Transformation of Prostaglandin D2 to 11-Dehydro Thromboxane B2 by Baeyer-Villiger Oxidation

Article abstract of DOI:10.1002/lipd.12206

Prostaglandin D₂ is one of five chief prostanoids formed in the cyclooxygenase pathway of arachidonic acid oxidation. Except for a single oxygen atom, PGD₂ is structurally identical to 11-dehydro thromboxane B₂ (11d-TxB₂), a urinary metabolite of the pro-aggregatory platelet activator, thromboxane A₂. The close structural relationship suggested that one might be transformed to the other. Accordingly, we tested whether the cyclopentanone of PGD₂ can be expanded to the δ-lactone of 11d-TxB₂ in a Baeyer-Villiger oxidation. Oxidation of PGD₂ with two standard oxidants showed that 11d-TxB₂ was formed only with H₂O₂ but not with peracetic acid. Byproducts of the H₂O₂-mediated oxidation were hydroperoxide derivatives and isomers of PGD₂. Chemical oxidation of PGD₂ to 11d-TxB₂ may be a model for an equivalent enzymatic transformation, suggesting a possible link in the metabolism of PGD₂ and thromboxane A₂.

Full text of DOI:10.1002/lipd.12206

Lipids (2019)
DOI 10.1002/lipd.12206
ORIGINAL ARTICLE
Transformation of Prostaglandin D2 to 11-Dehydro
Thromboxane B2 by Baeyer-Villiger Oxidation
Fumie Nakashima1 · Claus Schneider1
Received: 17 September 2019 / Revised: 5 November 2019 / Accepted: 15 November 2019
© 2019 AOCS
Abstract Prostaglandin D2 is one of five chief
prostanoids formed in the cyclooxygenase pathway of
arachidonic acid oxidation. Except for a single oxygen
atom, PGD2 is structurally identical to 11-dehydro throm-
boxane B2 (11d-TxB2), a urinary metabolite of the pro-
aggregatory platelet activator, thromboxane A2. The close
structural relationship suggested that one might be trans-
formed to the other. Accordingly, we tested whether the
cyclopentanone of PGD2 can be expanded to the δ-lactone
of 11d-TxB2 in a Baeyer-Villiger oxidation. Oxidation of
PGD2 with two standard oxidants showed that 11d-TxB2
was formed only with H2O2 but not with peracetic acid.
Byproducts of the H2O2-mediated oxidation were hydro-
peroxide derivatives and isomers of PGD2. Chemical oxi-
dation of PGD2 to 11d-TxB2 may be a model for an
equivalent enzymatic transformation, suggesting a possible
link in the metabolism of PGD2 and thromboxane A2.
Abbreviations
COX
FMO
HFIP
NMR
PG
cyclooxygenase
flavin-dependent monooxygenase
1,1,1,3,3,3-Hexafluoro-2-propanol
nuclear magnetic resonance
prostaglandin
TPP
Tx
triphenylphosphine
thromboxane
11d-TxB2 11-dehydro thromboxane B2
Introduction
Prostaglandins (PG) are formed in the cyclooxygenase
(COX)-mediated oxygenation of arachidonic acid
(Schneider et al., 2007; Smith et al., 2011; van der Donk
et al., 2002). PG, together with other eicosanoids formed in
the lipoxygenase, cytochrome P450, and autoxidative path-
ways, are a large and diverse group of lipid mediators
(Brash, 1999; Jahn et al., 2008; Spector, 2009). Additional
diversity comes from transformation of related fatty acids,
e.g., eicosapentaenoic and docosahexaenoic acids. The
resulting products vary in the number and type of oxygen
functional groups, cyclizations, and degree of unsaturation
(Sud et al., 2007).
Keywords Arachidonic acid Á Cyclooxygenase Á
Eicosanoid Á Lactone Á Peroxyhemiacetal
Lipids (2019).
The immediate COX product from arachidonic acid, the
PG endoperoxide PGH2, undergoes enzymatic transforma-
tion to the chief effector prostanoids, PGE2, PGD2, PGF2α,
PGI2, and thromboxane A2 (Smith et al., 2011). PG are bio-
synthesized in a tissue-specific manner and act via activa-
tion of their cognate G-protein-coupled receptors that are
involved in the regulation of physiological and pathophysi-
ological cellular events (Smyth et al., 2009).
