PHP-Tethered N-Acyl Carbamate: A Photocage for Nicotinamide

Article abstract of DOI:10.1021/acs.orglett.8b00697

The synthesis of a new photocaged nicotinamide having an N-acyl carbamate linker and a p-hydroxyphenacyl (pHP) chromophore is described. The photophysical and photochemical studies showed an absorption maximum at λ = 330 nm and a quantum yield for release of 11% that are dependent upon both pH and solvent. While the acyl carbamate releases nicotinamide efficiently, a simpler amide linker was inert to photocleavage. This photocaged nicotinamide has significant advantages with respect to quantum yield, absorbance wavelength, rate of release, and solubility that make it the first practical example of a photocaged amide.

Full text of DOI:10.1021/acs.orglett.8b00697

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pHP-Tethered N‑Acyl Carbamate: A Photocage for Nicotinamide
Farbod Salahi,† Vatsal Purohit,§ Guillermo Ferraudi,‡ Cynthia Stauffacher,§ Olaf Wiest,*,†,∥
and Paul Helquist*,†
†Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
‡Notre Dame Radiation Research Laboratory, Notre Dame, Indiana 46556, United States
§Department of Biological Sciences, Purdue University, 915 West State Street, West Lafayette, Indiana 47907, United States
∥Laboratory of Computational Chemistry and Drug Design, School of Chemical Biology and Biotechnology, Peking University,
Shenzhen Graduate School, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: The synthesis of a new photocaged nicotinamide
having an N-acyl carbamate linker and a p-hydroxyphenacyl (pHP)
chromophore is described. The photophysical and photochemical
studies showed an absorption maximum at λ = 330 nm and a
quantum yield for release of 11% that are dependent upon both pH
and solvent. While the acyl carbamate releases nicotinamide
efficiently, a simpler amide linker was inert to photocleavage. This
photocaged nicotinamide has significant advantages with respect to
quantum yield, absorbance wavelength, rate of release, and solubility
that make it the first practical example of a photocaged amide.
he nicotinamide moiety of NAD+ (Figure 1), the most
abundant cofactor in eukaryotic cells, is responsible for
and elucidation of their mechanisms in microsecond to
nanosecond time scales. One tool that can be employed for
this purpose is a photoremovable chromophore, which while
chemically bound to NAD+ can block its normal activity.2 Such
chromophores, known as photocaging groups, can be cleaved
from the cofactor upon light irradiation to effect release of
NAD+ and initiation of a reaction at a precisely controlled time
and location. This type of spatiotemporal control is a powerful
means to manipulate enzymes and release of a range of
bioactive molecules, such as neurotransmitters and cell-
signaling molecules.3−5 Although there are many examples of
photocaged phosphates or carboxylic acids,3,4 the photocaging
of poor leaving groups such as amides or amines is still a topic
of intense research.5e
T
Photocaging groups must have certain properties to be useful
in cellular studies.4c They should have a large molar extinction
coefficient above 300 nm to avoid absorption interference by
aromatic amino acids. Photocaged molecules should efficiently
undergo primary photocleavage with a quantum yield of at least
10% and be stable and soluble under physiological conditions.
The released caging group should be inert and not absorb at a
wavelength that interferes with the cleavage process. Finally, its
synthesis should be amenable to modifications for improve-
ment of these properties and caging of a variety of functional
groups.
Figure 1. Photocaged nicotinamides.
oxidoreduction chemistry in many enzymes. NAD(P)/NAD-
(P)H-dependent enzymes, such as sirtuins, CD38, or HMG-
CoA reductase, are involved in many redox pathways in living
cells. Understanding the mechanisms of these enzymes, the
malfunctions of which cause various diseases, is an important
goal in enzymology and could enable the design and
development of more efficient drugs for these important
pathways.1
One approach that provides control over both the time and
location of initiation of a reaction is the interruption of the
binding of this coenzyme in a reactive position. Activation by
an external trigger enables the study of the associated enzymes
The synthesis of a NAD+ derivative having the nicotinamide
moiety photocaged with an o-nitrobenzyl group was previously
reported by Salerno for use in time-resolved mechanistic
Received: March 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00697
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
studies of NAD+-dependent enzymes2b,6 and was employed by
Koshland in a study of isocitrate dehydrogenase.2a The main
drawbacks of this type of caging group are poor solubility,
absorption at an undesirably low wavelength of 260 nm, a slow
rate and low yield of photorelease, and the formation of a
reactive byproduct, o-nitrosobenzaldehyde.
