Novel valdecoxib derivatives by ruthenium?II)-promoted 1, 3-dipolar cycloaddition of nitrile oxides with alkynes - Synthesis and COX-2 inhibition activity

Article abstract of DOI:10.1039/c7md00575j

Novel valdecoxib-based cyclooxygenase-2 inhibitors were synthesized in one step via 1, 3-dipolar cycloaddition of nitrile oxides with a series of eleven aryl alkynes, six of them described for the first time. Application of Ru?II)-catalysis leads preferab

Full text of DOI:10.1039/c7md00575j

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Novel Valdecoxib Derivatives by Ruthenium(II)-Promoted 1,3-Dipolar
Cycloaddition of Nitrile Oxides with Alkynes - Synthesis and COX-2
Inhibition Activity.
Silvia Roscales1,#, Nicole Bechmann1,#, Daniel Holger Weiss2, Martin Köckerling2, Jens
Pietzsch1,3, Torsten Kniess1,*
1HelmholtzꢀZentrum DresdenꢀRossendorf, Institute of Radiopharmaceutical Cancer Research,
Department of Radiopharmaceutical and Chemical Biology, Bautzner Landstraße 400, 01328 Dresden,
Germany
2University of Rostock, Institute of Chemistry, Department of Inorganic Solid State Chemistry, Albert
Einstein Straße 3a, 18059 Rostock, Germany
3Technische Universität Dresden, Department of Chemistry and Food Chemistry, Bergstraße 66,
01062 Dresden, Germany
#present addresses:
S.R., Technological Institute PET, Manuel Bartolomé Cossio St 10, 28040, Madrid, Spain.
N.B., Technische Universität Dresden, University Hospital ‘Carl Gustav Carus’, Institute for Clinical
Chemistry and Laboratory Medicine, Fetscherstraße 74, 01307, Dresden, Germany
Abstract: Novel valdecoxibꢀbased cyclooxygenaseꢀ2 inhibitors were synthesized in one step via 1,3ꢀ
dipolar cycloaddition of nitrile oxides with a series of eleven aryl alkynes, six of them described for
the first time. Application of Ru(II)ꢀcatalysis leads preferably to the formation of the 3,4ꢀdiarylꢀ
substituted isoxazoles, while under thermal heating with base the 3,5ꢀdiaryl substitution pattern is
favoured. The new the 3,4ꢀdiarylꢀsubstituted isoxazoles possessing a small substituent (H and Me)
displayed high COXꢀ2 inhibition affinity (IC50=0.042–0.073 µM) and excellent selectivity (COXꢀ2 SI
> 2000). In contrast, the 3,5ꢀdiaryl substituted compounds displayed almost no COX activity. The
introduction of a 4ꢀfluorophenyl substituent resulted in retained high COXꢀ2 affinity, making these
compounds together with the feasible one step reaction promising candidates for the development of
fluorineꢀ18 labelled radiotracers.
1. Introduction
Nonsteroidal antiꢀinflammatory drugs (NSAIDs) are a widely used class of therapeutic agents for the
treatment of inflammation, fever and pain. The pharmacological effects of NSAIDs result from their
capability to inhibit the enzyme family of cyclooxygenases (COX), which catalyses the
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biotransformation of arachidonic acid to prostanoids, and exists as two distinct isoforms, a constitutive
form (COXꢀ1) and an inducible form (COXꢀ2).1,2 COXꢀ1 derived prostaglandins control homeostatic
functions, including gastric cytoprotection and homeostasis, while COXꢀ2 is responsible for the
synthesis of prostanoids involved in acute and chronic inflammatory states.3 Inflammation is a
common biological process shared by various diseases and elevated expression of COXꢀ2 has been
implicated in manifold pathological events, including rheumatoid arthritis, heart disease, stroke, and
neurodegenerative disorders.4
Recently, it has become more and more obvious that COXꢀ2 is also overexpressed in several human
cancer entities and is assumed to be implicated in tumour inflammogenesis and hypoxia.5 In
consequence, expression of COXꢀ2 has attracted considerable attention as a diagnostic marker and
therapeutic target in oncology.6,7
The therapeutic effect of NSAIDs is attributed to the selective inhibition of COXꢀ2; however,
undesired (e.g., gastrointestinal) side effects may arise from the disruption of COXꢀ1 by application of
nonselective COX inhibitors.8 Due to the structural similarities of the COXꢀ1 and the COXꢀ2 enzymes,
the development of selective COXꢀ2 inhibitors (Coxibs) with no affinity towards COXꢀ1 constitutes a
persistent challenge in medicinal chemistry. In this context, the 3,4ꢀdiaryl substituted isoxazole
scaffold is a frequently recurring pharmacophore found in a variety of NSAIDs/Coxibs,9 protein
kinase inhibitors, and hypertensive agents. Valdecoxib is one of the wellꢀknown examples of 3,4ꢀ
diaryl substituted isoxazoles derivatives commercialized in 2000 for clinical use10; but withdrawn
from the market in 2005 owing to its adverse cardiovascular side effects and skin reactions.11
However, parecoxib12 (Dynastat®), which was designed to be a waterꢀsoluble (> 50 g/L in normal
saline, pKa 4.9), parenterally safe prodrug form of valdecoxib (0.01 mol/L in normal saline, pKa 9.8),
is still in use for the management and treatment of acute pain.