Supporting information Additional supporting information may be
found online in the Supporting Information section at the end of the
article.
* Claus Schneider
claus.schneider@vanderbilt.edu
1
Department of Pharmacology, Division of Clinical
Pharmacology, and Vanderbilt Institute of Chemical Biology,
Vanderbilt University Medical School, Nashville, TN
37232, USA
The premise for this study is based on the close similar-
ity in structure of PGD2 and 11-dehydro thromboxane B2
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PGD2
OH
11d-TxB2
OH
LC–MS
Baeyer–Villiger
oxidation
OH
O
HO
CO2H
CO2H
11
12
12
Reactions were analyzed using a Thermo TSQ Vantage tri-
ple quadrupole MS instrument (Thermo Fisher Scientific)
equipped with a heated electrospray interface operated in
negative ion mode. Settings for sheath and auxiliary gas
pressures, temperature, and interface voltage were opti-
mized using direct infusion of a solution of PGD2 in aceto-
nitrile/water 1:1 (v/v). The electrospray needle was
maintained at 4.0 kV. The ion transfer tube was operated at
300 ꢀC. A Zorbax Eclipse Plus C18 1.8-μm column
(2.1 × 50 mm; Agilent Technologies, Santa Clara, CA,
USA) was used for the separation. Water: acetonitrile
(80:20, v/v) and acetonitrile: water (20:80, v/v) each con-
taining 0.1% formic acid were the mobile phases (A and B,
respectively) used at a flow rate of 0.5 mL/min. A linear
gradient was used starting with 100% of solvent A,
reaching 100% of solvent B at 5 min, and held for 1 min.
The initial conditions were re-established at 6.01 min and
held until 7 min. The signal intensities obtained for each
ion chromatogram are given in exponential format with the
maximum intensity set as 100%. Data acquisition and spec-
tral analysis were performed using the Thermo Finnigan
Xcalibur software.
11
O
O
Fig. 1 Proposed conversion of PGD2 to 11-dehydro thromboxane B2
(11d-TxB2) in a Baeyer-Villiger oxidation. The oxygen that expands
the cyclopentanone of PGD2 to the δ-lactone of 11d-TxB2 is shown
in red
(11d-TxB2), a urinary metabolite of thromboxane A2
(Roberts II et al., 1981). With identical side chains and
hydroxy and oxo functions at the 9- and 11-positions of the
prostanoid ring, the only difference is an additional oxygen
in 11d-TxB2, expanding the cyclopentanone of PGD2 to a
δ-lactone. Linear and cyclic ketones can be converted to
esters and lactones, respectively, in a Baeyer-Villiger oxi-
dation that inserts a peroxide-derived oxygen next to the
carbonyl (March, 1992). Thus, we tested the feasibility of
the Baeyer-Villiger oxidation to transform PGD2 to 11d-
TxB2 as illustrated in (Fig. 1) (Jarving et al., 1988; Jarving
et al., 1990). This resulted in the identification of novel
reaction products formed in the transformation.
Materials and Methods
Materials
NMR
Nuclear magnetic resonance (NMR) samples were dis-
solved in 150 μL of CDCl3 in a 3 mm-sample tube and ana-
lyzed on a Bruker AV-II 600 MHz spectrometer equipped
with a cryoprobe. Chemical shifts are reported relative to
residual unlabeled solvent (δ = 7.25 ppm).
PG were obtained from Cayman Chemical (Ann Arbor,
MI, USA). 1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP) was
obtained from ACROS Organics. Hydrochloric acid,
hydrogen peroxide, and triphenylphosphine (TPP) were
obtained from Sigma-Aldrich.
Oxidation Reactions
PGD2 (20 μg) was dissolved in 20 μL of HFIP. Water
(1.6 μL), hydrochloric acid (1 N; 0.4 μL), and hydrogen
peroxide (10 M; 0.4 μL) were added, and the solution was
placed at room temperature. After 1 h, the reaction was
evaporated to dryness, and the residue dissolved in 20 μL
of methanol. For isolation of products, reactions were
scaled 10-fold, and multiple reactions were conducted in
parallel.
