Stability, Kinetic, and Mechanistic Investigation of 1,8-Self-Immolative Cinnamyl Ether Spacers for Controlled Release of Phenols and Generation of Resonance and Inductively Stabilized Methides

Article abstract of DOI:10.1021/acs.orglett.6b03695

Three cinnamyl ether spacers (non-methyl, α-methyl, and γ-methyl) for caging of phenols have been synthesized and are physiologically stable. When triggered, the γ-methyl spacer releases phenols (pK_a 7.8 and 9.8) with a t_1/2 < 30 s and <2 min in aqueous and aqueous-organic solvent, respectively. The α-methyl spacer releases a phenol (pK_a 7.8) with a t_1/2 = 27 and 54 min. For the γ-methyl spacer, the results suggest the presence of a resonance and inductively stabilized aza-cinnamyl methide.

Full text of DOI:10.1021/acs.orglett.6b03695

Letter
pubs.acs.org/OrgLett
Stability, Kinetic, and Mechanistic Investigation of 1,8-Self-
Immolative Cinnamyl Ether Spacers for Controlled Release of
Phenols and Generation of Resonance and Inductively Stabilized
Methides
Siddharth S. Matikonda, Jessica M. Fairhall, Joel D. A. Tyndall, Sarah Hook, and Allan B. Gamble*
New Zealand’s National School of Pharmacy, University of Otago, Dunedin 9054, New Zealand
S
* Supporting Information
ABSTRACT: Three cinnamyl ether spacers (non-methyl, α-
methyl, and γ-methyl) for caging of phenols have been
synthesized and are physiologically stable. When triggered, the
γ-methyl spacer releases phenols (pKa 7.8 and 9.8) with a t1/2
<
30 s and <2 min in aqueous and aqueous−organic solvent,
respectively. The α-methyl spacer releases a phenol (pKa 7.8)
with a t1/2 = 27 and 54 min. For the γ-methyl spacer, the
results suggest the presence of a resonance and inductively
stabilized aza-cinnamyl methide.
he phenolic moiety is a key component for many
ethers) for less acidic phenols (pKa >9.2) in nonpolar
Tbiologically active drugs, fluorescent probes, and responsive environments, benzyl ethers exhibiting reduced aromaticity2e
and methoxy-substituted benzyl ethers (Scheme 1a)4 have been
materials.1 While strategies for protecting phenols in organic
syntheses are vast, caging with a self-immolative spacer for
prodrug therapy, diagnostics, and responsive materials is mostly
limited to esters, carbonates, and benzyl ethers.1a,2 The ester and
carbonate linkers have limited biological application because they
only form moderately stable conjugates with higher pKa phenols
or alcohols and can be subjected to nonspecific hydrolysis.1a,3 On
the other hand, benzyl ethers form stable conjugates, and in a
strictly aqueous (aq) environment, they have been successfully
utilized in the activation of prodrugs.2b However, when this
translates to a less polar solvent (e.g., 1:1 MeCN/buffer), a
requirement for many responsive material applications, the
benzyl ether is only capable of slow release of acidic phenols (pKa
<9.2; t1/2 < 3 h).4 Therefore, the need for stable benzyl ether−
phenol conjugates still capable of rapid release in prodrug/pro-
probe science and the need to control depolymerization rates for
responsive materials2e,5 warrant the investigation of faster self-
immolation mechanisms (t1/2 = seconds) for use with a broad
range of phenols (pKa 7−10.5).
Since the first report of 1,6-self-immolative p-aminobenzylox-
ycarbonyl/benzyl alcohol (PABC/PABA) spacers,6 variants have
been used as protecting groups in synthesis or for prodrugs,2b
pro-probes,3b and polymers.7 PABC spacers are beneficial in
caged drug/probe design as the amino (or hydroxyl) group can
be converted to a trigger designed to stabilize the caged adduct
(e.g., NO2, N3, N-/O-acyl) until an appropriate stimulus is
introduced.8 However, phenols (particularly acidic phenols, pKa
<8) and alcohols attached to the PABC spacer via a carbonate are
rapidly hydrolyzed under aq and aq−organic conditions, making
them poor caging groups for prodrugs/probes.3b,d To combat
low stability (esters, carbonates) and slow release (from benzyl
Scheme 1. Self-Immolative Ether Spacer Strategies
reported. The methoxy-substituted benzyl ethers form stable
conjugates of phenols and acidic benzyl alcohols and, once
triggered, decage phenols with varying acidities (pKa 7−12).4
This enables release of phenols from ethers in organics; however,
there is still a need to develop broadly applicable and
synthetically accessible spacers able to rapidly release phenols
of all acidities.