Nevertheless, valdecoxib is a very potent and selective inhibitor of COXꢀ2 (IC50 = 0.005 µmol) with
almost no inhibition of COXꢀ1 (IC50 =150 µmol)13 and represents an interesting lead structure for the
development of potential radiotracers for the functional imaging of COXꢀ2 via positron emission
tomography (PET). In the case of radiotracers the selectivity and affinity of drugs is of major
importance, while pharmacological side effects can mainly be neglected, since only a few nanomoles
of the drug are applied.
With our interest in imaging COXꢀ2 functional expression in vivo, our ongoing efforts are focused on
the development of novel radiolabeled COXꢀ2 inhibitors as radioactive probes for the characterization
of inflammatory and tumorigenic lesions.14 With this background, we aimed at the synthesis of novel
fluorineꢀbearing valdecoxib derivatives having varying substituents (Figure 1). While the substituent
A
represents an hydrogen or fluorine atom, the latter as surrogate for potential fluorineꢀ18 labelling;
the substituent
B
describes a number of functional groups. The sulfonamide or methylsulfonyl group
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C
located in paraꢀposition at one of the phenyl substituents interacts effectively with the COXꢀ2 side
pocket through slow tightꢀbinding kinetics15, and should be generally preserved.
Figure 1 Design concept of novel derivatives with valdecoxib as lead compound
Accordingly, in this paper we describe the one step synthesis of a series of diarylꢀsubstituted
isoxazoles, derivatives of valdecoxib, by 1,3ꢀdipolar cycloaddition of nitrile oxides with a panel of
various substituted phenyl acetylenes. To determine their potential suitability, the COXꢀ1 and COXꢀ2
inhibitory activity of the new compounds was evaluated in vitro.
2. Results and discussion
2.1 Chemistry
Although several literature reports depict the synthesis of substituted isoxazoles, in the case of 3,4ꢀ
diaryl substituted isoxazoles the question of selectivity in general is a crucial problem, whose solution
depends mostly on the availability of the starting materials.16 As displayed in Scheme 1, different
protocols for the synthesis of valdecoxib and analogues have been described. Among them, 1,3ꢀdipolar
cycloaddition of nitrile oxides with olefinic compounds followed by aromatization is often used.17
(Scheme 1A) A different approach starting from ketones, involves the synthesis of enamines. 1,3ꢀ
dipolar cycloaddition of enamine with arylnitrile oxides followed by treatment with HCl affords the
corresponding 3,4ꢀdiaryl substituted isoxazole.18
Secondly and as displayed at Scheme 1B, 1,3ꢀdipolar cycloaddition reaction of nitrile oxides with
alkynylboronates followed by Pdꢀmediated coupling reactions offers a regioꢀcontrolled access to
valdecoxib and analogues by furnishing isoxazole boronates.19,20,21. These readily prepared isoxazole
boronates are useful precursors for the Suzuki coupling reactions using arylhalides in the presence of
palladium catalysts.
In addition, the electrophilic cyclization, followed by crossꢀcoupling reaction, constitutes an interesting
alternative for the synthesis of diarylꢀsubstituted isoxazoles.22,23 (Scheme 1C) The iodine
monochloride promoted electrophilic cyclization of Oꢀmethyl oximes displays an access to 4ꢀ
iodoisoxazoles, which are useful precursors to synthesize 3,4ꢀdiaryl substituted isoxazoles through
Suzuki crossꢀcoupling with the corresponding boronic acid and palladium catalyst.24,25
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At Scheme 1D a concise synthesis of valdecoxib and its derivatives starting from deoxybenzoin
derivatives is shown.26
Scheme 1A-D Recent approaches used to synthesize 3,4ꢀdiaryl substituted isoxazoles
The 1,3ꢀdipolar cycloaddition between benzonitrile oxides and phenylacetylenes is a wellꢀknown
method for direct access to 3,5ꢀdiaryl substituted isoxazoles.17,27,28,29. However, the control of the
regiochemistry to obtain the 3,4ꢀregioisomer is, in this case, a considerable challenge.30
2.1.1 Ruthenium(II) catalysed 1,3-dipolar cycloaddition of nitrile oxides with alkynes
Although the cycloaddition of phenylacetylenes and benzonitrile oxides is the most direct route for
accessing 3,4ꢀdiaryl substituted isoxazoles, this method is rarely used for the synthesis of valdecoxib
derivatives.31 The reasons for this are simple: the nonꢀcatalysed, thermal cycloaddition reactions of
nitrile oxides with alkynes are neither chemoꢀ nor regioselective. Furthermore, examples of reactions
of nitrile oxides with internal alkynes are limited to highly activated alkynes (e.g., acetylene
dicarboxylate and related electronꢀdeficient acetylenes). Nonꢀactivated, electronꢀrich, or sterically
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hindered acetylenes usually do not react.32,33 Copper(I) acetylides have been reported to react
