4-Phenoxybutoxy-substituted heterocycles - A structure-activity relationship study of blockers of the lymphocyte potassium channel Kv1.3

Article abstract of DOI:10.1016/j.ejmech.2008.10.033

The voltage-gated potassium channel Kv1.3 constitutes an attractive pharmacological target for the treatment of effector memory T cell-mediated autoimmune diseases such as multiple sclerosis and psoriasis. Using 5-methoxypsoralen (5-MOP, 1), a compound isolated from Ruta graveolens, as a template we previously synthesized 5-(4-phenoxybutoxy)psoralen (PAP-1, 2) which inhibits Kv1.3 with an IC₅₀ of 2 nM. Since PAP-1 is more than 1000-fold more potent than 5-MOP, we here investigated whether attaching a 4-phenoxybutoxy side chain to other heterocyclic systems would also produce potent Kv1.3 blockers. While 4-phenoxybutoxy-substituted quinolines, quinazolines and phenanthrenes were inactive, 4-phenoxybutoxy-substituted quinolinones, furoquinolines, coumarins or furochromones inhibited Kv1.3 with IC₅₀s of 150 nM to 10 μM in whole-cell patch-clamp experiments. Our most potent new compound is 4-(4-phenoxybutoxy)-7H-furo[3,2-g]chromene-7-thione (73, IC₅₀ 17 nM), in which the carbonyl oxygen of PAP-1 is replaced by sulfur. Taken together, our results demonstrate that the psoralen system is a crucial part of the pharmacophore of phenoxyalkoxypsoralen-type Kv1.3 blockers.

Full text of DOI:10.1016/j.ejmech.2008.10.033

European Journal of Medicinal Chemistry 44 (2009) 1838–1852
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
4-Phenoxybutoxy-substituted heterocycles – A structure–activity relationship
study of blockers of the lymphocyte potassium channel Kv1.3
,
a
b
a,
*
Silke B. Bodendiek a , Cedrick Mahieux , Wolfram Hansel , Heike Wulff
¨
*
´
a Department of Pharmacology, University of California, Davis, Genome and Biomedical Sciences Facility, 451 Health Sciences Drive, Davis, CA 95616, USA
b Institute of Pharmaceutical Chemistry, University of Kiel, Gutenbergstrasse 76, 24118 Kiel, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The voltage-gated potassium channel Kv1.3 constitutes an attractive pharmacological target for the
treatment of effector memory T cell-mediated autoimmune diseases such as multiple sclerosis and
psoriasis. Using 5-methoxypsoralen (5-MOP, 1), a compound isolated from Ruta graveolens, as a template
we previously synthesized 5-(4-phenoxybutoxy)psoralen (PAP-1, 2) which inhibits Kv1.3 with an IC50 of
2 nM. Since PAP-1 is more than 1000-fold more potent than 5-MOP, we here investigated whether
attaching a 4-phenoxybutoxy side chain to other heterocyclic systems would also produce potent Kv1.3
blockers. While 4-phenoxybutoxy-substituted quinolines, quinazolines and phenanthrenes were inac-
tive, 4-phenoxybutoxy-substituted quinolinones, furoquinolines, coumarins or furochromones inhibited
Received 25 June 2008
Received in revised form
25 October 2008
Accepted 30 October 2008
Available online 5 November 2008
Keywords:
Kv1.3
Voltage-gated potassium channel
PAP-1
Immunosuppression
Kv1.3 with IC50s of 150 nM to 10 mM in whole-cell patch-clamp experiments. Our most potent new
compound is 4-(4-phenoxybutoxy)-7H-furo[3,2-g]chromene-7-thione (73, IC50 17 nM), in which the
carbonyl oxygen of PAP-1 is replaced by sulfur. Taken together, our results demonstrate that the psoralen
system is a crucial part of the pharmacophore of phenoxyalkoxypsoralen-type Kv1.3 blockers.
Ó 2008 Elsevier Masson SAS. All rights reserved.
1. Introduction
the scorpion toxins kaliotoxin and margatoxin and the sea
anemone toxin ShK and its more Kv1.3 selective derivative ShK(L5)
Voltage-gated Kv1.3 and calcium-activated KCa3.1 channels play
an important role in T cell activation by providing the counter-
balancing potassium efflux for the calcium influx which is
necessary for T cell activation [1]. However, which of these two
potassium channels is the dominating player in these events
depends on the activation and the differentiation state of the
respective T cell. While CCR7þ naive and central memory T cells
(TCM), which mediate acute immune responses, up-regulate KCa3.1
following activation, CCR7ꢀ effector memory T cells (TEM) up-
regulate Kv1.3 and rely on this channel for their calcium signaling
and proliferation [2,3]. Kv1.3 blockade has therefore been proposed
have been demonstrated to effectively prevent or treat delayed-
type hypersensitivity [5,6], experimental autoimmune encephalo-
myelitis [6–8], pristane-induced arthritis [3] and experimental
periodontal bone resorption [9] in rats. Although, many of these
peptides exhibit exquisite potency and selectivity and could
potentially be developed into drugs given the advances in peptide
delivery techniques, several pharmaceutical companies and
academic groups have attempted to identify non-peptidic small
molecule Kv1.3 blockers. The best known of the ‘‘industrial’’ Kv1.3
blockers are Pfizer’s CP-339818 and UK-78282 and Merck’s nor-
triterpene correolide and cyclohexyl-substituted benzamides
(PACs) (see a recent book chapter [10] and several reviews [1,11]).
However, none of these compounds are potent and selective
enough for development into drugs.
In the late 1980s anecdotal reports appeared from Chile and
Austria that drinking tea prepared from the leaves of Ruta grave-
olens, the common rue or the Herb of Grace, supposedly alleviated
the symptoms of multiple sclerosis. During the next few years the
groups of Wolfram Ha¨nsel and Eilhard Koppenho¨fer screened
extracts from Ruta and eventually identified various psoralens as
the potassium channel blocking principle of the plant [12,13]. The
main ingredient, 5-methoxypsoralen (5-MOP, 1), a drug that is used
in Europe for the treatment of psoriasis, was shown to block Kv1.3
and other Kv1-family channels in the micromolar range [14] and to
as
a promising pharmacological approach for the selective
suppression of TEM cell activation in T cell-mediated autoimmune
diseases such as type-1 diabetes, rheumatoid arthritis and multiple
sclerosis, where TEM cells are involved in the pathogenesis [3,4]. In
proof of this therapeutic concept Kv1.3 blocking peptides such as
Abbreviations: TCM, central memory T cell; TEM, effector memory T cell; 5-MOP,
5-methoxypsoralen; MPLC, middle pressure liquid chromatography; PAP, phenox-
yalkoxypsoralen; 4-PBB, 4-phenoxybutyl bromide; DMFDMA, N,N-dimethylforma-
mide dimethylacetal.
* Corresponding authors. Tel.: þ1 530 754 7400; fax: þ1 530 752 7710.
E-mail addresses: sbodendiek@ucdavis.edu (S.B. Bodendiek), hwulff@ucdavi-
s.edu (H. Wulff).
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.10.033

S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
1839
reduce visual field defects in single-case studies in multiple scle-
rosis patients [15]. Since 5-MOP’s phototoxicity precluded its use as
a drug for multiple sclerosis, we synthesized a large number of
differently substituted psoralens with the aim of eliminating pho-
toreactivity and increasing potency and selectivity for Kv1.3
[14,16,17]. As a result of this effort an over 1000-fold increase in
potency in comparison to 5-MOP (1) was achieved by exchanging
the methoxy group in 5-position with a 4-phenoxybutoxy group
(see Fig. 1). This 5-(4-phenoxybutoxy)psoralen (PAP-1, 2), blocks
Kv1.3 with an IC50 of 2 nM, is 23-fold selective over the cardiac
Kv1.5 channel (IC50 45 nM), 33- to 125-fold selective over Kv1.1,
Kv1.2, Kv1.4, Kv1.6 and Kv1.7 and more than 1000-fold selective
over more distantly related channels like HERG (Kv11.1), Naþ, Ca2þ
and Clꢀ channels [17]. PAP-1 further does not display any in vitro or
in vivo toxicity [17], and is orally available and has a half-life of 3 h
in rats and of 6.7 h in rhesus macaques [3,18]. In keeping with its
inhibitory effect on TEM cell function in vitro [3,17], PAP-1 also
effectively suppresses oxazolone-induced allergic contact derma-
titis [19] and significantly delays the onset and reduces the inci-
dence of type-1 diabetes [3] in rat models. Based on these results
our laboratory has proposed PAP-1 as a potential new drug for the
topical treatment of psoriasis and potentially for the oral treatment
of other TEM cell-mediated autoimmune diseases [19,20]. However,
despite the fact that we demonstrated that PAP-1 is not phototoxic
[17] and that administration for 28 days or 6 months does not lead
to any changes in liver enzymes or liver pathology in rats or rhesus
macaques [3,18], pharmaceutical companies have been very hesi-
tant to develop PAP-1 because psoralens are generally regarded as
‘‘toxicophores’’ due to the possibility that the coumarin ring could
act as a Michael acceptor in reactions with glutathione and thus
could potentially cause liver toxicity. There further is the possibility
that the psoralen system could be epoxidated by cytochrome P450
enzymes and thus generate reactive metabolites.
synthesis or in an analogous reaction using potassium carbonate or
CsF-Celite as solid base (Scheme 1: iv; Schemes 2 and 3). As shown
in Scheme 3 the alkylation of the acridine derivative 27 preferen-
tially resulted in the N-alkylated derivative 28. The O-alkylated
compound could not be isolated.
In cases where only methoxy-substituted scaffolds were
commercially available, we first demethylated the scaffold using
either HCl or the Lewis acid boron tribromide and then re-alkylated
the resulting phenols with 4-phenoxybutyl bromide (4-PBB)
(Scheme 1: iii; Scheme 4). Since the methoxy-substituted furo-
quinolines kokusagenine 29 and skimmianine 30 were not
commercially available in sufficient quantities and their extraction
is well established [21], we isolated them from dried leaves of R.
graveolens by MPLC (for details see Section 5).
If neither the alcohol nor the methoxy-substituted derivative of
a desired structure was commercially available, we built the
heterocyclic ring systems in various multi-step reactions (Scheme
1: i and ii; Schemes 5–8).
The coumarin derivative 42 (Scheme 5) was synthesized starting
from 2,6-dimethoxybenzaldehyde (39), which was reacted in
a Wittig reaction to the methoxycinnamate 40. In a subsequent
reaction with boron tribromide 40 was then demethylated in 5-
position under simultaneous ring closure to the 5-hydrox-
ycoumarin (41). In a final Williamson ether synthesis analogous
reaction using CsF-Celite as base 41 was reacted to 42 with 4-PBB.
The benzofuran derivative 45 (Scheme 5) was synthesized in two
steps: First, 6,7-dihydro-5H-benzofuran-4-one (43) was converted
into the aromatic 4-hydroxybenzofuran (44) using Pd–charcoal as
catalytic agent and 1-dodecene as hydrogen acceptor. In a second
step 44 was alkylated with 4-PBB in a Williamson ether synthesis
analogous reaction using potassium carbonate as base.
The chromone derivatives 51, 56 and 59 were synthesized
according to Scheme 6 using the natural product visnagin (46) as
starting compound. For compound 51 the chromone ring of 46 was
cleaved under basic conditions to afford the methylketone visna-
ginone (47). In a second step 47 was reacted with N,N-dime-
thylformamide dimethylacetal (DMFDMA) in an aldol condensation
to give 48. The enaminone 48 was refluxed with glacial acetic acid
to again form a chromone ring in an addition–elimination reaction
(49). The chromone 49 was then demethylated with boron tri-
bromide to the phenol 50 and afterwards alkylated using CsF-Celite
as base to afford 51. For the synthesis of compounds 56 and 59 the
furan ring of visnagin (46) was oxidatively cleaved with sulfuric
acid to afford 52. To obtain compound 56 the intermediate 52 was
reduced to 53, afterwards alkylated with dibromomethane to 54
and then demethylated with boron tribromide to the phenol 55. In
a final step, 55 was alkylated with 4-PBB in the presence of
potassium carbonate to render the ether 56. For compound 59 the
intermediate 52 was reacted in a Wittig reaction followed by an
intramolecular lactone ring formation. The resulting coumarin ring
substituted chromone 57 was then demethylated using boron tri-
bromide and afterwards alkylated using potassium carbonate to
give 59.
We are therefore searching for alternative heterocyclic systems
to replace the psoralen system of PAP-1. Since attachment of the 4-
phenoxybutoxy side chain in 5-position of 5-MOP led to the above
described dramatic increase in potency, we specifically investigated
whether attaching a 4-phenoxybutoxy side chain to other aromatic
and/or heterocyclic scaffolds, different from the psoralen structure,
would also result in potent Kv1.3 blockers. In order to determine
that we were not loosing selectivity for Kv1.3 over the cardiac Kv1.5
channel, which exhibits a very high degree of homology to Kv1.3 in
the pore region of the channel [1,10,11], we counter-screened all
newly synthesized compounds on Kv1.5.
2. Chemistry
We here synthesized a series of 4-phenoxybutoxy-substituted
aromatic and heteroaromatic systems. For this purpose mono-, bi-
and tricyclic ring systems containing either just carbon atoms or
the heteroatoms nitrogen, oxygen and sulfur were used as scaffolds.
A general overview of the synthesis sequences is given in Scheme 1.
In cases where the desired scaffolds were commercially avail-
able as aliphatic or phenolic alcohols, the 4-phenoxybutoxy side
chain could be directly attached in a classic Williamson ether
Compound 63 was synthesized starting from khellinone (60)
according to Scheme 7. Compound 60 was first reacted in a Wittig
O
OMe
O
Optimization
O
O
O
O
O
O
5-MOP (1)
IC50 (Kv1.3) = 101 μM
PAP-1 (2)
IC50 (Kv1.3) = 2 nM
Fig. 1. Design of PAP-1 based on the template 5-MOP.