To overcome the shortcomings of PABC-linked phenols and
increase the applications of ether-linked self-immolative spacers
(e.g., in prodrugs and degradable materials), we designed a series
of ether spacers based on the cinnamyl alcohol scaffold (Figure
1). 7-Hydroxycoumarin 3 and etoposide 4 were selected as
model phenols as they represent examples of phenols that can be
used in prodrug/pro-probe science and their leaving group
ability in polar and nonpolar solvents can be extrapolated to the
Received: December 12, 2016
© XXXX American Chemical Society
A
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ether spacers 1a−1c, the related carbonate ester 1d (PABC/
PABA analogue), and benzyl ether (PABA analogue) 1e, whose
syntheses via cinnamyl bromides 6, 9, 13, activated ester 15, and
benzyl bromide 16, respectively, are described in section S2 and
Scheme S1.
The instability of the carbonate in 1d, compared to the
cinnamyl ether spacers of 1a−1c under aq conditions (PBS and
4.5:4.5:1 mouse serum/PBS/DMSO) was confirmed in our
initial stability studies (Figure 2 and sections S3.1 and S3.3). In
Figure 1. Structures of phenolic pro-probes 1a−1e and prodrugs 2a and
2c used in this study.
majority of phenols encountered in the chemist’s toolbox.9 The
cinnamyl ether spacers were designed such that they would
undergo a 1,8-self-immolation (Scheme 1b) (cf. a 1,6-self-
immolation; Scheme 1a). Previous reports by de Groot and co-
workers utilizing an elongated self-immolative spacer10 demon-
strated that the increased conjugation resulted in an immolation
that was expected to be faster than a PABC-type 1,6-self-
immolation. In these examples, they described a p-amino-
cinnamyloxycarbonyl paclitaxel prodrug (linked via a carbonate
ester).10 However, for phenols, this is expected to be hydrolyti-
cally unstable. We hypothesized that by replacing the carbonate
ester with an ether, the majority of phenols (pKa 7−10.5) would
form physiologically stable cinnamyl ether-linked conjugates
capable of a controlled and rapid 1,8-self-immolation under
varying solvent polarities (Scheme 1b). We hypothesized that
spacers functionalized with α- and γ-methyl groups (relative to
the cinnamyl ether aromatic ring) would further stabilize the
partial positive (δ+) charge of the transition state11 and therefore
lead to accelerated rates of release over less conjugated PABC/
PABA-type linkers and non-methylated cinnamyl ethers
(Scheme 1 and Figure 1). Herein, we demonstrate that the
cinnamyl ether spacer is a physiologically stable caging group
with varying rates of decaging that can be programmed by the
absence, presence, and location of a methyl group. In 1:1 aq−
organic solvent, the rate of the self-immolation for the γ-methyl
spacer is similar to that of the PABC spacer and the methoxy-
substituted benzyl ether spacer.4 The α-methyl-substituted linker
resulted in a slower rate of release. These rate-differing spacers
could have potential in chemotherapy, imaging, degradable
polymers, and synthesis.12
Figure 2. Release of 3 measured by fluorescence (ex. 360 nm, em. 455
nm), demonstrating the stability of 1a−1d in (a) PBS and (b) 4.5:4.5:1
serum/PBS/DMSO (sections S3.1 and S3.3).
1:1 mouse serum/PBS (with 10% DMSO), cinnamyl ethers 1a−
1c did not release 3 over 24 h, whereas complete release of 3 from
carbonate 1d was observed in just 2 min. HPLC analysis
confirmed that the spacers 1a−1c remained intact and that there
were no other degradation processes occurring (Table S1 and
Figure S3).
The quantity of 3 released and its rate of release from 1a−1e
were then investigated using fluorescence (aq; PBS) and HPLC-
UV (aq−organic solvent; 1:1 PBS/MeCN) (Figure 3 and section
Figure 3. Release of 7-hydroxycoumarin 3 from pro-probes 1a−1e
following a reductive trigger measured by (a) fluorescence (PBS-only,
10 μM concn of 1a−1e, pH ∼6) and (b) HPLC-UV (1:1 PBS/MeCN,
50 μM concn of 1a−1e, pH ∼5). Results are an average of triplicate
experiments (section S4).