regioselectively with nitrile oxides to generate 3,5ꢀdisubstituted isoxazoles.34,28
An extension of the 1,3ꢀdipolar cycloaddition reaction of nitrile oxides and terminal or internal
alkynes was recently described by Fokin.35 They report on the use of ruthenium(II) complexes instead
of copper(I) for the cycloaddition reaction, leading exclusively to the formation of the corresponding
regiocomplementary 3,4ꢀdiꢀ and 3,4,5ꢀtrisubstituted isoxazoles, respectively. Whilst the natural
regioselectivity of the cycloaddition reaction is delivering isoxazoles with the 3,5ꢀsubstitution pattern,
Ru(II) complexꢀcatalysed 1,3ꢀdipolar cycloaddition would provide a direct route for accessing 3,4ꢀ
diaryl substituted isoxazoles. (Figure 2)
Figure 2 Synthesis of valdecoxib derivatives by Ruꢀcatalysed 1,3ꢀdipolar cycloaddition of nitrile
oxides with alkynes
The proposed mechanism of the Ru catalyst in this cycloaddition reaction is displayed in Scheme 2.35
In the first step the displacement of the cyclooctadiene ligand from the [Cp*RuCl(cod)] catalyst by an
alkyne and nitrile oxide produces the activated complex A, which mediates the oxidative coupling of a
nitrile oxide and alkyne, resulting in ruthenacycle B. The oxidative coupling step controls the regio
selectivity of the whole process. It appears that the new carbon–oxygen bond is formed between the
more electronegative carbon centre of the alkyne and the oxygen atom of the nitrile oxide, which
represents an unexpected mode of activation of nitrile oxides. Normally, their carbon centre is
electrophilic and readily reacts with nucleophiles. Thus, coordination to the ruthenium atom
effectively changes the polarity of the nitrile oxide. Ruthenacycle B undergoes reductive elimination
giving C, and release of the isoxazole product, then completes the catalytic cycle. The observation that
Cp*ꢀbased catalysts are especially catalytically active is consistent with the lability of the spectator
ligands in such ruthenium complexes.36
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Scheme 2 Proposed mechanism of Ru(II)ꢀcatalysed 1,3ꢀdipolar cycloaddition of nitrile oxides with
alkynes 35
To evaluate the scope and limitations of this approach, activated and nonꢀactivated alkynes have been
investigated. For this purpose we first prepared a series of paraꢀsubstituted phenyl acetylenes 1a-k
(Table 1) possessing the SO2R (R = NH2, CH3) pharmacophore for subsequent 1,3ꢀdipolar
cycloaddition reactions with nitrile oxides. The alkynes 1a,b were synthesized from the corresponding
4ꢀtrimethylsilylꢀsubstituted alkynes 1j and 1k respectively, by following literature procedures.37,38
Other alkynes carrying a methylꢀ (1c), trifluoromethylꢀ (1d), chloroꢀ (1e), formylꢀ (1f),
methoxycarbonylꢀ (1g) and acetylꢀsubstituent (1h) are novel; accordingly their synthesis had to be
established. The 4ꢀ(propꢀ1ꢀynꢀ1ꢀyl)benzenesulfonamide 1c was synthesized from 4ꢀ
bromobenzenesulfonamide by reaction with trimethylsilylacetylene and subsequent methylation with
methyl iodide. (Scheme 4) The synthesis of 1ꢀ(methylsulfonyl)ꢀ4ꢀ(3,3,3ꢀtrifluoropropꢀ1ꢀynꢀ1ꢀ
yl)benzene 1d started from 4ꢀmethylthiobenzaldehyde which was chloroꢀtrifluoroꢀpropenylated and
after elimination of HCl transformed into the 4ꢀtrifluoropropꢀ1ꢀynꢀsubstituted methylꢀphenylꢀsulfane.
Subsequent oxidation with oxone® delivered the final methylsulfone 1d in 18 % yield over three
steps. (Scheme 3) 1ꢀ(Chloroethynyl)ꢀ4ꢀ(methylsulfonyl)ꢀbenzene 1e could be obtained in 25 % yield
by reaction of 1ꢀethynylꢀ4ꢀ(methylsulfonyl)benzene 1b with Nꢀchlorosuccinimide in presence of
Ag2CO3 and K2CO3. (Scheme 3) The formylꢀ, methoxycarbonylꢀ, acetylꢀsubstituted alkynes 1f-h were
accessible by Sonogashira coupling of propꢀ2ꢀynꢀ1ꢀol or butꢀ3ꢀynꢀ2ꢀol with 1ꢀbromoꢀ4ꢀ
(methylsulfonyl)benzene followed by oxidation reactions in about 40 % overall yield. (Scheme 4) The
benzoylꢀsubstituted alkyne 1i was formed via a Pdꢀmediated coupling reaction of 1b with benzoyl
chloride. (Scheme 3)
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Scheme 3. Synthesis routes for alkynes 1d, 1e and 1i
Scheme 4. Synthesis routes for alkynes 1c and 1f-h
Since nitrile oxides are generally unstable, with a tendency to dimerization, we decided to synthesize
the corresponding hydroximoyl chlorides 2a and 2b which are storable and can be easily transformed
in situ to the nitrile oxide by treatment with Et3N. The hydroximoyl chlorides 2a and 2b are facile
available by the reaction of the corresponding benzaldoximes with Nꢀchlorosuccinimide.39
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With hydroximoyl chlorides 2a-b and a panel of various paraꢀsubstituted phenyl acetylenes 1a-k in
hand, we performed a ruthenium(II)ꢀcatalysed click reaction to prepare the desired 3,4ꢀdiaryl
substituted isoxazoles 3.