1840
S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
i
Different
Starting Compounds
Heterocycle
iii
OMe
OH
ii
Heterocycle
iv
O
Heterocycle
O
Scheme 1. General strategy of synthesis. Reagents: (i) Schemes 6–8, (ii) Scheme 5, (iii) Scheme 4, (iv) Schemes 2 and 3.
reaction to the furocoumarin 61, which was then cleaved to the
corresponding phenol 62 with boron tribromide. To obtain 63,
compound 62 was alkylated as described above for the chromone
derivatives.
in two main products, the O-alkylated (71, 27% yield) and the N-
alkylated (72, 5% yield) derivative, which were separated by flash
chromatography.
The thio-analog of PAP-1, 4-(4-phenoxybutoxy)-7H-furo[3,2-
g]chromene-7-thione (73), was synthesized in a one step reaction
adding Lawesson’s reagent to a solution of PAP-1 (Scheme 9). The
preceding synthesis of PAP-1 was performed as described by
Schmitz et al. [17] starting from 5-MOP.
Since the furoquinoline dictamnine (69) was commercially
available only in milligram quantities and furthermore too high-
priced for a synthetic starting compound, we synthesized it in a 6-
step reaction starting from 2,4-quinolinediol (64) according to
Scheme 8. The treatment of 64 in anhydrous benzene with methyl
iodide in the presence of silver carbonate afforded montanine (65).
Using n-butyllithium a formyl group was next introduced in 3-
position of the quinoline system (66). After a Wittig reaction (67)
and subsequent hydrolysis with HCl 68 was obtained. Treatment of
68 with polyphosphoric acid at 125 ꢁC resulted in the formation of
a furan ring to render the furoquinoline dictamnine (69). Surpris-
ingly the cleavage of the methoxy group on the C-4 carbon of 69
proved difficult. Neither boron tribromide nor HCl, both commonly
used reagents for demethylation reactions and used for the other
herein synthesized compounds, failed to cleave the methoxy group.
Finally, refluxing 69 with sodium isopropyl thiolate in DMF gave 70
in low but adequate yields. The alkylation of 70 with 4-PBB resulted
3. Results and discussion
3.1. Inhibition of Kv1.3 channels
The inhibition of Kv1.3 channels by the newly synthesized
compounds was determined by manual whole-cell patch-clamp on
L929 cells stably expressing Kv1.3. The results are listed in Table 1.
We first investigated whether simple aromatic carbocyclic systems
such as phenol, 1-naphthol and 9-hydroxyphenanthrene could be
turned into potent Kv1.3 blockers by attaching the 4-phenox-
ybutoxy side chain. All three derivatives (compounds 15, 16 and 26)
exhibited IC50 values higher than 10
mM demonstrating that the
i
O
R OH
R O
15-26
3-14
R:
N
N
O
O
N
N
N
O
Me
3, 15
4, 16
5, 17
6, 18
9, 21
7, 19
8, 20
O
O
OMe
O
5
4'
4
6
Me
3
5'
O
1'
O
O
O
7
2
8
1
OMe
O
12, 24
11, 23
13, 25
10, 22
14, 26
Scheme 2. Synthesis of 4-phenoxybutoxy-substituted aromatic systems using commercially available alcohols as starting compounds. (Numbers 3–14 correspond to starting
compounds and numbers 15–26 to products.) Reagents: (i) elemental sodium in ethanol, 4-phenoxybutyl bromide (4-PBB) (reflux); 4-PBB, CsF-Celite in CH3CN (reflux) or 4-PBB,
K2CO3/KI in acetone (reflux) or DMF (120 ꢁC or reflux).

S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
1841
O
OH
N
O
N
i
N
H
OMe
OMe
O
OMe
27
28
Scheme 3. Synthesis of compound 28. Reagents: (i) 4-PBB and CsF-Celite in CH3CN (reflux).
psoralen moiety of the phenoxyalkoxypsoralen-type Kv1.3 blockers
cannot be replaced by 1-, 2- or 3-membered ring systems without
heteroatoms. We next attached the 4-phenoxybutoxy side chain to
bicyclic ring systems containing nitrogen as a heteroatom and bi- or
tricyclic ring systems containing either only oxygen or oxygen and
nitrogen. The bicyclic compounds containing nitrogen like the
quinoline derivative 17 and the quinazoline derivative 19 were
ineffective at a concentration of 10 mM, whereas the isoquinoline
derivative 18 blocked Kv1.3 with an IC50 of 520 nM. The bicyclic
flavone derivative 22 containing oxygen as a heteroatom blocked
compound would be as potent or even more potent than PAP-1 (2,
IC50 2 nM). However, the dictamnine derivative 71 and the N-
alkylated compound 72 only showed IC50 values of 1 mM, whereas
the dimethoxy-substituted kokusagenine derivative 34 and the
skimmianine derivative 35 blocked Kv1.3 with IC50 values of
150 nM and 200 nM, respectively.
As neither attachment of the 4-phenoxybutoxy side chain to
simple carbo- or heterocyclic aromatic systems rendered low
nanomolar Kv1.3 blockers, we concluded that the scaffold has to be
more similar to the psoralen system of PAP-1. We therefore next
investigated which parts of the psoralen system were necessary for
high affinity Kv1.3 blockade and which parts, if any, could be
dispensed with. Since the psoralen (¼furocoumarin) ring system
contains both a benzofuran and a coumarin system as substruc-
tures, we attached the 4-phenoxybutoxy side chain to both these
scaffolds. The benzofuran derivative 45, which compared to the
psoralen lacks only the lactone ring, was potent with an IC50 of
650 nM. The coumarin derivatives 21 and 42, lacking the furan ring
of the psoralen system, showed IC50 values of 890 nM, when the
side chain was attached in the 4-position, and of 150 nM, when the
side chain was attached in the 5-position. However, since both
the benzofurans and the coumarins were 100-fold less potent than
the psoralen PAP-1, we next decided to look at even smaller vari-
ations on the psoralen scaffold. For the psoralen derivatives 23, 38
and 63 the position of the side chain was varied from 5-position to
4- and 8-positions and additional groups were added like methoxy
groups in 5- and 8-positions or a methyl group in 4-position.
Compound 38, which contained the side chain in 8-position and no
Kv1.3 with an IC50 of 1
containing oxygen, were only very weak Kv1.3 blockers with IC50
values of 12 and 7 M. Both compounds were not fully aromatic and
mM. The tricyclic compounds 24 and 25, both
m
in the case of 24 not planar suggesting that aromaticity and
planarity are required for high affinity Kv1.3 inhibition. The bicyclic
quinolinone derivative 20, containing both nitrogen and oxygen
and being an aza-analogous derivative of the coumarin system,
which is part of the psoralen moiety, blocked Kv1.3 with an IC50 of
670 nM. Compound 28, an acridone derivative with the side chain
connected to nitrogen, showed a remarkably low IC50 of 165 nM
demonstrating that there is a certain degree of flexibility in the
binding site assuming that 28 binds to the same site on Kv1.3 as
PAP-1.
We further synthesized a number of furoquinolines because
kokusagenine (29), a furoquinoline occurring in R. graveolens, had
been previously reported by our group to inhibit Kv1.3 with an IC50
of 10
mM [22]. Since this IC50 was lower than the IC50 of 5-MOP (1,
IC50 101
mM [14]), we hoped that the 4-phenoxybutoxy-substituted
i
ii
O
R O
R OMe
R OH
29-33
29a-33a
34-38
R:
OMe
OMe
O
O
N
N
OMe
OMe
29, 29a, 34
30, 30a, 35
O
O
O
8
7
4
3
5
O
O
O
6
2
5'
2
3
O
1
O
Me
Me
O
6
5
7
4'
4
9
8
OMe
32, 32a, 37
33, 33a, 38
31, 31a, 36
Scheme 4. Synthesis of 4-phenoxybutoxy-substituted aromatic systems using methoxy-substituted scaffolds as starting compounds. (Numbers 29–33 correspond to starting
compounds, numbers 29a–33a to the respective alcohols and numbers 34–38 to products). Reagents: (i) HCl (reflux) or BBr3 (5 ꢁC) and CH2Cl2 (reflux); (ii) 4-PBB, CsF-Celite in
CH3CN (reflux) or 4-PBB, K2CO3/KI in acetone (reflux) or DMF (120 ꢁC or reflux).