In this study, 7-hydroxycoumarin 3 (pKa 7.8)13 and etoposide
4 (pKa 9.8)14 were selected as model phenols; 3 has a pKa
representative of other fluorescent/bioluminescent probes, and 4
has a pKa representative of most phenols (pKa 10) encountered
in a chemist’s toolbox.9 The nitro group was selected as the
trigger so that release could be initiated via complete reduction to
the amine with zinc/acetic acid;10a,15 however, the trigger could
be modified to suit the desired stimulus for future applications.
Due to the importance of caging strategies in imaging (e.g.,
fluorescence, near-IR, bioluminescence), we focused our initial
efforts on the stability and rate of release of 3 from the cinnamyl
S4). Reduction of the nitro trigger was initiated with zinc in
MeCN/acetic acid,15 releasing 3 via the relevant 1,8- or 1,6-self-
immolation (Scheme 1 and section S4). Previous reports for the
release of a fluorescent probe from a carbonate linker (triggered
by reduced pH) had a reported half-life (t1/2) of 16 s.16 In our
hands, reduction of the nitro group on 1d and dilution into PBS
supported these data (Figure 3a), with complete release of 3
occurring in <30 s (time for diluting in PBS and measurement of
fluorescence = 30 s). The release kinetics for the 1,8-self-
immolation of 3 from the cinnamyl ethers 1a−1c demonstrated
that the presence and location of a methyl group on the cinnamyl
B
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spacer in the α- or γ-position resulted in significantly different
release kinetics (Figure 3). Non-methylated 1a undergoes a
relatively fast 1,8-self-immolation of 3 (50% release = 3.5 min),
whereas the α-methyl analogue 1b has a substantially slower
release of 3 (50% release = 27 min) and the γ-methyl analogue 1c
is extremely fast in releasing 3 (50% release < 30 s) (Figure 3a).
Benzyl ether 1e demonstrated kinetics (50% release = 60 s) faster
than that of non-methyl analogue 1a but kinetics slower than that
of γ-methyl analogue 1c. However, based on a previous report,4
under more organic-type conditions and with higher pKa
phenols, the rate of benzyl ether release would be expected to
slow down, and this was the case for our benzyl ether 1e (see
below). Notably, even with complete reduction of 1a−1c and 1e
under the reaction conditions (confirmed by HPLC; see
Schemes S10−S13), cinnamyl ethers 1a−1c deviated from the
expected pseudo-first-order kinetics after the initial release
period (i.e., <100% release observed at plateau). Ether 1a showed
a maximum release of ∼87%, and the methylated 1b and 1c
plateaued at ∼50−60% release of 3. Interestingly, when
activation of 1a−1c was performed in 1:1 aq−organic solvent
(1:1 PBS/MeCN) and analyzed by HPLC-UV, release of 3 was
significantly higher (∼91% for 1a and 1c) (Figure 3b).
The stability of 1a−1c/1e and the rate of self-immolation in
1:1 aq−organic solvent were investigated (Figure 3b) to gauge
the applicability of our spacers to other applications in materials
science (e.g., triggered polymer degradation). Cinnamyl ether 1b
showed significantly slower release kinetics in a 1:1 mixture of
aq−organic solvent (Figure 3b, ∼66% release after 100 min);
however, 1a and 1c maintained rapid 1,8-self-immolation of 3.
For 1a and 1c, 66 and 77% release of 3 was confirmed in <2 min;
the preparation time for the HPLC experiment (see section S4)
includes dilution, mixing, and injection time. These rates
compare favorably with those of the methoxy benzyl ethers
reported by Phillips and co-workers.4 In PBS-only (Figure 3a),
1e demonstrated a faster release profile than the non-methyl
analogue 1a and a slower release than the γ-methyl analogue 1c
(see above). However, in 1:1 aq−organic solvent (Figure 3b),
1,6-self-immolation of 1e was significantly slower than the
cinnamyl ether analogues 1a and 1c. At 2 min, 1e had only
released 11% of 3 (66 and 77% for 1a and 1c). At 20 min, ∼65%
of 3 had been released (77 and 84% for 1a and 1c). Comparison
of the HPLC trace of 1a/1c to 1e (Figures S10 and S12 cf. S13)
provided further evidence for the superior release rate of 3 from
1a/1c. After 20 and 2 min, the 1,8-self-immolation of the reduced
intermediate (tR(1a) = 6.3 min, tR(1c) = 7.3 min) was almost
complete for 1a and 1c, respectively, and 1,6-self-immolation was
incomplete (at 20 min) for the reduced intermediate of 1e (tR =
5.2 min).
