Synthesis and biological activities of novel dexibuprofen tetraacetylriboflavin conjugates

Article abstract of DOI:10.1016/j.bmcl.2006.10.087

A series of novel dexibuprofen derivatives covalently linked via alkylene spacers of variable length to tetraacetylated riboflavin have been developed. The target compounds became accessible by reaction of the chloromethyl ester of dexibuprofen with tetraacetylriboflavin (compound 7) or by synthesis of the appropriate N3-(ω-iodoalkyl)-2′,3′,4′,5′-Tetraacetylri boflavin followed by treatment with dexibuprofen (derivatives 8-11), respectively. Biological screening revealed that the target compounds exhibit antiproliferative effects on MCF-7 breast cancer and HT-29 colon carcinoma cells with IC₅₀ values in the range of 8-15 μM. Enzymatic studies on human platelets indicated significant COX-1 inhibitory activities of the target compounds.

Full text of DOI:10.1016/j.bmcl.2006.10.087

Bioorganic & Medicinal Chemistry Letters 17 (2007) 683–687
Synthesis and biological activities of novel dexibuprofen
tetraacetylriboflavin conjugates
Christian Banekovich,a Ingo Ott,b,* Thao Koch,b
Barbara Matuszczaka,* and Ronald Gustb
aInstitute of Pharmacy, Leopold-Franzens University of Innsbruck, Innrain 52a, 6020 Innsbruck, Austria
bInstitute of Pharmacy, Free University of Berlin, Ko¨nigin-Luise-Str. 2+4, 14195 Berlin, Germany
Received 11 September 2006; revised 30 October 2006; accepted 30 October 2006
Available online 2 November 2006
Abstract—A series of novel dexibuprofen derivatives covalently linked via alkylene spacers of variable length to tetraacetylated ribo-
flavin have been developed. The target compounds became accessible by reaction of the chloromethyl ester of dexibuprofen with
tetraacetylriboflavin (compound 7) or by synthesis of the appropriate N3-(x-iodoalkyl)-20,30,40,50-tetraacetylriboflavin followed
by treatment with dexibuprofen (derivatives 8–11), respectively. Biological screening revealed that the target compounds exhibit
antiproliferative effects on MCF-7 breast cancer and HT-29 colon carcinoma cells with IC50 values in the range of 8–15 lM. Enzy-
matic studies on human platelets indicated significant COX-1 inhibitory activities of the target compounds.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a
widely used class of therapeutic agents. Their main
mode of action is the inhibition of the cyclooxygenase
enzymes (i.e., COX-1 and COX-2) leading to a reduc-
tion in the synthesis of prostaglandins, the messenger
molecules in the process of inflammation. In recent
years, several epidemiological, clinical, and experimental
studies have shown that NSAIDs also exhibit anticancer
properties.1 Moreover, it was demonstrated that long-
term use of NSAIDs reduces the recurrence risk in var-
ious malignancies such as breast and colon cancer signif-
icantly.2–5 Despite showing good chemoprotective and
cytostatic in vivo activity, the NSAIDs only exhibit
good cell activity at high concentrations.6–11
On the contrary, a recent study demonstrates that the
antiproliferative effects of R- and S-ibuprofen do not de-
pend on COX activity.15 Thus, additional studies will be
necessary to understand the molecular mechanism of ac-
tion. In spite of the positive findings, long-term use of
non-selective NSAIDs in this area might be limited by
adverse gastrointestinal effects ranging from dyspepsia
to serious complications such as bleeding or perforated
gastroduodenal ulcers. The risk of gastrointestinal com-
plications results from decreased synthesis of gastroin-
testinal protective prostaglandins based on COX-1
inhibition.16,17 Additionally, classical NSAIDs can
cause local toxicity due to their acidic functionality17
which is required for proper receptor interaction and
inhibition.18 Consequently, there are two main possibil-
ities to lower the gastrointestinal toxicity. Though selec-
tive COX-2 inhibitors can significantly lower incidence
of gastrointestinal toxicity, however, their use is associ-
ated with increased risk of cardiovascular events. An
alternative approach to solve the problem of the ulcero-
genic properties of NSAIDs consists in masking the
acidic function.19–22
In this context, it should be noted so far that the mech-
anism for the antitumor activity of NSAIDs is still
unknown. However, some hypotheses have been pro-
posed. Several groups have postulated that both, anti-
inflammatory activities and anticancer effects are due
to a reduction of products formed by cyclooxygenase
(COX) or lipoxygenase (LOX) catalyzed reactions.12–14
The interesting activities mentioned above prompted us
to investigate novel NSAID derivatives with protected
carboxylic acid function. Here we report on ester deriv-
atives of dexibuprofen which was chosen for this con-
cept as it showed promising long-term results in
retrospective clinical studies and in animals. It should
Keywords: Cytotoxic; Dexibuprofen; Tetraacetylriboflavin conjugates;
COX-inhibitors.