1842
S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
O
OH
OMe
O
OMe O
O
iii
i
ii
OMe
H
O
O
OMe
OMe
O
O
O
41
42
40
39
O
O
OH
iv
v
O
O
O
44
45
43
Scheme 5. Synthesis of compounds 42 and 45. Reagents: (i) (C6H5)3PCHCOOCH3, toluene (reflux, 3 h); (ii) BBr3 (5 ꢁC) and CH2Cl2 (reflux); (iii) 4-PBB, CsF-Celite in CH3CN (reflux);
(iv) palladium–charcoal, 1-dodecene/decalin (reflux, 20 h); (v) 4-PBB, K2CO3/KI in DMF (reflux).
further variations compared to PAP-1, showed an IC50 value of 1
m
M.
two additional methoxy groups in 5- and 8-positions exhibited
IC50s of 318 nM and 450 nM, respectively. As further variations of
the psoralen system we next exchanged the lactone ring (2-chro-
mone ring) with the isomeric 4-chromone ring, which resulted in
Compound 63 with the side chain in 8-position and additional
groups, a methoxy group in 5-position and a methyl group in 4-
position, and compound 23 with the side chain in 4-position and
OMe O
OMe O
i
O
OMe O
vi
Me
H
O
Me
O
O
HO
O
Me
OH
46
52
47
vii
ii
OMe O
OMe O
HO
Me
Me
xi
N
HO
O
Me
O
O
OH
48
53
iii
viii
OMe O
OMe O
OMe O
O
O
O
Me
Me
O
O
O
O
O
O
Me
Me
49
57
54
xii
iv
ix
O
O
OH
O
O
OH
O
OH
O
O
O
O
50
55
58
xiii
v
x
O
O
O
O
O
O
O
O
O
4
3
5
O
O
6
7
2
O
1
Me
Me
O
O
O
O
O
9
8
51
56
59
Scheme 6. Synthesis of chromone derivatives 51, 56 and 59. Reagents: (i) KOH (0.2 M; reflux, 15 min); (ii) DMFDMA in toluene (reflux, 3 h); (iii) CH3COOH (reflux, 5 h); (iv) BBr3
(5 ꢁC) and CH2Cl2 (reflux); (v) 4-PBB, CsF-Celite in CH3CN (reflux); (vi) H2SO4 (1 M), K2Cr2O7 (0.3 M, 2 h); (vii) NaOH (1 M), H2O2 (10 M), 25 ꢁC (2–3 h); (viii) K2CO3, CH2Br2 in DMF
(95 ꢁC, 4 h); (ix) BBr3 (5 ꢁC) and CH2Cl2 (reflux); (x) 4-PBB, K2CO3/KI in DMF (reflux); (xi) (C6H5)3PCHCOOCH3, toluene (reflux, 6 h); (xii) BBr3 (5 ꢁC) and CH2Cl2 (reflux); (xiii) 4-PBB,
K2CO3/KI in DMF (120 ꢁC).

S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
1843
OMe O
OMe Me
OMe Me
Me
O
OMe
iii
ii
i
Me
OH
O
O
O
O
O
O
O
O
O
O
OMe
OMe
OH
O
60
62
63
61
Scheme 7. Synthesis of compound 63. Reagents: (i) (C6H5)3PCHCOOCH3, toluene (reflux, 3 h); (ii) BBr3 (5 ꢁC) and CH2Cl2 (reflux); (iii) 4-PBB and CsF-Celite in CH3CN (reflux).
a quite potent Kv1.3 blocker (51, 170 nM). Adding a methyl group in
7-position of 51 (corresponding to the 2-position of the psoralen
system) only slightly decreased potency (36, 233 nM), while further
substitution with a methoxy group in 9-position (corresponding to
the 8-position of the psoralen system) decreased the IC50 into the
Ringer solution for at least 24 h (data not shown). This demon-
strates that the Kv1.3 inhibition measured in the electrophysio-
logical experiments is due to 73 itself and not to PAP-1 resulting
from potential hydrolysis.
All our newly synthesized compounds exhibited Hill coefficients
close to 2 for Kv1.3 inhibition similar to the psoralens Psora-4 and
PAP-1 [16,17], 7-substituted khellinones [23], khellinone chalcones
[24] and the cyclohexyl-substituted benzamides (cyclohexanones)
[25], suggesting that two or more molecules of each compound
interact with one Kv1.3 channel protein in a cooperative manner.
However, the synthesized compounds differed in their blocking
kinetics (Fig. 2). Compounds 34–36 and 73 exhibited pronounced
‘‘use-dependence’’ (meaning that these compounds only reach
equilibrium block after 8–10 depolarizing pulses) indicating
a preferential block of the C-type inactivated state of Kv1.3 similar
to what had been previously described for the psoralens Psora-4
and PAP-1 [16,17] (Fig. 2A). In contrast, the remaining compounds
exhibited a typical open-channel block (Fig. 2B) similar to verap-
amil and the khellinone chalcones [24] and could be washed out
easily during the patch-clamp experiments.
micromolar range (37, 1.5
either a methylenedioxy group or a 2-chromone ring reduced
potency even further (56, 5 M; 59, 6 M). Based on these results
mM). An exchange of the furan ring with
m
m
we concluded that both the position of the side chain as well as the
substitution pattern of the psoralen system is crucial for obtaining
low nanomolar Kv1.3 inhibitors. Further it is not possible to
exchange the 2-chromone ring for a 4-chromone ring without
significantly loosing potency.
Since every greater variation of the psoralen scaffold resulted in
a significant loss of potency in comparison to PAP-1 (IC50 2 nM), we
next decided to only replace one atom in the psoralen scaffold and
exchanged the carbonyl oxygen in 2-position with a sulfur. This
variation resulted in 73 (IC50 17 nM), the most potent Kv1.3 blocker
in our current study. HPLC studies on stability showed that 73 is
stable in DMSO stock solutions for more than 12 months and in
OMe
OMe
OH
i
ii
CHO
OMe
OMe
N
N
OH
N
65
66
64
iii
OMe
OMe
OMe
v
iv
OMe
CHO
OH
O
OMe
N
N
N
69
68
67
vi
OH
O
O
vii
O
+
O
O
N
N
O
N
O
70
71
72
Scheme 8. Synthesis of compounds 71 and 72. Reagents: (i) silver carbonate in anhydrous hexane, iodomethane (room temperature, dark, 3 days); (ii) n-butyllithium (in hexanes)
(ꢀ10 ꢁC, 45 min) in anhydrous diethyl ether, anhydrous DMF in diethyl ether (0 ꢁC for 30 min, room temperature for 45 min); (iii) potassium tert-butoxide in THF (1 M),
methoxymethyltriphenylphosphonium chloride in anhydrous diethyl ether (room temperature, 1 h), 24 h; (iv) HCl (5.5 M, refluxed, 45 min); (v) polyphosphoric acid (125 ꢁC, 5 h);
(vi) isopropylthiol, sodium hydride in anhydrous DMF (10 min, reflux, 4 h), HCl (2 M, 0 ꢁC); (vii) KHCO3, 4-PBB in 2-butanone (reflux, 25 h).

1844
S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
O
O
O
O
i
O
O
O
S
O
O
73
2
Scheme 9. Synthesis of compound 73. Reagent: (i) Lawesson’s reagent in anhydrous toluene (reflux, 20 h).
3.2. Selectivity over Kv1.5 channels
5. Experimental section
In addition to testing the newly synthesized compounds on
Kv1.3, we determined their selectivity over the closely related Kv1.5
channel. Cross-reactivity to the cardiac potassium channel Kv1.5 is
a common problem for small molecule Kv1.3 blockers. Nearly all
known small molecule Kv1.3 blockers such as correolide [26], PAC
[25], Psora-4 [16] and the khellinone chalcones [24] inhibit Kv1.5 as
potently as Kv1.3 or only display a very moderate 2- to 3-fold
selectivity. Out of the existing small molecule Kv1.3 blockers, our
template PAP-1 currently displays the highest selectivity (23-fold)
for Kv1.3 over Kv1.5 [17].
As shown in Table 1, the selectivity, which we define as IC50 for
Kv1.5 divided by the IC50 for Kv1.3, ranged from 0.34-fold for
compound 56 to 22-fold for compound 73. While compounds 17, 63
and 56 inhibited Kv1.5 roughly 3 times more potently than Kv1.3,
most compounds were relatively unselective and inhibited both
channels with nearly equal affinity or showed a moderate 2–5
selectivity for Kv1.3. The only compound that exhibited a higher
selectivity is the thio-analog of PAP-1, compound 73, which is 22
times more potent on Kv1.5 and hence as selective as PAP-1.
5.1. Materials and methods
Melting points were determined in open capillary tubes using
an electrothermal melting point apparatus (Stuart Scientific,
SMP03) and are uncorrected. Mass spectra (MS) were recorded on
a Hewlett–Packard HP5989A-MS Engine mass spectrometer (70 eV,
low resolution) or a Finnigan MAT 8230 (70 eV, high resolution) at
the University of Kiel (Germany) or on a VG ProSpec spectrometer
(70 eV, low and high resolution) at the University of California,
Berkeley. Elemental analyses were performed by a Hewlett–Pack-
ard CHN autoanalyzer for carbon, nitrogen, hydrogen, and sulfur at
the University of Kiel, Germany. Proton nuclear magnetic resonance
(1H NMR) and carbon nuclear magnetic resonance spectra (13
NMR) were obtained on a Bruker ARX 300 (University of Kiel,
Germany) or on a Bruker ARX 500 (University of California, Davis)
with the mentioned solvents. Chemical shifts are reported in parts
per million (ppm) on the
appropriate solvent peaks (CDCl3 referenced to CHCl3 at dH
7.24 ppm; DMSO-d6 referenced to DMSO at 2.49 ppm) or TMS as
C
d scale and were referenced to the
4. Conclusions
Table 1
IC50 values on Kv1.3 and Kv1.5.
We here synthesized a series of 4-phenoxybutoxy-substituted
heterocycles with the aim of obtaining alternative Kv1.3 inhibitors
that do not contain the psoralen system of our previously described
Kv1.3 blocker PAP-1. A high percentage of these newly synthesized
compounds such as 4-phenoxybutoxy-substituted quinolinones,
furoquinolines, coumarins or furochromones blocked Kv1.3 with IC50
Compounda
IC50 value in
Kv1.3
m
M
Selectivity
IC50(Kv1.5)/IC50(Kv1.3)
Kv1.5
5-MOP [14]
PAP-1 [17]
15
101
0.002
20
177
0.045
n.d.
n.d.
3.5
0.52
w25
1.5
1.5
10
0.85
15
10
1.75
22.5
–
values between 150 nM and 10
m
M. Especially compound 42, which
16
17
18
19
15
–
>10
0.52
No effectb
0.67
0.89
1
<0.35
1
–
2.24
1.69
10
1.89
1.25
1.43
–
2.73
3.2
4.9
1.33
1.67
1
3.47
1.54
1.18
0.34
1
lacks only the furan ring of PAP-1, is a relatively potent Kv1.3 blocker
(IC50 ¼ 150 nM). In contrast, compounds where the psoralen system
was replaced by quinolines, quinazolines or simple carbocyclic
aromatic systems such as phenanthrene had no effect on Kv1.3
demonstrating that attaching a 4-phenoxybutoxy side chain is not
sufficient to render any aromatic system a potent Kv1.3 blocker. In
general, all variations of the PAP-1 structure significantly reduced
Kv1.3 blocking potency demonstrating that both the psoralen system
and the 4-phenoxybutoxy side chain are essential for potent Kv1.3
inhibition. The only structural variation that was tolerated in the
pharmacophore was a replacement of the carbonyl oxygen in the
coumarin ring of the psoralen system with a sulfur atom (73, IC50
17 nM). Despite the fact that we were not able to obtain a more potent
Kv1.3 blocker than our previously published compound PAP-1, the
newly synthesized compounds will be valuable tool compounds for
validating mutagenesis and/or molecular modeling studies that are
aiming to define the binding site of PAP-1 on the Kv1.3 protein.
Based on our results we conclude that phenoxyalkoxypsoralen-
type Kv1.3 blockers have a very steep structure–activity relation-
ship and that PAP-1 very likely already constitutes the optimum in
terms of potency and selectivity that is attainable with this phar-
macophore. However, in future it will be interesting to further
probe the pharmacophore with subtle variations such as replacing
more than one of the oxygen atoms in the psoralen system with
nitrogen or sulfur.
20
21
22
23
24
25
26
28
34
35
36
37
38
42
45
51
56
59
63
71
0.45
12
7
No effectb
0.165
0.15
0.2
No effectb
0.45
0.48
0.98
0.31
2.5
1
0.52
1
0.2
1.7
6
0.28
2
0.233
1.5
1
0.15
0.65
0.17
5
6
0.318
1
1
0.88
2
2
72
73
2
0.38
0.017
22
n.d. – not determined.
a
Each compound was tested three times at 4–5 concentrations. Each experiment
was performed on a different cell. Standard deviations: 3–20% (Kv1.3); 3–30%
(Kv1.5).
b
Tested at 10 mM.