(37%), but the best result was obtained using the Staudinger
reduction with PPh3 and p-TsOH, yielding 3 in 65% over two
steps. Subsequent amide bond formation by reaction of 3 with
nicotinoyl chloride failed when using triethylamine (TEA) as
base and DMF as solvent. Changing the solvent to a mixture of
DCM and pyridine gave the desired amide 1e in 50% yield.
We synthesized the corresponding N-acyl carbamate-linked
pHP derivative 1f to compare the efficiency of releasing the two
differently caged nicotinamides. Compound 1f was prepared in
five steps, starting with p-hydroxyacetophenone, which was first
protected as the TBDPS ether. Different methods for the
bromination to obtain α-bromo pHP 4 were explored,
including use of CuBr2,11 bromine,12 benzyltrimethylammo-
nium tribromide13 (BTMABr3), and DDB.9 While bromine
gave a low yield of monobrominated product (30%), the use of
CuBr2 improved the yield (58%) but gave a mixture of mono-
and dibrominated products. Changing to BTMABr3 decreased
the amount of dibrominated compound and increased the yield
of the monobrominated product (78%). The highest yield of 4
was obtained by applying DDB. For conversion of bromide 4 to
α-hydroxy ketone 5, different reagents such as sodium
formate14a and cesium formate14b were tested, but the yields
were not satisfactory. Utilizing trimethyl glycine14c in refluxing
ethanol afforded 5 in 60% yield. The multicomponent
carbonylative cross coupling of 5 with 3-bromopyridine and
an isocyanate salt to install the acyl carbamate linker15 yielded
only the recovered starting material. Thus, we chose to generate
nicotinoyl acyl isocyanate in situ by addition of oxalyl chloride16
to a solution of nicotinamide in 1,2-dichloroethane (DCE) and
trapping with 5 to form the desired N-acyl carbamate. Removal
of the TBDPS protecting group with TBAF afforded the
desired 1f in 60% yield over two steps.
Recently, our group reported the synthesis of caged
nicotinamides 1a−d (Figure 1) tethered to a coumarin
chromophore. The numerical values in the colored, horizontal
arrow show quantum yields (Φdis) over the range of
photocaged nicotinamides studied in the previous and current
work. The amides 1a,b did not undergo uncaging upon
irradiation (Φdis = 0). Redesign of the amide moiety to a
carbamate linkage based on an orbital analysis led to
photocages with low yields of cleavage.7 While coumarin
chromophores 1c,d have absorption wavelengths above 300 nm
and are thus an improvement over the o-nitrobenzyl group,
their main drawbacks were slow release, low quantum yields of
1−2% for photocleavage, and poor solubility in aqueous media.
These results indicate the need for new nicotinamide caging
groups that undergo faster release with better photolytic
efficiency and solubility. To address these problems, we
designed a new photocaged nicotinamide based on an N-acyl
carbamate-tethered p-hydroxyphenacyl (pHP) group. The pHP
chromophore has been employed for caging of carboxylate,
phosphate, alcohol, and ammonium leaving groups.8
The syntheses of pHP nicotinamide derivatives with either an
amide (1e) or an N-acyl carbamate linker (1f) are shown in
Scheme 1. The synthesis of the amide-linked pHP starts with
Scheme 1. Synthesis of Caged Nicotinamides
Because the same pHP chromophore is in both 1e and 1f,
the compounds should have similar photophysical character-
istics. Compound 1f was selected to study solvent and pH
dependence of the photophysical properties (Figure 2). An
Figure 2. UV−vis spectra of caged nicotinamide 1f at different pH
values.
absorption maximum with λmax = 273 nm was determined for
the neutral form of 1f in acetonitrile. A large red shift to 330
nm was observed as the pH was increased to 7.9 and above,
which is attributed to deprotonated pHP. The pKa of 1f was
determined to be 7.9 by pH screening (see Supporting
Information, SI). It was also observed that 1f is stable in wet
acetonitrile at ambient temperature in the dark over 24 h,
bromination of commercially available p-hydroxyacetophenone
with a dioxane dibromide complex9 (DDB) to give α-bromo-
pHP 2. α-Amino-pHP 3 was obtained by nucleophilic
substitution of 2 with sodium azide,10 followed by reduction
of the resulting azide to the amine. This conversion was
attempted with hydrogen and Pd/C (54%) and with SnCl2
B
DOI: 10.1021/acs.orglett.8b00697
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Organic Letters
Letter
demonstrating the stability toward hydrolysis, which is an
important property for biological studies.