*
Corresponding authors. Tel.: +49 30 83853249; fax: +49 30 83856906
(I.O.); tel.: +43 512 5262; fax: +43 512 2940 (B.M.); e-mail addresses:
ottingo@zedat.fu-berlin.de; barbara.matuszczak@uibk.ac.at
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.10.087

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C. Banekovich et al. / Bioorg. Med. Chem. Lett. 17 (2007) 683–687
be noted that this compound exhibits only low cell
growth inhibitory activity in vitro.2,23 The minor cell
growth inhibitory activity may be attributed to a low
cellular uptake under in vitro conditions. We chose dex-
ibuprofen since this pure enantiomer has been reported
to be more effective and better tolerated in long-term
studies than racemic ibuprofen.24
intermediate for the preparation of the target
compounds.
In the case of the envisaged 7 which is characterized by a
methylene spacer between the TAR carrier and the
NSAID, compound 230 was considered as a suitable syn-
thon. This chloromethyl ester of dexibuprofen (2) was
available in a two-step reaction using bromochlorome-
In our target compounds, the ibuprofen moiety is linked
via different spacer units to a riboflavin derivative. The
latter moiety was chosen due to the fascinating biologi-
cal activities described in the literature, especially pro-
tection against oxidant-mediated inflammatory organ
injury,25 reduction of cancer chemotherapy toxicity,26
and antiinflammation.27 20,30,40,50-Tetraacetylriboflavin
(TAR) was selected for reasons of good photostability
and solubility.28
Table 1. Antiproliferative activities expressed as IC50 value
(lM) standard errora
Compound
HT-29 cells
MCF-7 cells
Dexibuprofen
7
>1000
795 ( 119)
12.3 ( 0.0)
14.9 ( 1.1)
7.8 ( 2.2)
9.5 ( 1.6)
9.5 ( 1.4)
>100
12.1 ( 0.8)
12.7 ( 0.8)
9.3 ( 0.6)
10.5 ( 0.8)
13.1 ( 0.6)
>100
8
9
10
11
3a
1
The target compounds 7–11 were synthesized as depict-
ed in Scheme 1. Initially, treatment of riboflavin with
acetic acid anhydride and pyridine allowed us to obtain
the already known 20,30,40,50-tetraacetylriboflavin (1)29
in gram amounts. This derivative was used as a key
90.9 ( 0.8)
7.3 ( 1.0)
53.4 ( 3.5)
4.834
5-FU
a Data obtained from two independent experiments.
O
CH3
O
CH3
O
O
O
O
O
O
O
O
O
O
CH3
CH3
H3C
O
H3C
O
O
N
O
N
CH3
O
CH3
O
N
N
N
N
H3C
H3C
(i)
for n = 2 and 3: (iii)
for n = 4 and 5: (iv)
riboflavin
I
N
N
H3C
H3C
H
n
(1)
O
O
(3) - (6)
CH3
O
Cl
CH3
CH3
for n = 1
for n = 2-5
O
(2)
(ii)
(v)
O
CH3
O
O
O
O
O
CH3
H3C
O
O
N
CH3
O
N
N
H3C
H3C
CH3
N
O
CH3
n
O
O
CH3
(7) - (11)
Scheme 1. Synthesis of the target compounds 7–11. Reagents and conditions: (i) Ac2O, pyridine, reflux; (ii) N(C2H5)3, NaI (cat.) in acetone/CH2Cl2,
reflux; (iii) 1. HO–(CH2)n–X with X = I (n = 2) or Br (n = 3), K2CO3 in N,N-dimethylformamide, room temperature; 2. CH3SO2Cl, pyridine in
CH2Cl2, room temperature; 3. NaI in dry acetone, reflux; (iv) (CH2)nI2, K2CO3 in N,N-dimethylformamide, room temperature; (v) dexibuprofen,
N(C2H5)3, Na2SO4 in acetone, reflux.