S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
1845
A
B
[nA]
4
[nA]
63
73
control
control
10 nM
2
3
2
500 nM
1
0
1 μΜ
25 nM
1
0
100 nM
500 ms
500 ms
Fig. 2. Kinetics of block. The synthesized compounds can be divided into two groups depending on their kinetics of block. (A) Compounds 34–36 and 73 (shown) block the C-type
inactivated state. (B) All other compounds (63 shown as an example) are open-channel blockers.
internal standard. If necessary the 1H and 13C peaks were assigned
with the help of COLOC, COSY and NOESY experiments. Signals are
designated as follows: s (singlet), d (doublet), dd (doublet of
doublets), ddd (doublet of doublet of doublets), dt (doublet of
triplets), t (triplet), quint (quintet), m (multiplet). Yields were not
optimized. Analytical thin-layer chromatography (TLC) was per-
formed on Merck silica gel 60F254 aluminum-backed plates. Chro-
matographic separation was performed by flash (Merck silica gel,
and afterwards the pooled organic phases were evaporated. The
resulting residue was purified by recrystallization or MPLC to
obtain the pure alcohols.
5.3. Synthesized compounds
5.3.1. 1,10[1,4-Butanediyl(oxy)]bis-benzene (15)
350 mg (15 mmol) of sodium were dissolved in 80 mL ethanol
and 1.98 g of phenol (3, 21 mmol) were added. After subsequently
adding 2.75 g of 4-PBB (12 mmol) and refluxing the solution for 2 h
the solvent was evaporated and NaOH (1.5 M) was added to the
resulting residue. This solution was extracted twice with diethyl
ether. The pooled organic phases were washed with water, dried
over Na2SO4 and evaporated under vacuum. After recrystallization
from ethanol 15 (1.5 g, 30%) was obtained as white crystals: mp
101 ꢁC (Lit. 101 ꢁC [28]). The spectroscopic data were in accordance
with literature [28].
40–60
prepÒ Merck 25–40
active, basic, 63–200
m
m) or middle pressure chromatography (MPLC) (LiChro-
m and 40–63 m or aluminum oxide 90
m). The proportions of solvents for the
m
m
m
chromatography are expressed in volume to volume (v:v).
As described in Section 2 commercially available alcohols were
used directly for a Williamson ether synthesis or an analogous
synthesis (general procedure A or B, Schemes 2 and 3). Commer-
cially available methoxy-substituted starting compounds were
demethylated according to general procedure C (Scheme 4). All
non-commercially available starting compounds were synthesized
(Schemes 5–9).
5.3.2. 1-(4-Phenoxybutoxy)naphthalene (16)
350 mg (15 mmol) of sodium were dissolved in 80 mL ethanol
and 3.03 g of 1-naphthol (4, 21 mmol) were added. After adding
2.75 g of 4-PBB (12 mmol) and refluxing the solution for 2 h the
solvent was evaporated and NaOH (1.5 M) was added to the
resulting residue. This solution was extracted twice with diethyl
ether. The pooled organic phases were washed with water, dried
over Na2SO4 and evaporated under vacuum to give 16 (550 mg, 9%)
5.2. General synthesis procedure
5.2.1. Williamson analog ether synthesis
5.2.1.1. General procedure A. To a suspension of CsF-Celite (prepa-
ration of CsF-Celite see Lee and Choi [27]) and the respective
alcohol in dried acetonitrile the alkylating agent, 4-phenoxybutyl
bromide (4-PBB), was added dropwise and the reaction mixture
was refluxed. The progress of the reaction was monitored by TLC.
After completion of the reaction, the reaction mixture was filtered
and the solvent was evaporated in vacuo. The resulting residue was
purified by MPLC and/or recrystallized.
as white crystals: mp 76–77 ꢁC; 1H NMR (DMSO-d6)
d: 1.95–2.04
(m, 4H, 4-O–CH2–(CH2)2–CH2–O–C6H5), 4.08 (t, 2H, 3J ¼ 6.1 Hz, 4-
O–(CH2)3–CH2–O–C6H5), 4.22 (t, 2H, 3J ¼ 5.9 Hz, 4-O–CH2–(CH2)3–
O–C6H5), 6.91–6.97 (m, 4H, H-4, H-20, H-40 and H-60), 7.26–7.30 (m,
2H, H-30 and H-50), 7.41 (t, 1H, 3J ¼ 7.9 Hz, H-3), 7.45–7.53 (m, 3H, H-
2, H-6, H-7), 7.86 (d,1H, 3J ¼ 7.95 Hz, H-5), 8.15 (d,1H, 3J ¼ 8.3 Hz, H-
8); MS (EI) m/z 292 [Mþ] (12), 149 (81), 127 (10), 115 (24), 107 (100),
94 (6), 77 (37), 65 (7), 55 (31); Anal. calcd for C20H20O2: C, 82.16; H,
6.89; found: C, 82.46; H, 7.01.
5.2.1.2. General procedure B. The respective alcohol was dissolved
in acetone or DMF. K2CO3 and the alkylating agent, 4-PBB, were
added. Afterwards the mixture was refluxed in the presence of
a catalytic amount of KI, if necessary under nitrogen atmosphere.
The progress of the reaction was monitored by TLC. After comple-
tion of the reaction, the reaction mixture was filtered and the
solvent was evaporated in vacuo. The resulting residue was dis-
solved in CH2Cl2 and extracted three times with NaOH (0.5 M). The
pooled organic phases were dried over Na2SO4 and concentrated in
vacuo. The resulting residue was purified by MPLC or recrystallized
to give the pure compound.
5.3.3. 4-(4-Phenoxybutoxy)quinoline (17)
4-Hydroxyquinoline (5, 590 mg, 4.1 mmol), CsF-Celite (1.3 g,
6.1 mmol) and 4-PBB (1.87 g, 8.2 mmol), dissolved in 5 mL of dried
acetonitrile, were reacted according to general procedure A. The
crude product was purified by MPLC (cyclohexane/ethyl acetate/
methanol (11:9:1)) to give 17 (354 mg, 30%) as a white solid: mp
66.5 ꢁC; 1H NMR (DMSO-d6)
d: 1.94–2.08 (m, 4H, 4-O–CH2–(CH2)2–
CH2–O–C6H5), 4.07 (t, 2H, 3J ¼ 6.1 Hz, 4-O–(CH2)3–CH2–O–C6H5),
4.30 (t, 2H, 3J ¼ 5.9 Hz, 4-O–CH2–(CH2)3–O–C6H5), 6.89–6.95 (m,
3H, H-20, H-40 and H-60), 7.00 (d, 1H, 3J ¼ 5.2 Hz, H-3), 7.25–7.30 (m,
2H, H-30 and H-50), 7.52 (ddd, 1H, 3J ¼ 8.2 Hz, 3J ¼ 6.9 Hz, 4J ¼ 1.2 Hz,
H-6), 7.72 (ddd, 1H, 3J ¼ 8.4 Hz, 3J ¼ 6.9 Hz, 4J ¼ 1.5 Hz, H-7), 7.95 (d,
1H, 3J ¼ 8.3 Hz, H-8), 8.13 (dd, 1H, 3J ¼ 8.3 Hz, 4J ¼ 0.9 Hz, H-5), 8.72
5.2.2. Demethylation
5.2.2.1. General procedure C. The methoxy-substituted starting
compound was dissolved in CH2Cl2 and cooled with an ice bath.
Boron tribromide was slowly added so that the temperature
remained below 5 ꢁC. After the addition was completed the reac-
tion mixture was refluxed for 30 min to 4 h and then quenched
with water. The aqueous phase was extracted twice with CH2Cl2
(d, 1H, 3J ¼ 5.2 Hz, H-2); 13C NMR (DMSO-d6)
d: 25.08, 25.43, 66.85,
67.98, 101.46, 114.40, 120.38, 120.74, 121.45, 125.55, 128.59, 129.40,