Table 1 Ruthenium(II)ꢀcatalysed 1,3ꢀdipolar cycloaddition of nitrile oxides with alkynes.a
Alkyne
R1
oxime
X
time
3:4 ratiob
yield 3 c
yield 4 c
R2
H
NH2
NH2
CH3
CH3
NH2
CH3
CH3
CH3
F
H
F
H
F
F
F
F
F
F
F
F
F
5 min
5 min
5 min
5 min
24 h
24 h
24 h
1 h
99:1
98:2
98:2
99:1
ꢀ
3a (74%)
3b (74%)
3c (65%)
3d (64%)
3e (0)#
4a (0)
4b (0)
1a
1a
1b
1b
1c
1d
1e
1f
2a
2b
2a
2b
2a
2a
2a
2a
2a
2a
2a
2a
2a
H
H
4c (0)
H
4d (0)
CH3
CF3
Cl
4e (0)#
4f (52%)
4g (0)#
4h (0)
40:60
ꢀ
3f (29%)
3g (0)#
CHO
9:1
3h (57%)
3i (59%)
3j (63%)
3k (58%)
3l (0)#
CO2Me CH3
COMe CH3
COPh CH3
1 h
94:6
85:15
65:35
ꢀ
4i (0)
1g
1h
1i
24 h
18 h
24 h
24 h
4j (0)
4k (27%)
4l (0)#
4m (0)#
TMS
TMS
NH2
CH3
1j
ꢀ
3m (0)#
1k
a) Reaction conditions: alkyne (1.0 mmol), hydroximoyl chloride (1.6 mmol), Et3N (1.6 mmol), [Cp*RuCl(cod)]
1
(15% mol) in 1.2ꢀDCE at room temperature. b) Determined by HPLC and HꢀNMR analysis. c) Isolated yield
after purification by flash chromatography and recrystallization from ethyl ether. #) No reaction under Ruꢀ
catalysis, thermal activation required.
In a first set of reactions, we employed the Ru(II)ꢀcatalysed 1,3ꢀdipolar cycloaddition reaction between
hydroximoyl chlorides 2 and various phenyl acetylenes 1 to prepare regioselective isoxazoles 3
possessing a 3,4ꢀdiaryl substitution pattern. In accordance with the literature, we chosen
[Cp*RuCl(cod)] as the most suitable ruthenium(II) complex for this reaction. Briefly, alkynes 1 were
combined with hydroximoyl chlorides 2 (1.6 eq.) in the presence of 15 mol% of [Cp*RuCl(cod)] and
1.6 equivalents of Et3N and stirred at room temperature for the period of time indicated in Table 1.
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1
Terminal alkynes 1a and 1b reacted fast and HPLC and HꢀNMR analysis showed that the 3,4ꢀ
disubstituted isoxazoles 3a-d were the major regioisomers formed. The 3,4ꢀsubstitution pattern was
1
confirmed by the characteristic downꢀfieldꢀshifted H NMR signals (9.37ꢀ9.43 ppm) as typically
observed for the 3,4ꢀdisubstitued isoxazoles. (see Figure S61 Supporting Info)
The electronꢀdeficient alkynes (1d, 1f-1i) were effective cycloaddition partners as well, forming under
Ru(II) catalysis mixtures of 3,4ꢀdiaryl and 3,5ꢀdiaryl substituted isoxazoles; whereby the 3,4ꢀ
regioisomers were mostly the major product (Table1). It should be noted that significant longer
reaction times (1h – 24h) were needed to perform the cycloaddition. The methylꢀ, chloroꢀ and
trimethylsilylꢀsubstituted alkynes 1c, 1e, 1j-k did not react at r.t. and Ru(II) catalyses and required
thermal induced reaction conditions to perform 1,3ꢀdipolar cycloaddition (see 2.1.2 and Table 2).
2.1.2 Thermal induced 1,3-dipolar cycloaddition of nitrile oxides with alkynes
As described before, the Ru(II)ꢀcatalysed 1,3ꢀdipolar cycloaddition reaction failed, with nonꢀactivated
alkynes having a methyl (1c), or a chlorine substituent (1e), and also with the sterically hindered
acetylenes bearing a TMS group 1j and 1k. With these alkynes, we applied classic thermal conditions
(heating in the presence of a base) to synthesize the desired isoxazoles (Table 2). These reactions were
not regioselective and in most cases a 20:80 ratio of the 3,4ꢀdiarylated to the 3,5ꢀdiarylated isomers
was observed, indicating the favoured 3,5ꢀsubstitution pattern under thermal conditions. Additionally,
the thermal reaction conditions in the absence of the ruthenium(II) catalyst were performed for alkynes
1d, 1f and 1i, and we observed no 3,4ꢀregioisomers but exclusively the formation of the 3,5ꢀdiaryl
substituted isoxazoles 4f, 4h and 4k, respectively. Unlike the Ru(II)ꢀpromoted reaction, thermal
cycloadditions required drastic reaction conditions in an aprotic solvent at elevated temperature for
several hours, and the desired 3,4ꢀdiarylated isoxazoles 3e, 3g and 3l-o were obtained in significantly
lower chemical yields (4ꢀ11%) compared to compounds synthesized under ruthenium catalysis (29ꢀ
74%).