C. Banekovich et al. / Bioorg. Med. Chem. Lett. 17 (2007) 683–687
685
100
80
60
40
20
0
COX-1
12-LOX
dexibuprofen
7
8
9
10
11
Figure 1. Enzyme activities after incubation with the test compounds (10 lM) (results obtained from 3 to 5 independent experiments).
thane and chlorosulfonic acid followed by reaction with
the NSAID in a two-phase system in the presence of
tetrabutylammonium hydrogensulfate as the phase-
transfer catalyst. Finally, the target conjugate 7 resulted
from base-mediated reaction of 2 with 1 in a mixture of
acetone and dichloromethane as the solvent. The crude
reaction product was purified by column chromatogra-
phy to give a yellow oil which solidified in vacuo.
inhibition35 and initial studies showed that the conju-
gates were chemically stable (determined by incubation
in phosphate buffer, data not shown), the activities of
7–11 may be explained with an intracellular release of
dexibuprofen. Thus, the uptake into the cells and subse-
quent enzymatic ester hydrolysis should be critical
parameters. Another explanation for the elevated cyto-
toxicity of 7–11 is that these conjugates are able to act
not only as drug delivery agents but also as independent
bioactive compounds. In either case pharmacokinetic
parameters must be taken into account.
For the synthesis of 8–11, alternative reaction sequences
were employed. It was planned to introduce an appro-
priate x-iodo substituted alkylene spacer into the
20,30,40,50-tetraacetylriboflavin. Whereas employment
of a,x-diiodobutane and a,x-diiodopentane led to the
desired x-iodoalkylated derivatives 5 and 6, synthesis
of the corresponding iodoethyl and iodopropyl deriva-
tives failed. The latter were accessible by initial prepara-
tion of the x-hydroxyalkyl-substituted carrier units 3a
and 4a, followed by conversion to the appropriate mesy-
lates 3b and 4b, and subsequent treatment of the latter
with sodium iodide. The desired compounds 8–11 were
prepared starting from the iodoalkyl derivatives 3–6
and dexibuprofen in the presence of triethylamine. All
compounds were characterized by 1H NMR and IR
spectroscopy as well as by mass spectrometry and
elemental analysis.31
In order to gain additional insight into the mode of action,
we evaluated the inhibitory effects of 7–11 on COX-1 and
12-LOX using an established human platelet assay which
quantifies the eicosanoids 12(S)-hydroxy-5-cis-8,
10-trans-heptadecatrienoic acid (i.e., 12-HHT; COX-1
product) and 12(S)-hydroxy-5,8-cis-10-trans-14-cis-eico-
satetraenoic acid (i.e., 12-HETE; 12-LOX product),
respectively.36,37
Under the test conditions (i.e., incubation for 60 min in
buffer solution at 37 ꢁC), all novel dexibuprofen tetra-
acetylriboflavin conjugates (7–11) lowered the activity
of COX-1 (see Fig. 1). However, none of them reached
the potency of dexibuprofen (90% inhibition) which
was used as a reference. While 7–9 lowered the eicosa-
noid levels by approximately 15–30%, the compounds
10 and 11 were more active (37% and 43% inhibition,
respectively). These results indicate the uptake of com-
pounds 7–11 into the platelets and the intracellular re-
lease of ibuprofen which may also take place in the
case of the tumor cells MCF-7 and HT-29. Moreover,
our experiments indicated that the enzyme 12-LOX is
inhibited by dexibuprofen (29% inhibition), while 7–11
did not influence 12-LOX catalyzed eicosanoid forma-
tion significantly (inhibition lower than 11% in all cases).
Additional investigations to get insight into the mecha-
nism of action as well as into structure–activity relation-
ships are in progress.
For the proliferation experiments MCF-7 breast cancer
and HT-29 colon cancer cells were selected since these
types of tumors have been reported to exhibit high sen-
sitivity to NSAID treatments.12,13,32,33 In addition to the
novel conjugates 7–11, dexibuprofen, tetraacetylribofla-
vin (1), N3-(2-hydroxyethyl)-TAR (3a) as well as the
established cytostatic agent 5-fluorouracil (5-FU) were
used as additional references. IC50 values for these com-
pounds were determined and are presented in Table 1.