1846
S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
129.59, 148.68, 151.54, 158.53, 160.62; MS (EI) m/z 293 [Mþ] (23),
200 (14), 158 (21), 149 (100), 128 (12), 107 (99), 94 (13), 77 (38), 65
(7), 55 (50); Anal. calcd for C19H19NO2: C, 77.79; H, 6.53; N, 4.77;
found: C, 77.89; H, 6.75; N, 4.78.
5 mL of dried acetonitrile, were reacted according to general
procedure A. The crude product was purified by MPLC (cyclo-
hexane/ethyl acetate (3:1)) to give 21 (375 mg, 60%) as a white
solid: mp 79 ꢁC; 1H NMR (DMSO-d6)
d: 1.89–2.05 (m, 4H, 4-O–CH2–
(CH2)2–CH2–O–C6H5), 4.07 (t, 2H, 3J ¼ 6.0 Hz, 4-O–(CH2)3–CH2–O–
C6H5), 4.29 (t, 2H, 3J ¼ 6.0 Hz, 4-O–CH2–(CH2)3–O–C6H5), 5.90 (s,
1H, H-3), 6.90–6.96 (m, 3H, H-20, H-40 and H-60), 7.25–7.41 (m, 4H,
H-7, H-8, H-30 and H-50), 7.65 (ddd, 1H, 3J ¼ 8.6 Hz, 3J ¼ 7.3 Hz,
4J ¼ 1.6 Hz, H-6), 7.78 (dd, 1H, 3J ¼ 7.9 Hz, 4J ¼ 1.5 Hz, H-5); 13C NMR
5.3.4. 5-(4-Phenoxybutoxy)isoquinoline (18)
5-Hydroxyisoquinoline (6, 1.0 g, 6.89 mmol), 4-PBB (2.37 g,
10.35 mmol) and K2CO3 (2.75 g, 19.93 mmol) in 35.5 mL of dried
DMF were reacted according to general procedure B. The crude
product was purified by MPLC (cyclohexane/ethyl acetate/meth-
anol (30:9:1)) to give 18 (1.89 g, 94%) as a light yellow solid: mp
(DMSO-d6) d: 24.67, 25.21, 66.67, 69.12, 90.45, 114.36, 115.18, 116.35,
120.36, 122.73, 124.05, 129.37, 132.61, 152.69, 158.45, 161.57, 164.85;
MS (EI) m/z 310 [Mþ] (14), 217 (29), 175 (24), 163 (30), 149 (29), 120
(41), 107 (100), 94 (31), 77 (63), 55 (100); Anal. calcd for C19H18O4:
C, 73.53; H, 5.85; found: C, 73.60; H, 5.98.
80.5 ꢁC; 1H NMR (DMSO-d6)
d: 1.92–2.08 (m, 4H, 4-O–CH2–(CH2)2–
CH2–O–C6H5), 4.08 (t, 2H, 3J ¼ 6.0 Hz, 4-O–(CH2)3–CH2–O–C6H5),
4.25 (t, 2H, 3J ¼ 5.8 Hz, 4-O–CH2–(CH2)3–O–C6H5), 6.89–6.95 (m,
3H, H-20, H-40 and H-60), 7.21–7.30 (m, 3H, H-7, H-30, H-50), 7.58 (t,
1H, 3J ¼ 7.9 Hz, H-6 or H-8), 7.63 (t, 1H, 3J ¼ 8.5 Hz, H-6 or H-8), 7.92
(d, 1H, 3J ¼ 5.8 Hz, H-3), 8.47 (d, 1H, 3J ¼ 5.8 Hz, H-4), 9.26 (s, 1H, H-
5.3.8. 3-(4-Phenoxybutoxy)-2-phenyl-4H-[1]benzopyran-4-one
(22)
1); 13C NMR (DMSO-d6)
d
: 25.25, 25.48, 66.90, 67.72, 109.08, 114.33,
3-Hydroxy-2-phenyl-4H-[1]benzopyranone
(10,
550 mg,
114.39, 118.91, 120.33, 127.44, 127.79, 128.91, 129.35, 142.46, 151.67,
152.99, 158.51; MS (EI) m/z 293 [Mþ] (6), 149 (64), 117 (6), 116 (6),
107 (100), 94 (9), 77 (41), 65 (7), 55 (57), 41 (9); HRMS calcd for
C19H20NO2 [M þ H]þ 294.1494, found 294.1480.
2.3 mmol), CsF-Celite (1.89 g, 8.9 mmol) and 4-PBB (1.42 g,
6.2 mmol), added little by little, were reacted according to general
procedure A. The crude product was purified by MPLC (cyclo-
hexane/ethyl acetate (9:1)) to give 22 (850 mg, 96%) as a white
solid: mp 66 ꢁC; 1H NMR (DMSO-d6)
d: 1.74–1.78 (m, 4H, 3-O–CH2–
5.3.5. 4-(4-Phenoxybutoxy)quinazoline (19)
(CH2)2–CH2–O–C6H5), 3.93 (t, 2H, 3J ¼ 5.8 Hz, 3-O–(CH2)3–CH2–O–
C6H5), 4.06 (t, 2H, 3J ¼ 5.8 Hz, 3-O–CH2–(CH2)3–O–C6H5), 6.86–6.92
(m, 3H, H-200, H-400 and H-600), 7.23–7.28 (m, 2H, H-300 and H-500),
7.47–7.52 (m, 1H, H-6), 7.56–7.58 (m, 3H, H-20, H-40 and H-60), 7.73
(dd, 1H, 3J ¼ 8.3 Hz, 4J ¼ 0.8 Hz, H-8), 7.82 (ddd, 1H, 3J ¼ 8.5 Hz,
4-Hydroxyquinazoline (7, 315 mg, 2.16 mmol), CsF-Celite
(1.92 g, 9.0 mmol) and 4-PBB (945 mg, 4.12 mmol), dissolved in
5 mL of dried acetonitrile, were reacted according to general
procedure A. The crude product was purified by MPLC (cyclo-
hexane/ethyl acetate/methanol (32:8:1)) to give 19 (352 mg, 55%)
4
3J ¼ 7.0 Hz, J ¼ 1.6 Hz, H-7), 8.04–8.07 (m, 2H, H-30 and H-50), 8.11
as a white solid: mp 130 ꢁC; 1H NMR (DMSO-d6)
d
: 1.70–1.79 (m,
(dd, 1H, 3J ¼ 7.9 Hz, 4J ¼ 1.6 Hz, H-5); 13C NMR (DMSO-d6)
d: 25.18,
2H) and 1.82–1.92 (m, 2H) (4-O–CH2–(CH2)2–CH2–O–C6H5), 3.99 (t,
2H, 3J ¼ 6.2 Hz, 4-O–(CH2)3–CH2–O–C6H5), 4.06 (t, 2H, 3J ¼ 7.0 Hz,
4-O–CH2–(CH2)3–O–C6H5), 6.87–6.92 (m, 3H, H-20, H-40 and H-60),
7.22–7.28 (m, 2H, H-30 and H-50), 7.54 (ddd, 1H, 3J ¼ 8.1 Hz,
3J ¼ 7.7 Hz, 4J ¼ 1.1 Hz, H-7), 7.68 (dd, 1H, 3J ¼ 8.2 Hz, 4J ¼ 0.5 Hz, H-
5), 7.82 (ddd, 1H, 3J ¼ 8.4 Hz, 3J ¼ 7.3 Hz, 4J ¼ 1.5 Hz, H-6), 8.17 (dd,
1H, 3J ¼ 9.4 Hz, 4J ¼ 1.5 Hz, H-8), 8.42 (s, 1H, H-2); 13C NMR (DMSO-
26.00, 66.77, 71.50, 114.33, 118.31, 120.26, 123.47, 124.88, 124.91,
128.32, 128.42, 129.30, 130.47, 130.70, 133.90, 139.74, 154.68, 155.27,
158.49, 173.88; MS (EI) m/z 386 [Mþ] (4), 237 (21), 149 (100), 121
(9), 107 (75), 94 (8), 77 (47), 65 (10), 55 (43), 51 (9); Anal. calcd for
C25H22O4: C, 77.70; H, 5.74; found: C, 77.93; H, 5.86.
5.3.9. 5,8-Dimethoxy-4-(4-phenoxybutoxy)psoralen (23)
d6)
d: 25.46, 25.80, 45.59, 66.80, 114.37, 120.35, 121.50, 125.94,
4-Hydroxy-5,8-dimethoxypsoralen (11, 793 mg, 3.02 mmol),
K2CO3 (1.21 g, 8.77 mmol) and 4-PBB (1.04 g, 4.5 mmol), dissolved
in 10 mL of dried DMF (120 ꢁC), were reacted according to general
procedure B. The crude product was purified by MPLC (cyclo-
hexane/ethyl acetate (7:3)) to give 23 (260 mg, 21%) as a white
126.88, 127.08, 129.33, 134.10, 147.89, 147.92, 158.46, 160.12; MS (EI)
m/z 294 [Mþ] (5), 201 (100), 159 (38), 147 (42), 129 (26), 102 (11), 94
(12), 77 (29), 55 (82), 41 (17); Anal. calcd for C18H18N2O2: C, 73.45;
H, 6.16; N, 9.52; found: C, 73.52; H, 6.24; N, 9.40.
solid: mp 94.5 ꢁC; 1H NMR (DMSO-d6)
d: 1.88–1.99 (m, 4H, 4-O–
5.3.6. 1,2-Dihydro-N-methyl-4-(4-phenoxybutoxy)quinolin-2-one
(20)
CH2–(CH2)2–CH2–O–C6H5), 3.92 (s, 3H, 5-OCH3 or 8-OCH3), 4.02–
4.16 (m, 5H, 5-OCH3 or 8-OCH3 and 4-O–(CH2)3–CH2–O–C6H5),
4.23–4.30 (m, 2H, 4-O–CH2–(CH2)3–O–C6H5), 5.76 (s, 1H, H-3),
6.89–6.96 (m, 3H, H-200, H-400 and H-600), 7.19 (d, 1H, 3J ¼ 2.3 Hz, H-
40), 7.25–7.30 (m, 2H, H-300 and H-500), 8.07 (d, 1H, 3J ¼ 2.2 Hz, H-50);
1,2-Dihydro-4-hydroxy-N-methylquinolin-2-one (8, 430 mg,
2.45 mmol), CsF-Celite (1.89 g, 8.92 mmol) and 4-PBB (1.67 g,
7.27 mmol), dissolved in 5 mL of dried acetonitrile, were reacted
according to general procedure A. The crude product was purified by
MPLC (cyclohexane/ethyl acetate/methanol (32:8:1)) to give 20
13C NMR (DMSO-d6)
d: 24.93, 25.29, 61.01, 62.10, 66.76, 69.19, 88.55,
104.90, 105.33, 114.35, 118.78, 120.32, 128.59, 129.33, 143.05, 145.10,
146.55, 147.95, 158.51, 160.92, 167.17; MS (EI) m/z 410 [Mþ] (34), 220
(17), 205 (16), 177 (9), 149 (82), 107 (100), 79 (12), 77 (30), 65 (6), 55
(34); Anal. calcd for C23H22O7: C, 67.31; H, 5.40; found: C, 67.02; H,
5.52.
(130 mg,16%) as a white solid: mp 80 ꢁC; 1H NMR (DMSO-d6)
d: 1.88–
2.04 (m, 4H, 4-O–CH2–(CH2)2–CH2–O–C6H5), 3.55 (s, 3H, N-CH3),
4.06 (t, 2H, 3J ¼ 6.0 Hz, 4-O–(CH2)3–CH2–O–C6H5), 4.19 (t, 2H,
3J ¼ 5.8 Hz, 4-O–CH2–(CH2)3–O–C6H5), 6.02 (s, 1H, H-3), 6.89–6.95
(m, 3H, H-20, H-40 and H-60), 7.19–7.30 (m, 3H, H-7, H-30 and H-50),
7.47 (d, 1H, 3J ¼ 8.5 Hz, H-8), 7.63 (ddd, 1H, 3J ¼ 8.6 Hz, 3J ¼ 7.2 Hz,
4J ¼ 1.5 Hz, H-6), 7.87 (dd, 1H, 3J ¼ 8.0 Hz, 4J ¼ 1.3 Hz, H-5); 13C NMR
5.3.10. 9-(Phenoxybutoxy)-9H-dibenzo[b,e]pyran (24)
9-Hydroxy-9H-dibenzo[b,e]pyran (12, 3.5 g, 20 mmol), K2CO3
(8 g, 58 mmol) and 4-PBB (5.73 g, 25 mmol dissolved in 35 mL DMF
and added dropwise) were reacted in 100 mL of dried DMF
according to general procedure B at 120 ꢁC under a nitrogen
atmosphere. The crude product was purified by MPLC (cyclo-
hexane/ethyl acetate (19:1)) to give 24 (150 mg, 2%) as slightly
(DMSO-d6) d: 24.86, 25.38, 28.48, 66.78, 68.04, 96.64, 114.38, 114.50,
115.55, 120.34, 121.36, 122.54, 129.35, 131.26, 139.38, 158.48, 160.91,
162.26; MS (EI) m/z 323 [Mþ] (41), 230 (26), 176 (40), 175 (29), 149
(48), 120 (33), 107 (100), 94 (22), 77 (57), 55 (82); Anal. calcd for
C20H21NO3: C, 74.28; H, 6.55; N, 4.33; found: C, 74.39; H, 6.61; N, 4.31.
white crystals: mp 96.5 ꢁC; 1H NMR (DMSO-d6)
d: 1.46–1.66 (m, 4H,
5.3.7. 4-(4-Phenoxybutoxy)-2H-[1]benzopyran-2-one (21)
4-Hydroxy-2H-[1]benzopyran-2-one (9, 330 mg, 2 mmol), CsF-
Celite (1.91 g, 9 mmol) and 4-PBB (916 mg, 4 mmol), dissolved in
9-O–CH2–(CH2)2–CH2–O–C6H5), 3.25 (t, 2H, 3J ¼ 6.1 Hz, 9-O–
(CH2)3–CH2–O–C6H5), 3.82 (t, 2H, 3J ¼ 6.3 Hz, 9-O–CH2–(CH2)3–O–
C6H5), 5.70 (s, 1H, H-9), 6.83 (d, 2H, 3J ¼ 7.9 Hz, H-1 and H-8), 6.89