Scheme 2. Proposed Mechanism for Nucleophilic Attack of 3
on the Stabilized Methide Generated from 1c in (a)
Fluorescence and (b) HPLC-UV Experiments
fluorescence versus HPLC-UV assay. Under purely aq conditions
(fluorescence exp.), 0.05% acetic acid (AcOH) was present and
the solution had pH ∼6. In 1:1 aq−organic solvent (HPLC-UV
exp.), 0.25% AcOH was present and the solution was more acidic
(pH ∼5). The 5-fold increase in AcOH was a result of dilution
into the PBS-organic solution, which required a higher
concentration of 1a−1c and 1e (50 μM), so that aliquots
containing 2.5 nmol of analyte could be injected and quantified
by HPLC-UV (section S4.2). However, the increased acidity
results in the phenolic substituent on 3 (pKa 7.8) being
protonated to a greater extent in the PBS organic solvent assay
(Scheme 2b). This prevents, or at least slows down, the
nucleophilic attack of 3 on the methyl-stabilized spacers of 1b
and 1c, supporting the greater extent of release observed in the
PBS-organic (∼71% for 1b (at 240 min) and ∼91% for 1c)
versus PBS-only assay (∼62% for 1b and ∼69% for 1c).
The proposed mechanism in Scheme 2 suggests the methide
could have use in the design of prodrugs where additional
cytotoxicity is required, similar to the PABA-methide approach
reported by others.17 The increased methide stability is expected
to result in a greater residence time (compared to other aza- and
quinone methides),18 enabling it to react with stronger but less
abundant cellular nucleophiles (e.g., DNA, lysine, gluta-
thione).17,19
In regards to the release of 3 from α-methyl cinnamyl ether 1b
(Figure 3), we hypothesized that the slower rate of self-
immolation [50% at 27 min (PBS-only) and 54 min (1:1 aq−
organic)] was the result of steric clash of the methyl group with
the adjacent hydrogen atoms of the aryl ring. This would result in
distortion of the alkene, deviating from the 180° dihedral angle
required for π-orbital overlap and hindering the 1,8-self-
immolation. Examination of X-ray diffraction structures for α-
methyl-substituted cinnamyl analogues in the Cambridge
structural database confirmed disruption in planarity of the π-
conjugated system (section S5).20
Incomplete release for the cinnamyl ethers 1a−1c in PBS
(Figure 3a) and PBS-organic solution (Figure 3b) suggests that,
upon 1,8-self-immolation, the electrophilic methide is sufficiently
stabilized via resonance (for 1a−1c) and hyperconjugation (for
1b and 1c), enabling a reversible addition with the nucleophilic
phenolate of 3 (Scheme 2). As an alternate hypothesis,
quenching of fluorescence via noncovalent interactions could
occur in the PBS-only studies. However, the relatively low
concentration of 3 generated (≤10 μM) and the fact that the
observed release of 3 is only lower (<100%) for the cinnamyl
ethers 1a−1c (cf. 1d,e) suggest that the aza-cinnamyl methide is
significantly more stable than PABC-type methides (from 1d,e)
which react with the most abundant (and weaker) nucleophile,
that is, the surrounding water molecules. Further support for our
argument is the difference in nucleophilicity of 3 in the
Finally, we investigated the release of a model phenolic drug,
etoposide 4 (pKa 9.8),14 from two of our cinnamyl ethers.