Results
Oxidation reactions of PGD2 were carried out in hexa-
fluoroisopropanol (HFIP) in the presence of HCl using
peracetic acid or H2O2 as oxidant (Berkessel and Andreae,
2001). Reaction progress was monitored by RP-HPLC with
diode array detection. Use of peracetic acid resulted in dis-
appearance of PGD2 without detectable formation of 11d-
TxB2. The majority of products obtained with peracetic
acid had diene and triene chromophores, likely representing
dehydration products (data not shown). When H2O2 was
used as oxidant, 11d-TxB2 (product 2) was formed as the
intended Baeyer-Villiger product together with several
byproducts (Fig. 2). Identification of 11d-TxB2 was accom-
plished by LC–MS analysis in the MS1 and MS2 modes as
well as by co-elution with an authentic standard. The yield
of 11d-TxB2 was 21% based on peak intensities in HPLC
HPLC
Reactions were analyzed using a Waters Symmetry (Mil-
ford, MA, USA) C18 5 μm column (4.6 × 250 mm) eluted
with a linear gradient of 20–80% acetonitrile in 0.01%
aqueous acetic acid over 20 min. The samples were eluted
at a flow rate of 1 mL/min, and UV signals at 205 nm were
monitored using an Agilent 1200 diode array detector.
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4 (see below) suggested the hydroperoxide was more likely
to be located at C-15. The structural assignment is tentative
since NMR data for 1 could not be obtained.
Product 3 (m/z 351.0 in negative ion LC–MS; Fig. 3)
was identified as an isomer of PGD2 with the double bond
changed from 5Z to 5E configuration (J = 15 Hz; Table 1)
(Fig. 4). Peak 4 (m/z 367.1) showed near-identical NMR
data to PGD2 with the exception of H-15 that was shifted
to 4.36 ppm compared with 4.53 ppm in PGD2. Reduction
of 4 with TPP yielded PGD2, confirming that 4 was 15S-
hydroperoxy-PGD2. NMR data of peak 5 suggested a
13-hydro(pero)xy isomer of PGD2 with the double bond
shifted to 14E and side chains on the prostanoid ring in cis
configuration (12-iso). Treatment of 5 with TPP gave four
more polar peaks of about equal intensity in LC–MS ana-
lyses. Since LC–MS analyses gave inconclusive data for
5 and its reduced products, the structural assignment is con-
sidered tentative. None of the products co-eluted with a
standard of 15R-PGD2.
The absolute configuration of products 1–5 as shown in
Fig. 4 was determined based on the assumption that the ste-
reochemistry of C-9 was unchanged during the reaction.
The 2JH,H coupling constants used to determine the relative
configuration of substituents on the prostanoid ring of 1–5
were obtained through selective spin decoupling experi-
ments (Table 1 and Supporting Information). Reference
values for cis and trans configured hydrogens at the
prostanoid ring were obtained from analysis of commer-
cially available PG with configuration changed relative to
PGD2, namely, 8-iso-PGE1 and 11β-PGE2 (Table 2).
Fig. 2 Analysis of Baeyer-Villiger oxidation of PGD2. PGD2was
reacted with H2O2 in acidic hexafluoroisopropanol at room tempera-
ture for 1 h. products were analyzed using RP-HPLC with diode array
detection. The chromatogram was recorded at 205 nm
analyses, similar in yield to a previous report (Jarving
et al., 1988).
LC–MS analyses of crude oxidation reactions (Fig. 3)
and isolated peaks were used to determine the molecular
weights of the products. The analyses confirmed that 11d-
TxB2 was the main product resulting from insertion of
oxygen.
Several byproducts of the H2O2-mediated oxidation of
PGD2 were isolated using RP-HPLC. NMR data were col-
lected for some of the products (Table 1 and Supporting
Information). Product 1 was tentatively identified as the
hydroperoxyhemiacetal of 15-hydroperoxy-PGD2 (Fig. 4).
