groups
that increase solubility is complicated by the need to balance
this property with membrane permeability. In fact, drugs are
classified based solely on these two properties to predict
intestinal absorption in the biopharmaceutics classification
system (BCS).1 A poorly soluble compound can yield
misleading results in biological assays and suffer from low
bioavailability in vivo.2,3 Formulation is frequently used to
mitigate inadequate physicochemical properties in vivo, but this
technique is less prevalent in in vitro screening. To increase the
concentration of lipophilic small organic molecules in
biochemical assays, DMSO is often added, but toxicity in
cell-based screens or interference with the assay readout limits
the percentage of DMSO that can be used. Ultimately, an
improvement in the intrinsic water solubility of a compound
would be desirable and requires the addition of polar functions
or global structural changes such as disruption of symmetry or
molecular planarity.4 Adding ionizable side chains such as
dimethylamines, morpholines, piperidines, or carboxylic acids
usually causes a decrease in lipophilicity, which consequently
decreases cell permeability and hydrophobic compound−
receptor interactions.5 Examples of nonionizable, covalent
modifications that can improve solubility6 include glycolyl
and glyceryl,7 polyethylene glycol,8 glycoside,9 and mesylpro-
poxy10 side chains.
We have exploited the properties of the oxetane moiety in
our recent search for new solvents.17 MMS-350 (Figure 1, 1), a
Figure 1. Structure of MMS-350 (1),18 an oxetanyl DMSO derivative
that is an effective cosolvent for increasing the aqueous solubility of
lipophilic organic molecules.
symmetric oxetanyl sulfoxide, was successfully used as a solvent
additive to increase the solubility of a number of low solubility
drugs.18 In a comparison to the commonly used cosolvent
DMSO, MMS-350 was superior in maintaining solute stability
as an aqueous solubility enhancement. For example, MMS-350
increased the solubility of naproxen by 200 μg/mL over an
equal weight percentage of DMSO as an additive. Furthermore,
it was found to be stable19 and relatively nontoxic, and it did
not influence in vitro screening results.18
We envisioned that a covalently attachable variant of 1 would
further expand upon the use of the oxetanyl sulfoxide moiety as
a novel solubility enhancing function in medicinal chemistry.
Bioactive compounds with low solubility that require an
ionizable group were chosen for covalent modification (Figure
2). Specifically, bioactive agents containing carboxylic acid
groups, such as naproxen (2), lithocholic acid (3), and
Recent work has highlighted the utility of the oxetanyl group
as a polar isostere of the popular gem-dimethyl group in drug
design, as well as the concomitant enhancement of solubility
and log P.11,12 Oxetanes are more polar and better metal
ligands than dialkylethers,13 and they are superior hydrogen
bond acceptors. They also have the added benefit of increasing
Received: April 12, 2014
Accepted: June 27, 2014
Published: June 27, 2014
© 2014 American Chemical Society
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ACS Medicinal Chemistry Letters
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Since we had success in solubilizing naproxen (2) in water
with MMS-350 as an additive,18 it was chosen for validation
studies of our covalent modification. Using the conditions
outlined in Scheme 1, naproxen (2) was esterified with alcohol
11 to provide compound 13. Analogously, esters 14 and 15
were accessed via standard coupling conditions using alcohol
11. Activated carbonate 12 was converted to carbamates 16, 17,
18, and 19 by reaction with the free amine functional groups of
the selected compounds under basic conditions. Since
sulfoxides 11 and 12 are racemic, it should be noted that the
derivatization of a chiral parent compound results in a
diastereomeric product mixture (e.g., 13, 14, and 19), which
can complicate NMR analyses.
Measuring solubility by UV−vis spectroscopy is a common,
straightforward method of analysis. Unfortunately, because
several of our test compounds did not contain a suitable
chromophore, UV−vis could not be used as a standard method
of detection. Instead, we chose to measure the solubility by
mass recovery. To ascertain that this method was accurate, we
chose UV-active naproxen derivative 13 and compared the
solubility of 13 by both methods. The results obtained for these
measurements were in good agreement (for details see
Supporting Information) and supported our use of mass
recovery determinations for other non-UV active compounds.
The thermodynamic solubility of 13 was measured in water
after an equilibration at 30 °C for 24 h in an end-over-end
rotator. Gratifyingly, the oxetanyl sulfoxide derivative showed a
>10-fold increase in solubility compared to naproxen (Table 1,
Figure 2. Structures of poorly water-soluble drugs and drug candidates
used in this study.
meclofenamic acid (4), were modified to form oxetanyl
sulfoxide ester derivatives. Amine-containing bioactive mole-
cules, which are either used as the hydrochloride salt (as in
ciprofloxacin (5) and sulfamethoxazole (6)) or acylated to
prevent salt formation (as in some kinase inhibitors (e.g., 7)
and the radiation mitigator JP4-039 (8)), were derivatized to
form the corresponding oxetanyl sulfoxide carbamates.