Scheme 2. Proposed Mechanism for Uncaging Nicotinamide
Next, the photochemistry of the pHP nicotinamides was
investigated. Previous studies showed that caged nicotinamides
1a−1d, linked to a coumarin by an amide or an N-acyl
carbamate linker, do not undergo efficient photorelease of
nicotinamide, as shown by low quantum yields in the 1% range
for the acyl carbamates and no detectable cleavage of the
amides (Table 1, entries 1−4). The first attempt at photo-
Table 1. Comparative Studies of Caged Nicotinamide
entry
compound
λmax(nm)
pH
ε (M−1 cm−1
)
Φdis
1
2
3
4
5
1a8
1b8
1c8
1d8
1f
370
380
330
379
330
8.1
7
22731
24375
11442
14027
11730
-
intermediate B. Finally, nucleophilic attack of water on B leads
to formation of arylacetic acid.
-
7
1%
1.6%
1%
In conclusion, we have developed a new photoremovable
protecting group for caging an amide functionality by
combining the p-hydroxyphenacyl chromophore with an acyl
carbamate linker. It undergoes cleavage with a quantum yield of
11% upon irradiation at 300 nm and neutral pH in an aqueous
medium. These conditions are favorable for studies of
biological systems. This set of properties provides major
improvements over previously reported caging of nicotinamide
by coumarin and nitrobenzyl groups. The new photocage has a
number of potential applications, including time-resolved
studies of NAD(P)-dependent enzymes. The combination of
an acyl carbamate linker with the pHP chromophore may be
applicable for photocaging other amide moieties present in
other important cofactors such as vitamin B12, biotin, and
coenzyme A.
7
8.5
cleavage of the new acyl carbamate-tethered pHP derivative 1f
at 330 nm in a mixture of phosphate buffer and acetonitrile at
pH 8.5 also showed a low quantum yield (entry 5). This result
can be attributed to the lower reactivity of the conjugate base of
the phenolic group of the pHP chromophore in comparison
with its neutral form.17
Therefore, the need to study solvent and pH effects became
apparent (Table 2). Changing the solvent to a nonaqueous,
Table 2. pH and Solvent Studies of the Photochemical
Reaction of 1e and 1f
c
d
e
f
entry
compound
solvent
λ(nm)
λirr(nm)
pH
Φdis
ASSOCIATED CONTENT
* Supporting Information
a
■
1
2
3
4
1f
1f
1f
1e
CH3CN
CH3CN
330
273
273
273
330
300
300
300
8.5
7
1%
-
S
b
b
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00697.
CH3CNaq
CH3CNaq
7
11%
-
7
a
b
CH3CN 20% 50 mM phosphate buffer, pH: 8.5. 20% water in
CH3CN. Other organic cosolvents, such as MeOH and DMSO, in
combination with water gave rise to solubility issues. Maximum
wavelength. Wavelength of radiation. Quantum yield of cleavage
c
Experimental procedures include 1H and 13C spectra and
characterization data of all compounds (PDF)
d
e
f
AUTHOR INFORMATION
Corresponding Authors
■
organic medium completely inhibits the photochemical path-
way, even at pH 7 with the pHP group in its neutral form
(entry 2). This result suggests that water plays a crucial role in
the release of nicotinamide. The use of an organic solvent/
water mixture at pH 7 provided an increase of the quantum
yield to a useful value of 11% (entry 3). To the best of our
knowledge, this is the highest quantum yield that has been
reported for releasing such an amide, and consequently the first
time that a practical method for photocaging of an amide has
been achieved. Consistent with our earlier results,7 photo-
cleavage of the amide-linked 1e, which was used as a control
experiment, did not occur (entry 4) under the most favorable
conditions for 1f.
*E-mail: owiest@nd.edu.
*E-mail: phelquis@nd.edu.
ORCID
Olaf Wiest: 0000-0001-9316-7720
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to acknowledge support of this research by the
National Institutes of Health (1R01GM111645), valuable
discussions with Professor R. S. Givens (University of Kansas),
and technical assistance by Dr. Douglas Miller and Dr. William
Boggess (Notre Dame).
A possible mechanism14a,18 for photocleavage of the acyl
carbamate-linked pHP nicotinamide 1f is shown in Scheme 2.
1
Absorption of light by 1f leads to a singlet excited state, [1f],
which undergoes an intersystem crossing to the triplet state
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