The structure of 1 was assigned based on LC–MS (m/z
401.0 in negative ion LC–MS; Fig. 3) and from the fact that
treatment of 1 with TPP to reduce peroxide groups yielded
PGD2. It was unclear whether the hydroperoxy group was
located at C-9 or C-15, although comparison to product
Discussion
Treatment of PGD2 with H2O2 in acidic solvent resulted in
Baeyer-Villiger oxidation to 11d-TxB2. Insertion of oxygen
between C-11 and C-12 was compatible with the known
mechanism that favors placing oxygen on the side of the
higher substituted carbon (Renz and Meunier, 1999). Thus,
Baeyer-Villiger oxidation provides convenient synthetic
access to corresponding 11-dehydro thromboxanes starting
from the respective PGD precursors. Of two standard per-
oxide reagents used in Baeyer-Villiger oxidations, only
H2O2 yielded the intended product with low to moderate
yield. Peracetic acid did not form 11d-TxB2.
Quantification of 11d-TxB2 in urine is used to assess the
antiplatelet effect of low-dose aspirin therapy (Patrono,
2014; Patrono et al., 2005). The pharmacodynamic target
of low-dose aspirin is COX-1 in platelets (Pedersen and
FitzGerald, 1984), supplying PGH2 as substrate for synthe-
sis of thromboxane A2 (TxA2) by thromboxane synthase
(Hamberg and Samuelsson, 1974). TxA2 is the major pro-
Fig. 3 LC–MS analysis of a crude Baeyer-Villiger oxidation reaction
of PGD2. The chromatograms represent the ion traces for detection of
PGD2 (m/z 351) and products 11d-TxB2 (2; m/z 367) and 1 (m/z 401)
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Table 1 1H NMR chemical shifts and correlations for products 3, 4, and 5 formed in the Baeyer-Villiger oxidation of PGD2
3
4
5
Proton
no.
Coupling
1H (ppm) Multiplicity constant (Hz)
Coupling
constant (Hz)
1H
(ppm) Multiplicity constant (Hz)
Coupling
1H (ppm) Multiplicity
2
3
4
5
2.34
1.73
2.13
5.49
m
m
2.41
1.74
2.19
5.50
t
J2,3 = 3.7
2.37
1.72
2.14
5.43
t
J2,3 = 7.0
m
m
dt
m
m
dt
m
dd
J5,6 = 15.1;
J5,4 = 8.4
J5,6 = 10.5;
J5,4 = 5.6
J5,4 = 7.3;
J5,6 = 10.4
6
5.61
2.19
dd
dd
J6,5 = 14.9;
J6,7 = 6.2
5.58
2.30
m
5.34
2.08
ddd
m
J6,5 = 10.8;
J6,7b = 6.7
7a
J7a,7b = 14.9;
J7a,6 = 7.1
ddd
J7a,7b = 10.6;
J7a,6 = 6.8;
J7a,8 = 3.8
7b
8
2.48
1.91
ddd
ddd
J7a,7b = 14.3;
J7b,8 = 3.9;
J7b,6 = 8.0
2.39
2.05
m
2.36
2.08
m
m
J8,12 = 11.8;
J7,8 = 3.8;
J8,9 = 3.6
dddd
J8,12 = 15.5;
J7a,8 = 4.1;
J7b,8 = 8.1;
J8,9 = 4.1
9
4.54
2.44
dt
d
J9,10 = 2.6;
J9,8 = 3.6
4.54
2.45
dd
d
J9,10 = 3.7;
J9,8 = 3.4
4.50
2.27
dt
dt
J9,10 = 4.8;
J9,8 = 9.2
10
J10,9 = 2.8
J10,9 = 4.2
J10a,10b = 14.5;
J10,9 = 5.0
11
12
—
2.80
—
2.91
—
2.85
dd
dd
dd
dt
m
m
t
J8,12 = 12.1;
J12,13 = 8.4
dd
dd
dd
dt
m
m
t
J8,12 = 11.9;
J12,13 = 7.3
dd
dd
dd
dt
J8,12 = 6.1;
J12,13 = 6.1
13
14
15
16
5.47
5.62
4.21
1.58
J13,14 = 15.4;
J13,12 = 8.4
5.70
5.51
4.36
J13,14 = 15.7;
J13,12 = 7.3
4.47
5.37
5.87
2.06
1.38,
0.88
J13,14 = 7.7;
J12,13 = 7.6
J14,13 = 15.3;
J14,15 = 7.3
J14,13 = 15.7;
J14,15 = 8.1
J14,13 = 8.3;
J14,15 = 15.4
J15,16 = 6.3;
J14,15 = 6.7
J15,16 = 6.9;
J14,15 = 8.0
J15,16 = 6.8;
J14,15 = 15.4
1.45,
1.61
m
17, 18, 19 1.23–1.44
20 0.89
1.26–1.41
1.28
t
m
J19,20 = 6.8
0.88
J19,20 = 7.1
J19,20 = 7.2
Spectra were recorded in CDCl3 using a Bruker AV-II 600 MHz spectrometer equipped with a cryoprobe. Coupling constants of complex signals
were determined using selective spin decoupling experiments. NMR spectra are shown in supporting information.