Table 2 Thermal induced 1,3ꢀdipolar cycloaddition of nitrile oxides with alkynes.
alkyne
oxim
e
2a
X
F
reaction
conditions
KF, 1,2ꢀDME
time
18 h
3:4
yield 3b
3e (4%)
yield 4b
4e (8%)
R1
R2
ratioa
37:63
CH3
NH2
1c
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CF3
Cl
CH3
CH3
CH3
Et3N, toluene
Et3N, toluene
18 h
18 h
ꢀ
3f (0)
4f (62%)
4g (37%)
1d
1e
2a
2a
F
18:82
3g (8%)
F
F
CHO
Et3N, toluene
Et3N, toluene
KF, 1,2ꢀDME
KF, 1,2ꢀDME
KF, 1,2ꢀDME
KF, 1,2ꢀDME
5 h
ꢀ
3h (0)
3k (0)
4h (45%)
4k (85%)
4l (59%)
4m (66%)
4n (65%)
4o (70%)
1f
1i
2a
2a
2a
2a
2b
2b
COPh CH3
F
18 h
18 h
18 h
18 h
18 h
ꢀ
TMS
TMS
TMS
TMS
NH2
CH3
NH2
CH3
F
17:83
22:78
16:84
11:89
3l (11%)
3m (7%)
3n (5%)
3o (4%)
1j
1k
1j
1k
F
H
H
a) Determined by HPLC and 1HꢀNMR analysis. b) Isolated yield after purification by flash chromatography and
recrystallization form ethyl ether.
The identity of the 3,4ꢀ and 3,5ꢀdiaryl substituted regioisomers 3f, 3h-k and 4f, 4h-k was established
by NMRꢀbased analyses as exemplified for 3f and 4f (see Figure S62 Supporting Info). The signal of
the trifluoromethyl group in the 13C NMR spectrum, identified as a quartet is much more downꢀfieldꢀ
shifted in the 3,4ꢀdiarylꢀsubstituted isoxazole 3f than in 4f.
The determination of the regiochemistry of the cycloaddition by 1HꢀNMR analysis was difficult in the
case of the diarylꢀtrimethylsilylꢀsubstituted isoxazoles 3l-3o, and 4l–4o, therefore the purified
trisubstituted compounds 4l-o were subjected to protodesilylation to obtain the corresponding
disubstituted isoxazoles 4a-d having a proton instead of the trimethylsilyl group (Scheme 5).
1
Protodesilytation was performed with CsF in good yield (74ꢀ90%). HꢀNMR analysis showed a
characteristic signal between 7.77 ppm and 7.86 ppm, which is indicative for the proton in isoxazole
rings containing a 3,5ꢀsubstitution pattern, as visible for 4a (Supporting Info). The minor 3,4ꢀdiarylꢀ5ꢀ
trimethylsilyl substituted regioisomer 3l was subjected to the same reaction conditions and afforded
exclusively the compound 3a.
Scheme 5 Protodesilylation of isoxazoles 4l-o and 3l.
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Further evidence confirming the supposed 3,4ꢀsubstitution pattern was possible in case of the trimethyl
silyl substituted compounds 3l and 3m for which crystals suitable for xꢀray structural analysis could be
obtained. Figure 3 displays the molecular structures as obtained by Xꢀray diffraction analysis of 3l and
3m that undoubtedly confirmed the composition of both compounds. Both crystallize in the triclinic
ꢀ
space group P1, 3l: a = 9.705(6) Å, b = 9.854(6) Å, c = 11.726(8) Å , α = 65.43(3)°, β = 68.51(3)°, γ
= 76.92(2)°, V = 945(1) Å3, Z = 2, R1 = 4.87 %; 3m: a = 7.6192(5) Å, b = 10.3601(7) Å, c =
13.1271(9) Å, α = 102.578(4)°, β = 92.847(4)°, γ = 101.855(4)°, V = 984.9(1) Å3, Z = 2, R1 = 5.77 %;
For more details of the Xꢀray structure analysis see Supporting Information. Even though the two
molecules have a very similar structure, their packing in the crystal is different with respect to the
orientation to each other. All bond lengths within the molecules fall within those ranges which are
expected for the respective bonds. Intermolecular contacts are dominated by VanꢀderꢀWaals
interactions. Only 3l shows a weak hydrogen bond contact.