Interestingly, our conjugates 7–11 displayed IC50 values
in the range of 7.8–14.9 lM in both cell lines. Therefore,
these novel derivatives are of comparable activity with
5-FU which is widely employed in the treatment of can-
cer. By contrast, the main components of 7–11 [i.e., dex-
ibuprofen and TAR (1)] as well as the potential
decomposition product 3a showed weak or no antipro-
liferative activity.
Acknowledgments
We acknowledge financial support from D. Swarovski &
Co. (‘Fo¨rderungsbeitra¨ge fur die Leopold-Franzens
¨
These findings could be interpreted in different ways: on
the one hand, the cytotoxicity of the target compounds
7–11 might be the result of COX inhibition. Since it is
known that an acidic substructure is essential for COX
Universita¨t Innsbruck’). Moreover, we thank Dr. Diet-
mar Rakowitz (Institute of Pharmacy, LFU Innsbruck)
for recording the mass spectra and for helpful
discussions.

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Supplementary data
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmcl.
2006.10.087.
30. Loubinoux, B.; Colin, J. L.; Thomas, V. Eur. J. Med.
Chem. 1991, 26, 461.
References and notes
31. General procedures for the synthesis of the target
compounds 7–11: Synthesis of compound (7): A solution
of 3.5 mmol of the chloromethylester of dexibuprofen (2)
in 5 mL of dry acetone was added to a stirred cold (ice
bath) mixture of 1 (0.545 g, 1.0 mmol), triethylamine
(1.0 mmol), anhydrous Na2SO4 (0.03 g), and catalytic
amounts of NaI in 3 mL of a mixture of acetone and
dichloromethane (3/2), and treated as described below.
Synthesis of compounds (8–11): A solution of dexibuprofen
(3.0 equiv, 1.3–2.0 mmol) and triethylamine (3.0 equiv) in
1.0–2.5 mL of dry acetone was added to a stirred cold (ice
bath) mixture of 1.0 equiv (0.43–0.68 mmol) of the
appropriate N3-(x-iodoalkyl)-substituted 20,30,40,50-tetra-
acetylriboflavin (3–6) and 0.03 g anhydrous Na2SO4 in
1.5–2.5 mL of dry acetone. Then, the appropriate reaction
mixture was slowly warmed to ambient temperature by
removing the ice bath and the mixture was stirred for 1 h
at room temperature. The reaction temperature was then
increased to 50 ꢁC (7) or 60 ꢁC (8–11), respectively, until
the alkylating reagent was completely consumed (TLC
monitoring: dichloromethane:ethyl acetate = 2/1). Then,
the reaction mixture was diluted with 20 mL of dichloro-
methane, the organic phase was washed with water,
saturated NaCl solution, dried over anhydrous Na2SO4,
and evaporated. The crude residue was purified by column
and/or circular chromatography to give the appropriate
target compound which was taken up in one milliliter of a
1:1 mixture of dichloromethane and diisopropyl ether.
Finally, the organic solvents were slowly evaporated to
give a foamy solid which could be scrapped out of the
flask.
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20,30,40,50-Tetraacetyl-3-{[1-(4-isobutylphenyl)ethyl]car-
bonyloxymethyl}riboflavin (7): Column chromatography
(dichloromethane:ethyl acetate = 2/1) yielded 0.110 g
(14.4%) of a yellow product. IR (KBr) 1748 cmꢀ1; MS
1
m/z 763 (M+1)+. H NMR (CDCl3) d 8.03 (s, 1H, 9-H),
7.55 (s, 1H, 6-H), 7.19 (d, J = 8.2 Hz, 2H, phenyl-H),
7.05 (d, J = 8.2 Hz, 2H, phenyl-H), 6.14, 6.09 (both d
with J = 9.3 Hz, 2H, N–CH2–O), 5.72–5.61 (m, 1H,
ribityl-CH), 5.49–5.36 (m, 2H, 2· ribityl-CH), 5.26–4.69
(m, 2H, 2· ribityl-CH), 4.44 (dd, J = 2.6 Hz, J = 12.4 Hz,
1H, ribityl-CH), 4.24 (dd, J = 5.3 Hz, J = 12.3 Hz, 1H,
ribityl-CH), 3.77–3.65 (m, 1H, –CHMe), 2.56 (s, 3H,
CH3), 2.44 (s, 3H, CH3), 2.41 (d, J = 7.4 Hz, 2H, –CH2–
CHMe2), 2.28 (s, 3H, COCH3), 2.22 (s, 3H, COCH3),
2.07 (s, 3H, COCH3), 1.91–1.69 (m, 1 H, –CH2–CHMe2),
1.74 (s, 3H, COCH3), 1.49(d, J = 7.0 Hz, 3H, –CHCH3),
0.87 (d, J = 6.6 Hz, 6H, –CH2–CH(CH3)2). Anal.