S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
1847
(t, 1H, 3J ¼ 7.3 Hz) and 7.19–7.27 (m, 6H) (H-3, H-6, H-20, H-30, H-40,
8.99, 7.34/7.39; 1H,1H-NOESY (C6D6): cross-peaks: 1.42–1.49/3.58,
1.83–1.90/7.34, 3.33/6.74, 3.58/6.91, 4.22/7.34, 6.74/7.05, 6.91/7.23–
7.30, 6.97/7.25–7.30, 7.05/8.75, 7.09/7.39, 7.09/8.99, 7.34/7.39; 13C
H-50 and H-60), 7.40–7.45 (m, 2H, H-2 and H-7), 7.56 (dd, 2H,
3J ¼ 7.5 Hz, 3J ¼ 1.3 Hz, H-4 and H-5); 13C NMR (DMSO-d6)
d: 25.44,
25.78, 64.44, 66.82, 69.28, 114.29, 116.19, 120.24, 120.55, 123.25,
129.30, 129.60, 130.08, 151.63, 158.47; MS (EI) m/z 346 [Mþ] (1), 197
(29), 181 (100), 152 (8), 149 (8), 94 (16), 77 (7), 71 (7), 55 (5), 41 (5);
HRMS calcd for C23H22O3 [Mþ] 346.1569, found 346.1552.
NMR (C6D6) d: 27.37, 27.49, 52.61, 56.59, 67.71, 115.51, 116.34, 117.11,
121.00, 121.70, 122.21, 122.70, 124.71, 127.37, 128.67, 130.44, 133.98,
135.88, 145.98, 150.67, 160.15, 178.47; 13C,1H-COSY (C6D6): cross-
peaks: 27.37/1.83–1.90, 27.49/1.42–1.49, 52.61/4.22, 56.59/3.33,
67.71/3.58, 115.51/6.91, 116.34/6.74, 117.11/7.34, 121.00/8.75, 121.70/
6.97, 122.21/7.09, 122.70/7.05, 128.67/8.99, 130.44/7.23–7.30, 133.98/
7.39; 13C,1H-COLOC (C6D6): cross-peaks: 52.61/4.22 (1J), 56.59/3.33
(1J), 67.71/3.58 (1J), 115.51/6.97 (3J), 116.34/8.75 (3J), 117.11/7.09 (3J),
121.70/6.91 (3J), 122.21/7.34 (3J), 122.70/6.74 (2J), 124.71/7.09 (3J),
124.71/7.34 (3J), 127.37/7.05 (3J), 130.44/7.23–7.30 (1J), 133.98/7.09
(2J),133.98/7.39 (1J), 133.98/8.99 (3J), 135.88/6.74 (3J),135.88/8.75 (3J),
145.98/7.39 (3J), 145.98/8.99 (3J), 150.67/3.33 (3J), 150.67/7.05 (3J),
160.15/7.23–7.30 (3J), 178.47/8.75 (3J), 178.47/8.99 (3J); MS (EI) m/z
373 [Mþ] (69), 280 (3), 238 (100), 223 (59), 210 (7), 166 (6), 149 (54),
107 (46), 77 (23), 65 (7), 55 (14); Anal. calcd for C24H23NO3: C, 77.19;
H, 6.21; N, 3.75; found: C, 77.09; H, 6.38; N, 3.72.
5.3.11. 1-(4-Phenoxybutoxy)anthraquinone (25)
1-Hydroxyanthraquinone (13, 897 mg, 4 mmol), K2CO3 (1.6 g,
11.6 mmol) and 4-PBB (1.37 g, 6 mmol) in 40 mL of dried DMF
(120 ꢁC) were reacted according to general procedure B. The crude
product was purified by MPLC (cyclohexane/ethyl acetate (19:1)) to
give 25 (600 mg, 40%) as a yellow solid: mp 151.5 ꢁC; 1H NMR
(DMSO-d6)
d: 1.94–2.13 (m, 4H, 1-O–CH2–(CH2)2–CH2–O–C6H5),
4.15 (t, 2H, 3J ¼ 6.2 Hz, 1-O–(CH2)3–CH2–O–C6H5), 4.29 (t, 2H,
3J ¼ 5.7 Hz, 1-O–CH2–(CH2)3–O–C6H5), 6.90–7.00 (m, 3H, H-20, H-40
and H-60), 7.27–7.32 (m, 2H, H-30 and H-50), 7.61–7.64 (m, 1H, H-2),
7.83–7.97 (m, 4H, H-3, H-4, H-7 and H-8), 8.15–8.19 (m, 2H, H-6 and
H-9); 13C NMR (DMSO-d6)
d: 25.29, 25.48, 67.01, 68.68, 114.35,
118.80, 119.89, 120.23, 120.67, 125.99, 126.53, 129.29, 131.89, 133.39,
134.47, 134.92, 135.29, 158.56, 159.33, 181.01, 182.75; MS (EI) m/z
372 [Mþ] (1), 279 (26), 237 (9), 225 (17),147 (8), 120 (7), 107 (14), 94
(9), 77 (19), 55 (100); Anal. calcd for C24H20O4: C, 77.40; H, 5.41;
found: C, 77.60; H, 5.46.
5.3.14. Kokusagenine and skimmianine derivatives
5.3.14.1. Extraction of kokusagenine (29) and skimmianine (30) from
R. graveolens. The isolation was carried out according to Ohta et al.
[21]. Fine cut, dried herb R. graveolens (6 kg) were extracted twice
with 20 L of methanol for 48 h. The solvent was filtered off and
evaporated. The black syrupy residue was refluxed with 10 L of HCl
(2.5 M) for 3–4 h and stirred afterwards at room temperature for
15 min. After filtration, the aqueous phase was extracted with
diethyl ether, alkalized with concentrated ammonia and extracted
again with CH2Cl2. The solvent was evaporated and the resulting
oily residue was purified by MPLC. In the first step we used Al2O3
5.3.12. 9-(4-Phenoxybutoxy)phenanthrene (26)
9-Hydroxyphenanthrene (14, 700 mg, 3.6 mmol), K2CO3 (1.49 g,
10.8 mmol) and 4-PBB (2.67 g, 11.6 mmol) in 25 mL of dried DMF
(120 ꢁC) were reacted according to general procedure B. After dis-
solving the resulting residue in CH2Cl2 the crude product was
precipitated by adding cyclohexane/ethyl acetate (3:2) and
recrystallized from ethanol to give 26 (700 mg, 57%) as pale yellow
(90 active, basic, 63–200
toluene and acetone (7:1) as solvent. For the second step the
residue was purified over a silica gel column (40–63 m) with
mm) as column material and a mixture of
crystals: mp 105.5 ꢁC; 1H NMR (DMSO-d6)
d: 1.99–2.09 (m, 4H, 9-O–
m
CH2–(CH2)2–CH2–O–C6H5), 4.09 (t, 2H, 3J ¼ 6.0 Hz, 9-O–(CH2)3–
CH2–O–C6H5), 4.31 (t, 2H, 3J ¼ 5.8 Hz, 9-O–CH2–(CH2)3–O–C6H5),
6.90–6.96 (m, 3H, H-20, H-40 and H-60), 7.16–7.31 (m, 3H, H-10, H-30
and H-50), 7.47–7.74 (m, 4H, H-2, H-3, H-6 and H-7), 7.85 (dd, 1H,
3J ¼ 7.8 Hz, 4J ¼ 1.1 Hz, H-1 or H-8), 8.29 (dd, 1H, 3J ¼ 8.0 Hz,
4J ¼ 1.1 Hz, H-1 or H-8), 8.69 (d, 1H, 3J ¼ 7.9 Hz, H-4 or H-5), 8.78 (d,
a mixture of toluene and methanol (100:1) to give 404 mg of 29 and
1.5 g of 30. Identity was confirmed by TLC with authentic samples.
5.3.14.2. 4-Hydroxy-6,7-dimethoxyfuro[2,3-b]quinoline
(29a). In
a slight modification of the methods of Lamberton and Price [29]
and Ishii [30] 4,6,7-trimethoxyfuro[2,3-b]quinoline (29, kokusage-
nine, 800 mg, 3.1 mmol) was dissolved in 70 mL ethanol and 14 mL
of HCl (10 M) and refluxed for 10 h. After cooling the precipitate
was filtered off and 25 mL NaOH (3 M) were added. The remaining
insoluble residue was removed and the solution was acidified with
glacial acetic acid to give 29a (214 mg, 28%) as a light grayish
1H, 3J ¼ 8.0 Hz, H-4 or H-5); 13C NMR (DMSO-d6)
d: 25.32, 25.63,
66.93, 67.37, 102.80, 114.39, 120.32, 121.96, 122.56, 122.80, 124.24,
126.49, 126.94, 127.19, 127.24, 125.67, 125.86, 129.35, 130.64, 132.54,
134.47, 134.92, 151.92, 158.53; MS (EI) m/z 342 [Mþ] (17), 194 (20),
165 (30), 149 (100), 107 (92), 95 (5), 94 (5), 79 (13), 77 (29), 65 (6),
55 (35); HRMS calcd for C24H22O2 [M]þ 342.1620, found 342.1614.
powder: mp 235 ꢁC dec; 1H NMR (DMSO-d6)
d: 3.89 (s, 3H, 6-OCH3
or 7-OCH3), 3.91 (s, 3H, 6-OCH3 or 7-OCH3), 5.97 (s, 1H, 4-OH), 7.42
5.3.13. 9,10-Dihydro-4-methoxy-N-(4-phenoxybutyl)acridin-9-one
(28)
(s, 2H, H-3 and H-6), 7.56 (s, 1H, H-5), 7.78 (s, 1H, H-2); 13C NMR
(DMSO-d6) d: 55.26, 55.25, 102.80, 103.23, 105.25, 105.61, 115.16,
9-Hydroxy-4-methoxyacridine (27, 450 mg, 2 mmol), CsF-Celite
(1.91 g, 9 mmol) and 4-PBB (1.15 g, 5.1 mmol), dissolved in 5 mL of
dried acetonitrile, were reacted according to general procedure A.
The crude product was purified by MPLC (cyclohexane/ethyl acetate/
methanol (30:9:1)) to give 28 (180 mg, 24%) as a yellow solid: mp
138.88,141.61,145.35,151.51,162.48,162.72,172.23; MS (EI) m/z 245
[Mþ] (100), 230 (26), 202 (23), 187 (8), 174 (8), 159 (10), 122 (5), 50
(5); HRMS (C13H11NO4) calcd. 245.0688, found 245.0680. Without
further purification 29a was used for the synthesis of compound 34.
128.5 ꢁC; 1H NMR (C6D6)
d: 1.42–1.49 (m, 2H, N–(CH2)2–CH2–CH2–
5.3.14.3. 6,7-Dimethoxy-4-(4-phenoxybutoxy)furo[2,3-b]quinoline
(34). 4-Hydroxy-6,7-dimethoxyfuro[2,3-b]quinoline (29a, 178 mg,
0.73 mmol), 4-PBB (371 mg, 1.62 mmol) and K2CO3 (477 mg,
3.45 mmol) in 20 mL of dried DMF (120 ꢁC) were reacted according
to general procedure B. The crude product was purified by MPLC
(cyclohexane/ethyl acetate/methanol (30:9:1)) and afterwards
recrystallized from ethanol to give 34 (108 mg, 38%) as a light
O–C6H5), 1.83–1.90 (m, 2H, N–CH2–CH2–(CH2)2–O–C6H5), 3.33 (s,
3H, 4-OCH3), 3.58 (t, 2H, 3J ¼ 6.1 Hz, N–(CH2)3–CH2–O–C6H5), 4.22 (t,
2H, 3J ¼ 7.7 Hz, N–CH2–(CH2)3–O–C6H5), 6.74 (dd, 1H, 3J ¼ 7.8 Hz,
4J ¼ 1.5 Hz, H-3), 6.91 (dd, 2H, 3J ¼ 8.7 Hz, 4J ¼ 1.0 Hz, H-20 and H-60),
6.97 (t, 1H, 3J ¼ 7.4 Hz, H-40), 7.05 (t, 1H, 3J ¼ 7.9 Hz, H-2), 7.09 (ddd,
4
1H, 3J ¼ 7.9 Hz, 3J ¼ 6.2 Hz, J ¼ 1.6 Hz, H-7), 7.23–7.30 (m, 2H, H-30
and H-50), 7.34 (dd, 1H, 3J ¼ 9.6 Hz, 4J ¼ 2.1 Hz, H-5), 7.39 (ddd, 1H,
3J ¼ 8.4 Hz, 3J ¼ 6.3 Hz, 4J ¼ 1.7 Hz, H-6), 8.75 (dd, 1H, 3J ¼ 8.0 Hz,
4J ¼ 1.5 Hz, H-1), 8.99 (dd, 1H, 3J ¼ 7.9 Hz, 4J ¼ 1.2 Hz, H-8); 1H,1H-
COSY (C6D6): cross-peaks: 1.42–1.49/3.58, 1.83–1.90/4.22, 6.74/7.05,
6.74/8.75, 6.91/7.23–7.30, 6.97/7.23–7.30, 7.05/8.75, 7.09/7.39, 7.09/
yellow solid: mp 130 ꢁC; 1H NMR (DMSO-d6)
d: 1.97–2.10 (m, 4H, 4-
O–CH2–(CH2)2–CH2–O–C6H5), 3.84 (s, 3H, 6-OCH3 or 7-OCH3), 3.92
(s, 3H, 6-OCH3 or 7-OCH3), 4.10 (t, 2H, 3J ¼ 6.0 Hz, 4-O–(CH2)3–CH2–
O–C6H5), 4.76 (t, 2H, 3J ¼ 5.9 Hz, 4-O–CH2–(CH2)3–O–C6H5), 6.88–
6.93 (m, 3H, H-20, H-40 and H-60), 7.19–7.29 (m, 3H, H-8, H-30, H-50),