Figure 3. Molecular structures of compounds 3l (left) and (3m) (right) in the crystal (ORTEP plot,
ellipsoids at the 50% probability level at 123 K)
2.2 In vitro COX-1/COX-2 inhibitory activity
Structureꢀactivity relationship (SAR) studies have revealed that monoꢀ and bicyclic compounds
possessing two vicinal aryl moieties on the central heterocyclic ring system represent one major class
of selective COXꢀ2 inhibitors.40 The vicinal 1,2ꢀdiaryl substitution pattern results in high affinity
towards COXꢀ2; however, examples of 1,3ꢀdiarylꢀsubstituted isoindole or pyrimidine derivatives
showing an metaꢀsubstitution pattern for the aryl rings, have also been reported to be highly affine
towards COXꢀ2.41
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Based on 1,3ꢀdipolar cycloaddition reactions between nitrile oxides and various phenyl acetylenes 1,
we prepared two classes of compounds possessing a central isoxazole moiety; the vicinal 3,4ꢀdiarylꢀ
substituted isoxazoles 3 and 3,5ꢀdiarylꢀsubstituted isoxazoles 4. Compounds 3 are structural closely
related to traditional selective COXꢀ2 inhibitors e.g. valdecoxib and parecoxib (see Figure 1). For
determining the resulting combined different steric and electronic effects upon COXꢀ1 and COXꢀ2
inhibitory affinity and COX isoenzyme selectivity, all isolated compounds were subjected to an in
vitro COX Fluorescent Inhibitor Screening Assay (Cayman Chemicals; Item nr: 700100). Valdecoxib
as lead compound was used as the reference. The determined in vitro enzyme inhibition data, along
with the calculated COXꢀ2 selectivity index (COXꢀ2 SI) and calculated lipophilicity values (cLogP) of
the new 3,4ꢀ and 3,5ꢀdiarylꢀsubstituted isoxazoles, are summarized in Table 3.
Table 3. In vitro COXꢀ1 and COXꢀ2 enzyme inhibition data of 3,4ꢀ and 3,5ꢀdiarylꢀsubstituted
isoxazoles
R1
R2
X
COX-1 COX-2 IC50
IC50
COX-2
SIb
cLogPc
(µM)a
(µM)a
> 100
(150)d
> 100
> 100
> 100
> 100
> 100
> 100
10.07
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
valdecoxib
CH3
NH2
H
0.050±0.002
(0.005)d
> 2000
2.73
H
H
H
H
NH2
NH2
CH3
CH3
NH2
CH3
CH3
CH3
F
H
F
H
F
F
F
F
F
F
F
F
F
H
H
F
H
F
H
F
F
H
0.042±0.033
0.048±0.002
0.057±0.006
0.247±0.028
0.073±0.008
8.145±0.191
0.351±0.026
13.777±0.50
> 100
> 2400
> 2100
> 1800
> 400
> 1400
> 12
28.7
> 7
2.68
2.51
2.85
2.69
2.90
3.99
3.65
2.88
2.92
2.99
4.55
5.19
5.36
5.02
5.20
2.87
2.71
3.05
2.88
5.19
5.36
5.02
3a
3b
3c
3d
3e
3f
3g
3h
3i
CH3
CF3
Cl
CHO
CO2Me CH3
COMe
COPh
TMS
TMS
TMS
TMS
H
H
H
H
TMS
TMS
TMS
ꢀ
ꢀ
ꢀ
CH3
CH3
NH2
CH3
NH2
CH3
NH2
NH2
CH3
CH3
NH2
CH3
NH2
> 100
> 100
3j
3k
3l
0.93±1.70
1.87±1.24
0.13±0.001
4.17±3.35
81.2±5.10
10.79±0.01
> 100
13.55±5.05
38.16±0.01
> 100
> 110
> 54
> 770
23.9
> 1.2
> 9.3
ꢀ
> 7.4
> 2.6
ꢀ
3m
3n
3o
4a
4b
4c
4d
4l
4m
4n
11.05±1.31
> 9.0
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TMS
CH3
H
> 100
> 100
ꢀ
5.20
4o
a) Values are means of two determinations with standard deviation. b) In vitro COXꢀ2 selectivity index (IC50
COXꢀ1/IC50 COXꢀ2). c) cLogP values have been calculated based on molinspiration predictions
(www.molinspiration.com) d) Literature value.13
As expected, valdecoxib proved to be a potent and selective COXꢀ2 inhibitor in the performed enzyme
inhibitory assay; the COXꢀ2 inhibitory activity was determined by us with an IC50 value of 0.05 µM
(see Figure S63, Supporting Info), a value that is by a factor of 10 higher than reported (0.005 µM)13.
This difference is owed to the fact that in this work a fluorescenceꢀbased assay was used as oppose to
3
the Hꢀbased radioligand assay from the literature. However, useful information is provided by
comparing the results of all compounds measured by this procedure.
The first series of compounds (3a–o) containing the common vicinal substitution pattern of the aryl
moieties showed interesting results with regard to the inhibitory activity, depending on the substituents
at position 5 of the isoxazole. All compounds of this series displayed no inhibitory potency against the
constitutive form of cyclooxygenase (COXꢀ1) (>100 µM), with one exception, compound 3g (IC50
COXꢀ1 = 10 µM).
Regarding the inhibition against COXꢀ2, a more differentiated picture within compounds 3a–o was
observed (Table 3). Compounds 3a-3e containing an H or CH3 substituent displayed a nanomolar
COXꢀ2 inhibitor potency (0.042–0.247 µM), compound 3g with a chloroꢀatom and 3l as well as 3n
bearing a TMSꢀsubstituent showed submicromolar affinity (0.13–0.93 µM). Compounds 3i-k
containing carbonyl substituents CO2Me, COMe and COPh showed no inhibitory potency against
COXꢀ2 (>100 µM) and compounds 3f and 3h (containing electronꢀwithdrawing groups CF3 and CHO)
as well as compounds 3m and 3o (with a bulky TMS group) displayed only very low inhibition of the
COXꢀ2 enzyme as reflected by IC50 values in a micro molar range (1.87 µM to 13.77 µM).