The synthesis of the covalent solubility modifier moiety 11
began with the known oxetanyl tosylate 9 (Scheme 1).20
a
Table 1. Aqueous Solubility of Naproxen Derivatives
Scheme 1. Synthesis of Oxetanyl Sulfoxide Derivatives of
Carboxylic Acid (13, 14, 15) and Amine (16, 17, 18, 19)-
Containing Bioactive Compounds
a
Solubility was measured in H2O after an incubation period of 24 h at
30 °C and rounded to 2 significant digits. See SI for full experimental
b
details including standard deviations. Calculated with Instant JChem
c
6.3, 2014, ChemAxon (http://www.chemaxon.com). n = 1, consistent
d
e
with literature results.26 n = 3. n = 2.
13 and 2, respectively). To determine whether the sulfoxide
was necessary and represented the optimal oxidation state of
the sulfur atom, sulfide 20 and sulfone 21 were also
synthesized. Naproxen was esterified with thioether alcohol
10 to furnish ester 20, which was also oxidized to the
corresponding sulfone 21 by treatment with oxone (see
Supporting Information). The thioether displayed similar
solubility to naproxen itself (Table 1, 20), while the sulfone
provided a 3-fold increase in solubility over the free acid (Table
Reaction with mercaptoethanol under basic conditions led to
thioether 10, which was then oxidized to sulfoxide 11 using
sodium periodate. The alcohol was converted to the activated
carbonate 12 using diphthalimidyl carbonate.21 This alkox-
ycarbonyl transfer agent was chosen in order to provide a
balance between stability and reactivity along with ease of
purification.
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ACS Medicinal Chemistry Letters
Letter
1, 21). Following indentification of the sulfoxide as the optimal
oxidation state with regard to solubility, the influence of the
oxetane on the solubility was tested next. Analog 22, which
contains a sulfoxide but lacks the oxetanyl ring, was synthesized
by coupling of naproxen to 2-(methylthio)ethanol followed by
oxidation. Compound 22 was more soluble than either the
sulfone or the thioether derivatives but less soluble than the
oxetanyl sulfoxide with solubility of 830 μM. Overall, the
oxetanyl sulfoxide led to the most significant improvement in
the aqueous solubility of naproxen. In this instance, and in the
case of most of the oxetanyl sulfoxide derivatives, the calculated
log D values did not closely track the solubility trends (Table
1).
compensate for a slight decrease in solubility. The naproxen
derivative 13 was compared to the parent naproxen (2) to test
how the permeability was affected by the incorporation of the
solubilizing moiety. Using a PAMPA permeability protocol, it
was found that 13 had improved permeability over 2 with a log
Pe (log of the effective permeability) of −4.9 vs −6.2,
respectively.27
Subsequent to the esterification of carboxylic acid-containing
bioactive compounds, a series of biologically active amines were
derivatized as carbamates by reaction with carbonate 12 to
study the effects of the oxetanyl sulfoxide on their solubility.
Ciprofloxacin, an antibacterial agent, is a BCS class III drug
with a solubility of 90 μM for the neutral amine (Table 3, 5).
After this successful validation of the oxetanyl sulfoxide as a
covalent solubility enhancer, we sought to test additional
derivatives to determine the scope of this approach. The bile
constituent and selective antineuroblastoma agent lithocholic
acid (3), which has detergent-like properties due to a polar
carboxylic acid−lipophilic steroid backbone combination,22 has
a reported aqueous solubility of 1 μM at pH 2,23 consistent
with our experimental results in unbuffered water (Table 2, 3).
Table 3. Aqueous Solubility of Amine-Containing Bioactive
Compounds
a
Table 2. Aqueous Solubility of Carboxylic Acid-Containing
a
Bioactive Compounds
a
Solubility in H2O was measured after an incubation period of 24 h at
30 °C and rounded to 2 significant digits. See SI for full experimental
b
details including standard deviations. Calculated with Instant JChem
c
6.3, 2014, ChemAxon (http://www.chemaxon.com). The mass
recovery of this compound was undetectable, which is consistent
d
e
with the reported trace solubility of 1 μM.23 n = 4. n = 3.