Etoposide is a potent, clinically used topoisomerase inhibitor,
and prodrugs masking the phenol have been reported to reduce
cytotoxicity of the parent drug;2b,21 hence, two analogues, 2a and
2c, were synthesized via the intermediate cinnamyl bromides 6
and 13, respectively (Scheme S2). The high stability of 2a and 2c
in 1:1 mouse serum/PBS (with 10% DMSO) was demonstrated
over 48 h (section S3.2 and Table S2), and the decaging rate of 4
from 2a and 2c was measured by HPLC in a 1:1 aq−organic
solvent (section S4.2 and Figure S7). Release of 4 from 2c was
rapid (t1/2 < 2 min), with 76% measured at 2 min. The decaging
rate from 2a was slower than that from 2c (45% after 42 min),
C
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(4) Schmid, K. M.; Jensen, L.; Phillips, S. T. J. Org. Chem. 2012, 77,
4363−4374.
demonstrating that the γ-methyl spacer promotes rapid release of
higher pKa phenols (≥9.8) in aq−organic conditions.
(5) Peterson, G. I.; Larsen, M. B.; Boydston, A. J. Macromolecules 2012,
45, 7317−7328.
In summary, we have developed cinnamyl ether spacers that
are effective at caging phenols of high to moderate acidity (pKa
7.8−9.8), making them broadly applicable to the majority of
phenols (pKa 7−10.5). The spacers are stable and, following a
trigger, undergo a self-immolative release of the parent phenol.
The strategic placement of a methyl group results in different
rates of phenol release. The γ-methyl group helps stabilize the δ+
charge of the transition state, resulting in extremely fast (almost
spontaneous) decaging of phenols, a highly desirable property of
prodrugs, pro-probes, and degradable polymers. When a methyl
group is situated on the α-carbon of the alkene, the rate of
decaging is significantly slower. The cinnamyl ether spacers could
have applications in the fields of organic and medicinal chemistry,
drug delivery, or materials science where rapid or sustained
decaging is required. Due to the increased stability of the methide
in 1c, which we demonstrated in our release experiments,
investigations are underway to see if the spacer could be used as a
cytotoxic agent, capable of inhibiting cellular nucleophiles.17
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03695.
(15) Warnecke, A.; Kratz, F. J. Org. Chem. 2008, 73, 1546−1552.
(16) Muller, I. A.; Kratz, F.; Jung, M.; Warnecke, A. Tetrahedron Lett.
̈
Full experimental details; NMR spectra of 1a−1e, 2a, 2c,
13, sections S1−S8, Figures S1−S17, Tables S1−S3
(PDF)
2010, 51, 4371−4374.
(17) (a) Weinert, E. E.; Dondi, R.; Colloredo-Melz, S.; Frankenfield, K.
N.; Mitchell, C. H.; Freccero, M.; Rokita, S. E. J. Am. Chem. Soc. 2006,
128, 11940−11947. (b) Weinstain, R.; Baran, P. S.; Shabat, D.
Bioconjugate Chem. 2009, 20, 1783−1791.
2D NMR spectra of 1c and 2c (PDF)
(18) Gnaim, S.; Shabat, D. Acc. Chem. Res. 2014, 47, 2970−2984.
(19) Modica, E.; Zanaletti, R.; Freccero, M.; Mella, M. J. Org. Chem.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: allan.gamble@otago.ac.nz.
ORCID
(20) (a) Bullock, R. M.; Rappoli, B. J.; Samsel, E. G.; Rheingold, A. L. J.
Chem. Soc., Chem. Commun. 1989, 261−263. (b) Bombieri, G.; Artali, R.;
Barlocco, D.; Meneghetti, F. Heterocycles 2002, 57, 439. (c) Shi, W. J.;
Liu, Y.; Butti, P.; Togni, A. Adv. Synth. Catal. 2007, 349, 1619−1623.
(d) Koch, M. H. J.; Evrard, G. Acta Crystallogr., Sect. B: Struct. Crystallogr.
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Allan B. Gamble: 0000-0001-5440-8771
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
̀
(21) (a) van Maanen, J. M. S.; Retel, J.; de Vries, J.; Pinedo, H. M. J.
This research was supported by a contract from the Health
Research Council of New Zealand. We also thank Dr. Pummy
Krittaphol from the University of Otago for HPLC advice.
Natl. Cancer Inst. 1988, 80, 1526−1533. (b) Senter, P. D.; Saulnier, M.
G.; Schreiber, G. J.; Hirschberg, D. L.; Brown, J. P.; Hellstrom, I.;
Hellstrom, K. E. Proc. Natl. Acad. Sci. U. S. A. 1988, 85, 4842−4846.
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