In conclusion, compounds 3a-c and 3e containing an H or CH3 substituent are 2ꢀ to 22ꢀfold more
potent COXꢀ2 inhibitors compared to compounds 3d, 3g, 3l and 3n having an Cl or TMS group.
Compounds 3a-c and 3e containing an H or CH3 substituent behave as particularly highly potent
COXꢀ2 inhibitors, and it can be concluded that the inhibitory activity determined for COXꢀ2 is in the
same range as valdecoxib.
Within this series, compounds 3a-c and 3e also showed the highest COXꢀ2 selectivity. The SI value of
>2400 makes compound 3a the most COXꢀ2 selective compound within all studied isoxazole
containing compounds, and even more selective than valdecoxib (SI > 2000). According to these data,
increasing size and electronꢀwithdrawing properties of the substituents at position 5 in the isoxazole
ring, as found for the CF3, COR, and TMS group in compounds 3f, 3h-k, 3m and 3o, decreases their
COXꢀ2 inhibitory potency.
Compounds 3a-d and 3l-o showed interesting results regarding inhibitory activity depending on the
substituents at the paraꢀposition of the aryl rings. The structureꢀactivity relationship study of
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compounds 3a-e indicated that the order of COXꢀ2 inhibitory potency was in the same range
comparing a fluoro with a hydrogen substituent (3a vs. 3b and valdecoxib vs. 3e). This result suggests
that the presence of electronꢀwithdrawing groups like fluorine favours selective and potent inhibition
of COXꢀ2. This observation is interesting with regard to former investigations which we have made
with vicinal diarylꢀsubstituted (dihydro)pyrrolo[3,2,1ꢀhi]indoles where a paraꢀfluoro substituent did
not result in enhanced or steady COXꢀ2 affinity.42
Compounds 3a-d and 3l-o possess the typical SO2R COXꢀ2 relevant substituent in the paraꢀposition
of one of the aryl rings attached to the central isoxazole unit with R = NH2 or CH3. Comparison of the
IC50 values for these compounds suggests that compounds 3a, 3b, 3l, and 3n bearing a SO2NH2 group
as pharmacophore are more selective and potent COXꢀ2 inhibitors than the compounds 3c, 3d, 3m,
and 3o with a SO2Me group (compare 3a vs. 3c, 3b vs. 3d, 3l vs. 3m, and 3n vs. 3o).
The second class of compounds (4) contains the uncommon 3,5ꢀdisubstitution pattern of the aryl
moieties. All these compounds displayed no inhibitor activity towards COXꢀ1 (IC50 >100 µM).
Additionally, these substances showed only very low or no inhibitory potency against COXꢀ2 in the
range of 10.79 µM to >100 µM. Direct comparison of compounds 3 and compounds 4 further
confirms the favourable vicinal diaryl substitution pattern with regard to potent COXꢀ2 inhibition.
Changing the 3,5ꢀdiaryl substitution pattern in compounds 4d and 4l-o to the vicinal diaryl substitution
design in compounds 3d and 3l-o is accompanied by a 24ꢀ to 85ꢀfold increase in COXꢀ2 inhibition
affinity. Highly affine compound 3b is 225ꢀfold more potent than its corresponding 3,5ꢀdiarylꢀ
substituted counterpart 4b. The positive effect of the vicinal diaryl substitution on COXꢀ2 inhibition
potency was even more pronounced for comparing compounds 3a versus 4a and 3c versus 4c (see
Table 3). To summarize, in the case of the arylꢀsubstituted isoxazoles the 3,5ꢀdisubstitution pattern
does not result in potent inhibitors of COXꢀ2 .
2.3 Lipophilicity calculations
Range of lipophilicity is a crucial criterion in drug development and especially in the design of
radiotracers. With increasing lipophilicity smallꢀmolecule drugs tend towards unspecific binding to
plasma proteins and membranes. For the hydrogenꢀbearing isoxazoles 3a-d a favourable lipophilicity
was calculated (cLogP = 2.51ꢀ2.85); however, the replacement of the hydrogen atom at position 5 with
more lipophilic substituents (Cl, CF3, COPh, TMS) , as done in compounds 3f,g and 3k-o resulted in a
significant increase in lipophilicity by 1ꢀ2 orders of magnitude (cLogP = 3.99ꢀ5.20). On account not
only of their low COXꢀ2 affinity but also their lipophilicity range the COPhꢀ and TMSꢀsubstituted
compounds would represent unfavourable candidates for the further design of radiotracers.
Conversely, the promising results as regard COXꢀ2 inhibition selectivity and affinity, and the
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comparatively low lipophilicity of compounds 3a and 3c, make these 3,4ꢀdiaryl substituted isoxazoles
interesting candidates for further development as potential fluorineꢀ18 labelled COXꢀ2 inhibitors.