aggregatory eicosanoid in platelets, and its inhibition is the
key mechanism for the cardioprotective effects of aspirin
(FitzGerald et al., 1983; Patrignani et al., 1982). TxA2 is
hydrolyzed to inactive TxB2 and further metabolized to
11d-TxB2 (Patrono et al., 1985; Roberts II et al., 1981).
Thus, if 11d-TxB2 may also be derived from PGD2, appli-
cation of the former as a biomarker for platelet activation in
cardiovascular disease will need to be reconsidered,
depending on the efficiency of the metabolic pathway.
Enzymatic Baeyer-Villiger oxidations catalyzed by
flavin-dependent monooxygenases (FMO) are well
described in microorganisms, with many of the reactions
and enzymes characterized at the molecular level (Huijbers
et al., 2014; Rossner et al., 2017). In microorganisms, the
reactions appear to be involved in the mobilization of car-
bon sources as fuel for cell growth (Tolmie et al., 2019)
while the mammalian enzymes play a role in the metabo-
lism of xenobiotics (Phillips and Shephard, 2017). Human
flavin-dependent monooxygenase 5 (FMO5) has been
shown to catalyze Baeyer-Villiger oxidations of two cancer
drugs (Lai et al., 2011; Meng et al., 2015). Although no
endogenous substrates for Baeyer-Villiger oxidations have
been described, metabolism of the cancer drugs suggests
that the corresponding enzymatic machinery is functional
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OH
O
HO
O
HO
O
CO2H
CO2H
CO2H
O
OH
OOH
OH
4
2
3
(15-OOH-PGD2)
MW 368.47
(11d-TxB2)
MW 368.47
(5E-PGD2)
MW 352.47
HO
HO
O
CO2H
CO2H
HO
OOH
OOH
OOH
1
5
MW 402.48
MW 368.47
Fig. 4 Products of the H2O2-mediated oxidation of PGD2 conducted in the presence of HCl. Products 1 and 5 shown in square brackets have
been identified only tentatively
Table 2 Coupling constants for cis and trans configured hydrogens in the prostanoid ring of select prostaglandins
Prostanoid
PGD2
8-iso-PGE1
11β-PGE2
Coupling constant J (Hz)
H8-H12
H8-H9
11.6 (trans)
3.5 (cis)
—
8.2 (cis)
11.9 (trans)
—
3.4 (cis)
—
H11-H12
1.6 (trans)
NMR spectra were recorded in CDCl3 at 600.13 MHz using a Bruker AV-II 600 MHz spectrometer equipped with a cryoprobe.
responsibility of the authors and does not necessarily represent official
views of the National Institutes of Health.
in humans. With regard to transformation of oxylipins
Baeyer-Villiger oxidation of a linoleic acid α-ketol, pro-
duced by the lipoxygenase-allene oxide synthase pathway
in plants (Tijet and Brash, 2002), was catalyzed by a micro-
organism isolated from soil (Schneider et al., 1997). The
predicted ester product of the Baeyer-Villiger oxidation
was unstable and underwent hydrolysis to yield the plant
hormone, traumatic acid (Schneider et al., 1997;
Zimmerman and Coudron, 1979).
Exploring the scope of the Baeyer-Villiger oxidation
regarding substrates, products, synthetic application, and its
possible occurrence in vivo will add novel facets to the
wealth of enzymatic and chemical reactions involved in the
formations and metabolism of bioactive lipids.
Conflict of Interest The authors declare that they have no conflict
of interest.
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