1848
S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
7.32 (d, 1H, 3J ¼ 2.8 Hz, H-3), 7.44 (s, 1H, H-5), 7.92 (d, 1H,
and demethylated with boron tribromide (482 mL, 5 mmol)
3J ¼ 2.7 Hz, H-2); 13C NMR (DMSO-d6)
d: 25.30, 25.95, 55.30, 55.54,
according to procedure C. The crude compound was purified by
MPLC (cyclohexane/CH2Cl2/methanol (5:5:1)) to give 4-hydroxy-9-
methoxy-7-methyl-5H-furo[3,2-g][1]benzopyran-5-one (32a, yie-
ld: 60%). The spectroscopic data were in accordance with literature
[23]. In a second step 32a (456 mg, 1.85 mmol), CsF-Celite (1.81 g,
8.5 mmol) and 4-PBB (895 mg, 3.9 mmol), dissolved in 5 mL of
dried acetonitrile, were reacted according to general procedure A.
The crude product was purified by MPLC (cyclohexane/ethyl
acetate (3:1)) to give 37 (191 mg, 26%) as a white solid: mp 105 ꢁC;
66.91, 71.09, 100.00, 102.33, 105.14, 106.58, 112.44, 114.35, 120.34,
129.33,141.90,143.08,147.49,152.32,154.22,158.45,162.46; MS (EI)
m/z 393 [Mþ] (18), 258 (3), 245 (9), 230 (6), 149 (100), 107 (98), 95
(5), 79 (10), 77 (23), 55 (31); HRMS calcd for C23H24NO5 [M þ H]þ
394.1655, found 394.1642.
5.3.15. 7,8-Dimethoxy-4-(4-phenoxybutoxy)furo[2,3-b]quinoline
(35)
In a slight modification of the methods of Lamberton and Price
[29] and Ishii [30] 4,7,8-trimethoxyfuro[2,3-b]quinoline (30, skim-
mianine, 323 mg, 1.25 mmol) was heated under reflux in 13 mL of
ethanol and 2.6 mL HCl (10 M) for 10 h. After cooling the precipitate
was filtered off and 25 mL of NaOH (3 M) were added. In an addi-
tional filtration the insoluble residue was removed and the filtrate
was acidified by using glacial acetic acid to give 4-hydroxy-7,8-
dimethoxyfuro[2,3-b]quinoline (30a, yield: 70%). Without any
further purification or characterization 30a (245 mg, 1 mmol), 4-
PBB (599 mg, 2.61 mmol) and K2CO3 (361 mg, 2.61 mmol) were
heated in 35 mL of dried DMF (120 ꢁC) in the presence of a catalytic
amount of KI according to procedure B. The crude product was
purified by MPLC (cyclohexane/ethyl acetate (3:2)) and recrystal-
lized from ethanol to give 35 (52 mg, 11%) as a white solid: mp
1H NMR (CDCl3)
d: 2.05–2.09 (m, 4H, 4-O–CH2–(CH2)2–CH2–O–
C6H5), 2.39 (s, 3H, 7-CH3), 4.08 (t, 2H, 3J ¼ 5.9 Hz, 4-O–(CH2)3–CH2–
O–C6H5), 4.20 (s, 3H, 9-OCH3), 4.23 (t, 2H, 3J ¼ 6.0 Hz, 4-O–CH2–
(CH2)3–O–C6H5), 6.03 (s, 1H, H-6), 6.89–6.94 (m, 3H, H-20, H-40 and
H-60), 6.97 (d,1H, 3J ¼ 2.3 Hz, H-3), 7.24–7.29 (m, 2H, H-30 and H-50),
7.60 (d, 1H, 3J ¼ 2.2 Hz, H-2); 1H,1H-NOESY (CDCl3): cross-peaks:
2.05–2.09/6.97, 2.29/6.03, 4.23/6.97, 6.79/7.60; 13C NMR (DMSO-d6)
d: 19.43, 25.34, 26.34, 61.13, 67.08, 74.31, 105.15, 109.93, 113.33,
114.33, 119.36, 120.27, 129.35, 145.67, 146.50, 146.93, 148.08, 158.57,
164.11, 176.57; MS (EI) m/z 394 [Mþ] (12), 259 (37), 246 (13), 231
(100), 149 (83), 107 (85), 94 (13), 79 (14), 77 (39), 55 (29); Anal.
calcd for C23H22O6: C, 70.04; H, 5.62; found: C, 70.20; H, 5.80.
5.3.18. 8-(4-Phenoxybutoxy)psoralen (38)
107.5 ꢁC; 1H NMR (DMSO-d6)
d
: 1.98–2.09 (m, 4H, 4-O–CH2–
8-Methoxypsoralen (33, 8-MOP, 720 mg, 3.33 mmol) was
(CH2)2–CH2–O–C6H5), 3.92 (s, 3H, 7-OCH3 or 8-OCH3), 3.95 (s, 3H,
7-OCH3 or 8-OCH3), 4.09 (t, 2H, 3J ¼ 5.9 Hz, 4-O–(CH2)3–CH2–O–
C6H5), 4.78 (t, 2H, 3J ¼ 5.7 Hz, 4-O–CH2–(CH2)3–O–C6H5), 6.90–6.94
(m, 3H, H-20, H-40 and H-60), 7.24–7.41 (m, 4H, H-3, H-6, H-30 and H-
demethylated with boron tribromide (337 mL, 3.5 mmol) according
to procedure C. The crude compound was recrystallized from
methanol/water to give 8-hydroxypsoralen (33a, yield: 90%).
Without any further characterization 33a (520 mg, 2.57 mmol), 4-
PBB (2.36 g, 10.3 mmol) and K2CO3 (1.03 g, 7.46 mmol) in 25 mL of
dried acetone were reacted in a second step according to general
procedure B. The crude product was purified by MPLC (cyclohexane/
ethyl acetate (4:1)) to give 38 (486 mg, 54%) as a slightly yellow
50), 7.95–7.98 (m, 2H, H-2 and H-5); 13C NMR (DMSO-d6)
d: 25.28,
25.86, 56.51, 60.67, 66.85, 71.22, 101.99, 105.31, 112.54, 114.30,
114.36, 117.73, 120.32, 129.33, 140.66, 141.38, 151.79, 155.91, 158.45,
163.68; MS (EI) m/z 393 [Mþ] (12), 224 (4), 230 (7), 149 (84), 107
(100), 94 (6), 79 (11), 77 (25), 55 (36), 44 (7), 41 (17); HRMS calcd for
C23H24NO5 [M þ H]þ 394.1655, found 394.1653.
solid: mp 53 ꢁC; 1H NMR (DMSO-d6)
d: 1.92–2.08 (m, 4H, 8-O–CH2–
(CH2)2–CH2–O–C6H5), 4.05 (t, 2H, 3J ¼ 6.1 Hz, 8-O–(CH2)3–CH2–O–
C6H5), 4.46 (t, 2H, 3J ¼ 6.1 Hz, 8-O–CH2–(CH2)3–O–C6H5), 6.42 (d, 1H,
3J ¼ 9.5 Hz, H-3), 6.87–6.93 (m, 3H, H-200, H-400 and H-600), 7.08 (d, 1H,
3J ¼ 2.2 Hz, H-40), 7.22–7.29 (m, 2H, H-300 and H-500), 7.66 (s, 1H, H-5),
8.09 (d, 1H, 3J ¼ 2.2 Hz, H-50), 8.12 (d, 1H, 3J ¼ 9.7 Hz, H-4); 13C NMR
5.3.16. 7-Methyl-4-(4-phenoxybutoxy)-5H-furo[3,2-
g][1]benzopyran-5-one (36)
According to Schonberg and Badran [31] 4-methoxy-7-methyl-
5H-furo[3,2-g][1]benzopyran-5-one (30, visnagin, 2.5 g, 10.9 mm-
ol) was dissolved in HCl (5.5 M) and the solution was refluxed for
1 h. After cooling the precipitate was filtered off and recrystallized
from methanol/water to give 4-hydroxy-7-methyl-5H-furo[3,2-
g][1]benzopyran-5-one (31a, 1.7 g, 72%). The spectroscopic data
were in accordance with literature [32]. In a second step 31a
(432 mg, 2 mmol), CsF-Celite (1.9 g, 9 mmol) and 4-PBB (1.39 g,
6.1 mmol), dissolved in 5 mL of dried acetonitrile, were reacted
according to general procedure A. The crude product was purified
by MPLC (cyclohexane/ethyl acetate (3:1)) and recrystallized from
methanol/water to give 34 (575 mg, 79%) as a white solid: mp
(DMSO-d6) d: 25.19, 26.26, 66.91, 73.09, 106.97, 113.95, 114.08, 114.34,
116.36, 120.28, 125.68, 129.32, 130.84, 142.81, 145.13, 147.32, 147.67,
158.52,159.65; MS (EI) m/z 350 [Mþ] (2), 202 (16),174 (10),149 (100),
107 (87), 94 (8), 89 (13), 77 (34), 63 (9), 55 (39), 51 (8); Anal. calcd for
C21H18O5: C, 71.99; H, 5.18; found: C, 71.65; H, 5.30.
5.3.19. 5-(4-Phenoxybutoxy)-2H-[1]benzopyran-2-one (42)
According to Dubuffet et al. [33] 2,6-dimethoxybenzaldehyde
(40, 5 g, 30.09 mmol) and methoxycarbonylmethylene-triphenyl-
phosphorane (12.1 g, 36.1 mmol) were refluxed in 90 mL toluene.
After completion of the reaction (controlled by TLC) the solvent was
evaporated and 90 mL diethyl ether was added. The triphenyl-
phosphinoxide was filtered off and the solvent was evaporated. The
crude product was purified by MPLC (cyclohexane/ethyl acetate
(4:1)) to give 3-(2,6-dimethoxyphenyl)acryl acid methylester (40,
yield: 72%). For identification 1H NMR data were recorded: 1H NMR
90 ꢁC; 1H NMR (DMSO-d6)
d: 1.91–1.95 (m, 4H, 4-O–CH2–(CH2)2–
CH2–O–C6H5), 2.31 (s, 3H, 7-CH3), 4.04 (t, 2H, 3J ¼ 5.8 Hz, 4-O–
(CH2)3–CH2–O–C6H5), 4.29 (t, 2H, 3J ¼ 5.6 Hz, 4-O–CH2–(CH2)3–O–
C6H5), 6.02 (s, 1H, H-6), 6.88–6.93 (m, 3H, H-20, H-40 and H-60), 7.17
(d,1H, 3J ¼ 2.2 Hz, H-3), 7.23–7.29 (m, 2H, H-30 and H-50), 7.49 (s,1H,
H-9), 8.03 (d, 1H, 3J ¼ 2.3 Hz, H-2); 13C NMR (DMSO-d6)
d
: 19.30,
(DMSO-d6)
d
: 3.71 (s, 3H, –COO–CH3), 3.87 (s, 6H, 20-OCH3 and 60-
3
25.31, 26.35, 67.09, 73.86, 95.11, 105.29, 110.15, 112.12,114.35,117.26,
120.28, 129.37, 146.46, 151.92, 155.29, 156.90, 158.58, 164.01, 176.47;
MS (EI) m/z 364 [Mþ] (69), 271 (57), 229 (78), 216 (87), 201 (33), 149
(62), 107 (100), 77 (64), 55 (70), 43 (39); Anal. calcd for C22H20O5: C,
72.51; H, 5.53; found: C, 72.61; H, 5.71.
OCH3), 6.73 (d, 2H, J ¼ 8.5 Hz, H-30 and H-50), 6.78 (d, 1H,
3J ¼ 16.3 Hz, H-
a
), 7.37 (t, 1H, J ¼ 8.4 Hz, H-40), 7.99 (d, 1H,
). In a second step 40 (4.8 g, 21.6 mmol) was
3
3J ¼ 16.3 Hz, H-
b
demethylated with boron tribromide (4.18 mL, 43.4 mmol)
according to procedure C. The crude compound was purified by
MPLC (cyclohexane/ethyl acetate (80:20)) to give 5-hydroxy-2H-
[1]benzopyran-2-one (41, yield: 65%). 1H NMR data were in accor-
dance with literature [34]. In a final step 41 (520 mg, 3.2 mmol),
CsF-Celite (2.97 g,14 mmol) and 4-PBB (1.47 g, 6.4 mmol), dissolved
in 5 mL of dried acetonitrile, were reacted according to general
5.3.17. 9-Methoxy-7-methyl-4-(4-phenoxybutoxy)-5H-furo[3,2-
g][1]benzopyran-5-one (37)
4,9-Dimethoxy-7-methyl-5H-furo[3,2-g][1]benzopyran-5-one
(32, khellin, 1.35 g, 5.19 mmol) was dissolved in 15 mL of CH2Cl2