3. Conclusion
We have prepared by Ruthenium(II) promoted 1,3ꢀdipolar cycloaddition a series of new compounds
on the basis of a valdecoxib lead structure displaying a central isoxazole scaffold, with two aryl
substituents and one additional substituent on the heterocycle. An outstanding feature of this approach
is that it delivers the 3,4ꢀdiaryl substituted isoxazoles in one step in yields of up to 74%, making this
approach very promising for radiotracer synthesis.
In general, compounds having a vicinal diaryl substitution pattern showed a COXꢀ2 inhibition, whilst
their corresponding 3,5ꢀdiarylꢀsubstituted counterparts turned out to be inactive. The 3,4ꢀdiaryl
substituted compounds possessing a small substituent at position 5 of the isoxazole ring (3a-c and 3e)
displayed highest COXꢀ2 inhibition potency with IC50 values of 0.042–0.073 µM, being in the same
range as found for valdecoxib (0.050 µM). Isoxazoles bearing bulky or electronꢀwithdrawing groups
showed significantly lower affinity towards COXꢀ2.
Interestingly, the introduction of a fluorine substituent by application of a fluoroꢀsubstituted nitrile
oxide 2a resulted in remaining high COXꢀ2 affinity. This finding, along with their ease in synthesis
through versatile Ru(II)ꢀcatalysed click chemistry make compounds 3a and 3c to interesting
candidates for the design of potent fluorineꢀ18 labelled PET tracers. That might be put into practice by
application of 1,3ꢀdipolar cycloaddition with 4ꢀ[18F]fluorobenzonitrile oxide, in analogy to the work of
Zlatopolskiy et al.43 As extension, further analogues of 3a and 3c might be explored, having the
fluorine atom in ortho or meta position of the benzene ring with view on COXꢀ2 affinity and
radiolabelling; an approach that is challenging since 2ꢀ and 3ꢀ[18F]fluorobenzonitrile oxides are not
described so far.
4. Experimentals
4.1 Chemistry
Synthesis procedures, NMR data and spectra of all new synthesized compounds are available free of
charge as supporting information.
4.2 X-ray crystallography
The crystallographic data were collected using an Apex-II CCD diffractometer (Bruker), with Mo Kα
radiation (λ = 0.71073 Å). The structures were solved using SHELXSꢀ97 and refined against F2 on all
data by fullꢀmatrix leastꢀsquares with SHELXLꢀ97.44 All nonꢀhydrogen atoms were refined
anisotropically; all hydrogen atoms bonded to carbon atoms were placed on geometrically calculated
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positions and refined using a riding model. Details of the Xꢀray structure analysis of compounds 3l
1
and 3m and copies of the H and 13C NMR spectra of all compounds are available as supporting
information. Crystallographic data for compounds 3l and 3m were deposited with the Cambridge
Crystallographic Data Centre as supplementary publication nos. CCDCꢀ1483007 (compound 3m),
CCDCꢀ1483008 (compound 3l). Copies can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: +44(0)1223 336033 or eꢀmail: deposit@ccdc.cam.ac.uk.
4.3 COX Inhibition assay
COXꢀ1 and human COXꢀ2 was determined using the fluorescenceꢀbased COX assay “COX
Fluorescent Inhibitor Screening Assay Kit” (catalogue number 700100; Cayman Chemicals, USA)
according to the manufacturer’s instructions. All compounds were assayed in a concentration range of
0.01 ꢀ 100 ꢁM, as described elsewhere.45 Two technical replicates were performed for each inhibitor
concentration. The mean of these two values was used for estimating the IC50 values using a nonlinear
logistic regression fitting procedure (sigmoidal dose−response model) with Origin® Software.
Exemplary, doseꢀresponse curves for valdecocib and 3a are shown in the Supporting Information
(Figure S63)
Acknowledgements
The excellent technical assistance of Johanna Pufe and Mareike Barth in performing COX inhibitory
assays is greatly acknowledged. Silvia Roscales was a grateful for a postdoctoral fellowship from
Ramón Areces Foundation (2015ꢀ2016). Nicole Bechmann was a grateful recipient (2011ꢀ2014) of a
fellowship by European Social Fund (ESF). Constantin Mamat and Reik Löser are acknowledged for
recording the Nuclear Magnetic Resonance (NMR) spectra. The authors thank the Helmholtz
Association for providing support to this work (J.P. and T.K.) through the Helmholtz Cross
Programme Initiative "Technology & Medicine – Adaptive Systems”. This study also was part of the
research initiative “RadiationꢀInduced Vascular Dysfunction (RIVAD)”.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed. No prior subsequent publication.
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Novel Valdecoxib Derivatives by Ruthenium(II)-promoted 1,3-
Dipolar Cycloaddition of Nitrile Oxides with Alkynes – Synthesis and
COX-2 Inhibition activity.
Silvia Roscales, Nicole Bechmann, Daniel Holger Weiss, Martin Köckerling, Jens
Pietzsch, Torsten Kniess
By Ru(II)-promoted 1,3-dipolar cycloaddition of nitrile oxides with alkynes 3,4-diaryl-substituted
isoxazoles are formed in one step, showing high inhibition potency for COX-2.