(C39H46N4O12) C, H, N.
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bonyloxy}ethyl}riboflavin (8): Column chromatography
(dichloromethane:ethyl acetate = 2/1 followed by ethyl
acetate:diethyl ether = 2/1) yielded 0.060 g (26%) of a
yellow product. IR (KBr) 1748 cmꢀ1; MS m/z 777 (M+1)+.
1H NMR (CDCl3) d 8.06 (s, 1H, 9-H), 7.55 (s, 1H, 6-H),
7.16 (d, J = 8.1 Hz, 2H, phenyl-H), 6.99 (d, J = 8.1 Hz,
2H, phenyl-H), 5.73–5.60 (m, 1H, ribityl-CH), 5.49–5.37
(m, 2H, 2· ribityl-CH), 5.27–4.63 (m, 2H, 2· ribityl-CH),
4.58–4.20 (m, 6H, N–CH2, –COOCH2, 2· ribityl-CH),
3.67 (q, J = 7.1 Hz, 1H, –CHMe), 2.56 (s, 3 H, CH3), 2.45
23. Robertson, F. M.; Parrett, M. L.; Joarder, F. S.; Ross, M.;
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1998, 122, 165.
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´
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´
´

C. Banekovich et al. / Bioorg. Med. Chem. Lett. 17 (2007) 683–687
687
(s, 3H, CH3), 2.33 (d, J = 7.2 Hz, 2H, –CH2–CHMe2),
2.30 (s, 3H, COCH3), 2.22 (s, 3H, COCH3), 2.07 (s, 3H,
COCH3), 1.82–1.69 (m, 1H, –CHMe2), 1.75 (s, 3H,
COCH3), 1.45 (d, J = 7.1 Hz, 3H, –CHCH3), 0.84 (d,
J = 6.6 Hz, 6H, –CH2–CH(CH3)2). Anal. (C40H48N4O12)
C, H, N.
(d, J = 7.2 Hz, 3H, –CHCH3), 0.87 (d, J = 6.8 Hz, 6H,
–CH2–CH(CH3)2). Anal. (C42H52N4O12 · 0.2 diisopropyl
ether · 0.3 H2O) C, H, N.
20,30,40,50-Tetraacetyl-3-{5-{[1-(4-isobutylphenyl)ethyl]car-
bonyloxy}pentyl}riboflavin (11): Column chromatography
(dichloromethane:ethyl acetate = 2/1) and circular chroma-
tography (dichloromethane:ethyl acetate = 2/1) yielded
20,30,40,50-Tetraacetyl-3-{3-{[1-(4-isobutylphenyl)ethyl]car-
bonyloxy}propyl}riboflavin (9): Column chromatography
(dichloromethane:ethyl acetate = 2/1 followed by ethyl
acetate:diethyl ether = 2/1) yielded 0.140 g (35%) of a
yellow solid. IR (KBr) 1751 cmꢀ1; MS m/z 791 (M+1)+.
1H NMR (CDCl3) d 8.03 (s, 1H, 9-H), 7.54 (s, 1H, 6-H),
7.22 (d, J = 8.2 Hz, 2H, phenyl-H), 7.07 (d, J = 8.2 Hz,
2H, phenyl-H), 5.74–5.60 (m, 1H, ribityl-CH), 5.50–5.37
(m, 2H, 2· ribityl-CH), 5.22–4.71 (m, 2H, 2· ribityl-CH),
4.44 (dd, J = 2.5 Hz, J = 12.3 Hz, 1H, ribityl-CH), 4.28–
4.07 (m, 5H, N–CH2, –COOCH2, ribityl-CH), 3.72 (q,
J = 7.2 Hz, 1H, –CHMe), 2.55 (s, 3H, CH3), 2.44–2.40 (m,
5H, CH3, –CH2–CHMe2), 2.29 (s, 3H, COCH3), 2.22 (s,
3H, COCH3), 2.11–1.69 (m, 3H, –CH2–, CH2–CHMe2),
2.07 (s, 3H, COCH3), 1.73 (s, 3H, COCH3), 1.50 (d,
J = 7.2 Hz, 3H, –CHCH3), 0.88(d, J = 6.4 Hz, 6H, –CH2–
CH(CH3)2). Anal. (C41H50N4O12) C, H, N.