a
Solubility was measured in H2O after an incubation period of 24 h at
30 °C and rounded to 2 significant digits. See SI for full experimental
b
details including standard deviations. Calculated with Instant JChem
Esterification with the oxetanyl sulfoxide alcohol 11 resulted in
a solubility of 480 μM for 14, thus providing a very substantial
improvement over lithocholate 3 (Table 2, 14). In contrast,
meclofenamic acid (4), an NSAID that inhibits prostaglandin
synthesis24 and has an aqueous solubility of 1,900 μM exhibited
a decrease in solubility to 540 μM when esterified with 11
(Table 2, 4 and 5, respectively). We attribute this negative
effect of the oxetanyl sulfoxide attachment in 15 to the
potential for increasing solubility by anionic dimer and trimer
formation of the ionizable parent, anthranilic acid derivative
4.25
The relative decrease in solubility for ester 15 vs
meclofenamate 4 highlights an apparent downside in generating
nonionizable derivatives for solubility purposes. However, in
general, neutral compounds are also often much more
membrane permeable than their ionized counterparts. If the
solubility of the oxetanyl sulfoxide derivatives is at an acceptable
level, then the expected increase in permeability may well
c
6.3, 2014, ChemAxon (http://www.chemaxon.com). n = 1 (literature
d
e
value for HCl salt was 1,000 μg/mL).28 n = 3. n = 1 (literature value
f
for HCl salt is 100 μg/mL).28 n = 2.
While the solubility of its HCl salt is more than sufficient for
oral dosing, the compound is not very permeable, likely due to
the basic piperazine.28 The oxetanyl sulfoxide derivative of 5
increased the solubility to 350 μM; that is, it was more than
three times as soluble as the parent compound (Table 3, 16).
Sulfamethoxazole, a BCS class IV antibacterial agent, has a
solubility of 1,000 μM. The oxetanyl sulfoxide derivative of this
compound at 2,200 μM was more than two times as soluble
(Table 3, 6 and 17, respectively).
Experimental drug candidates from our own laboratory were
also derivatized and analyzed for solubility enhancements. First,
benzothienothiazepine 7, a selective PKD inhibitor29,30 that
suffers from low aqueous solubility, was derivatized with
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ACS Medicinal Chemistry Letters
Letter
Author Contributions
oxetanyl sulfoxide to yield 18. This new carbamate analog
showed a marked increase in aqueous solubility to 960 μM, an
almost 5-fold increase over the parent ethyl carbamate (Table
3, 18). Finally, our mitochondrial-targeted nitroxide, JP4-039
(8),31−33 was converted to the oxetanyl sulfoxide derivative 19.
The parent compound has an aqueous solubility of 580 μM
(Table 3, 8), while 19 displayed an aqueous solubility of 44
mM (Table 3), a 76-fold increase in solubility.
‡The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript. M.Z.K. and J.S. contributed equally to this
work.
Funding
This research was supported by the NIH/NIGMS CMLD
program (P50 GM067082).
A comparison of the microsomal stability of these analogs
further demonstrates a subtle balance between solubility and
other physical and biological properties. For example, when
JP4-039 (8) was incubated with mouse liver microsomes, 15%
of the parent compound remained after 1 h. The oxetanyl
sulfoxide derivative 19 displayed equivalent results to those of
the microsome assay, with 16% remaining after 1 h.34
Conversely, when naproxen and its oxetanyl sulfoxide derivative
were exposed to mouse liver microsomes, a decrease in stability
from 81% to 2%, respectively, was observed. These results
could be due, in part, to the presence of a negative charge in the
parent naproxen, vs the neutral character of the oxetanyl
sulfoxide ester and/or ester hydrolysis.
In conclusion, we have developed a new oxetanyl sulfoxide
solubility modifier and demonstrated its utility for several
bioactive carboxylic acids and amines. In most cases, the
oxetanyl sulfoxide group increased the solubility of the parent
compound by 5−10-fold. In two instances, a more significant
improvement was observed. The solubility of JP4-039 (8) was
increased 76-fold by addition of the oxetanyl sulfoxide (19)
while the solubility of lithocholic acid (3) was even increased
from 0.05 μM to 480 μM in analog 14. However, the
conversion of an ionizable acid group to a neutral ester
derivative can also lead to a decrease in solubility, as shown for
meclofenamic acid analog 15. Not surprisingly, metabolic
stability is variable between parent compounds and solubilized
analogs.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Mr. Peter Chambers for QC analysis and stability
testing of MMS-350 and Dr. Melissa M. Sprachman for the
synthesis of the MMS-350 sample used in the stability testing.
ABBREVIATIONS
■
BCS, biopharmaceutics classification system; DIPEA, N,N-
diisopropylethylamine; DMAP, 4-dimethylaminopyridine;
EDCI, 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hy-
drochloride; MMS-350, 3,3′-sulfinylbis(methylene)bis(3-meth-
yloxetane) (1); NSAID, nonsteroidal anti-inflammatory drug;
PAMPA, parallel artificial membrane permeability assay; PKD,
protein kinase D; SAR, structure activity relationship
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