0.320 g (59%) of a yellow solid; IR (KBr) 1752 cmꢀ1
;
1
MS m/z 819 (M+1)+. H NMR (CDCl3) d 8.03 (s, 1H, 9-
H), 7.53 (s, 1H, 6-H), 7.20 (d, J = 8.2 Hz, 2H, phenyl-H),
7.09 (d, J = 8.2 Hz, 2H, phenyl-H), 5.71–5.63 (m, 1H,
ribityl-CH), 5.46–5.37 (m, 2H, 2· ribityl-CH), 5.27–4.67
(m, 2H, 2· ribityl-CH), 4.44 (dd, J = 2.5 Hz, J = 12.3 Hz,
1H, ribityl-CH), 4.24 (dd, J = 5.3 Hz, J = 12.5 Hz, 1H,
ribityl-CH), 4.11–3.96 (m, 4H, N–CH2, COOCH2), 3.68
(q, J = 7.1 Hz, 1H, –CHMe), 2.55 (s, 3H, CH3), 2.44 (s,
3H, CH3), 2.44 (d, J = 7.2 Hz, 2H, –CH2–CHMe2), 2.29
(s, 3H, COCH3), 2.22 (s, 3H, COCH3), 2.07 (s, 3H,
COCH3), 1.91–1.58 (m, 5H, 2· –CH2–, –CH2–CHMe2),
1.73 (s, 3H, COCH3), 1.50–1.26 (m, 2H, –CH2), 1.48 (d,
J = 7.1 Hz, 3H, –CHCH3), 0.89 (d, J = 6.6 Hz, 6H, –CH2–
CH(CH3)2). Anal. (C43H54N4O12 · 0.4 diisopropyl
ether · 0.4 H2O) C, H, N.
20,30,40,50-Tetraacetyl-3-{4-{[1-(4-isobutylphenyl)ethyl]car-
bonyloxy}butyl}riboflavin (10): Column chromatography
(dichloromethane:ethyl acetate = 2/1 followed by ethyl
acetate:diethyl ether = 2/1) yielded 0.280 g (51%) of a
yellow compound. IR (KBr) 1752 cmꢀ1; MS m/z 805
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1
(M+1)+. H NMR (CDCl3) d 8.03 (s, 1H, 9-H), 7.53 (s,
1H, 6-H), 7.20 (d, J = 8.3 Hz, 2H, phenyl-H), 7.07 (d,
J = 8.3 Hz, 2H, phenyl-H), 5.73–5.62 (m, 1H, ribityl-CH),
5.50–5.37 (m, 2H, 2· ribityl-CH), 5.24–4.68 (m, 2H, 2·
ribityl-CH), 4.44 (dd, J = 2.4 Hz, J = 12.2 Hz, 1H, ribityl-
CH), 4.24–4.03 (m, 5H, N–CH2, –COOCH2, ribityl-CH),
3.68 (q, J = 7.2 Hz, 1 H, –CHMe), 2.55 (s, 3H, CH3), 2.44–
2.40 (m, 5H, CH3, –CH2–CHMe2), 2.29 (s, 3H, COCH3),
2.22 (s, 3H, COCH3), 2.07 (s, 3H, COCH3), 1.93–1.64 (m,
5H, 2· –CH2, –CH2–CHMe2), 1.73 (s, 3H, COCH3), 1.48
36. Albert, D.; Zundorf, I.; Dingermann, T.; Muller, W. E.;
¨
Steinhilber, D.; Werz, O. Biochem. Pharmacol. 2002, 64,
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1767.
37. Ott, I.; Koch, T.; Shorafa, H.; Bai, Z.; Poeckel, D.;
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2282.