S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
1849
procedure A. The crude product was purified by MPLC (cyclo-
hexane/ethyl acetate (3:1)) and recrystallized from methanol to
give 42 (546 mg, 55%) as a white solid: mp 82 ꢁC; 1H NMR (DMSO-
characterization 1H NMR and 13C NMR data were recorded: 1H NMR
(DMSO-d6)
d
: 6.38 (d, 1H, 3J ¼ 5.9 Hz, H-7), 7.09 (dd, 1H, 3J ¼ 2.3 Hz,
5J ¼ 0.9 Hz, H-3), 7.37 (d, 1H, 5J ¼ 0.9 Hz, H-9), 8.03 (d, 1H,
3J ¼ 2.3 Hz, H-2), 8.34 (d, 1H, 3J ¼ 5.9 Hz, H-6), 13.56 (s, 1H, 4-OH);
d6) d: 1.87–1.98 (m, 4H, 5-O–CH2–(CH2)2–CH2–O–C6H5), 4.05 (t, 2H,
3J ¼ 5.9 Hz, 5-O–(CH2)3–CH2–O–C6H5), 4.19 (t, 2H, 3J ¼ 5.8 Hz, 5-O–
CH2–(CH2)3–O–C6H5), 6.35 (d, 1H, 3J ¼ 9.7 Hz, H-3), 6.89–6.95 (m,
5H, H-6, H-8, H-20, H-40 and H-60), 7.24–7.30 (m, 2H, H-30 and H-50),
7.53 (t, 1H, 3J ¼ 8.4 Hz, H-7), 8.08 (d, 1H, 3J ¼ 9.7 Hz, H-4); 13C NMR
13C NMR (DMSO-d6)
d: 91.08, 103.86, 106.24, 109.60, 112.39, 146.39,
153.73, 154.25, 158.19, 158.49, 183.28. In a final step 50 (800 mg,
3.96 mmol), CsF-Celite (5.72 g, 27 mmol) and 4-PBB (1.83 g,
8 mmol), dissolved in 5 mL of dried acetonitrile, were reacted
according to general procedure A. The crude product was purified
by MPLC (cyclohexane/ethyl acetate (7:3)) to give 51 (554 mg, 40%)
(DMSO-d6)
d: 25.20, 25.64, 51.42, 66.71, 108.68, 114.35, 116.50,
120.39,123.09,125.77, 126.73,129.36,131.90,139.52,144.38, 158.42,
176.18; MS (EI) m/z 310 [Mþ] (8), 217 (7), 175 (8), 163 (6), 149 (73),
107 (100), 94 (10), 79 (17), 77 (40), 55 (52); Anal. calcd for C19H18O4:
C, 73.53; H, 5.85; found: C, 73.58; H, 6.00.
as a light yellow solid: mp 70 ꢁC; 1H NMR (DMSO-d6)
d: 1.93–1.99
(m, 4H, 4-O–CH2–(CH2)2–CH2–O–C6H5), 4.05 (t, 2H, 3J ¼ 5.8 Hz, 4-
O–(CH2)3–CH2–O–C6H5), 4.31 (t, 2H, 3J ¼ 5.7 Hz, 4-O–CH2–(CH2)3–
O–C6H5), 6.13 (d, 1H, 3J ¼ 5.9 Hz, H-7), 6.88–6.93 (m, 3H, H-20, H-40
3
5.3.20. 4-(4-Phenoxybutoxy)benzofuran (45)
and H-60), 7.19 (d, 1H, J ¼ 1.5 Hz, H-3), 7.23–7.29 (m, 2H, H-30 and
According to Kneen and Maddocks [35] 6,7-dihydro-5H-
benzofuran-4-one (43, 5 g, 36.7 mmol), 10 mL of 1-dodecene and
3.3 g palladium–charcoal (10% Pd) in 60 mL decalin were heated at
reflux under nitrogen atmosphere for 20 h. After the reaction
mixture was cooled down to 80 ꢁC 50 mL of ethanol were added.
The resulting precipitate was filtered off and purified by MPLC
(cyclohexane/ethyl acetate (4:1)) to give 4-hydroxybenzofuran (44,
2.22 g, 45%). The spectroscopic data were in accordance with
literature [36]. In a second step 44 (2.1 g, 15.7 mmol), 4-PBB (7.21 g,
31.5 mmol) and K2CO3 (6.48 g, 47 mmol) in 25 mL of dried DMF
were reacted according to general procedure B. The crude product
was purified by MPLC (cyclohexane) to give 45 (300 mg, 7%) as
H-50), 7.54 (s, 1H, H-9), 8.04 (d, 1H, 3J ¼ 2.2 Hz, H-2), 8.10 (d, 1H,
3J ¼ 5.9 Hz, H-6); 13C NMR (DMSO-d6)
d: 25.26, 26.32, 67.08, 73.85,
95.29, 105.27, 112.48, 113.38, 114.34, 117.30, 120.24, 129.31, 146.53,
152.04, 154.40, 155.18, 156.98, 158.56, 175.94; MS (EI) m/z 350 [Mþ]
(5), 257 (79), 215 (54), 202 (100), 149 (83), 107 (99), 79 (24), 77 (68),
55 (65), 51 (24); Anal. calcd for C21H18O5: C, 71.99; H, 5.18; found: C,
72.18; H, 5.34.
5.3.22. 5-Hydroxy-2-methyl-6,7-methylendioxy-4H-
[1]benzopyran-4-one (55)
The oxidation of 46 (10 g, 43.5 mmol) was carried out according
to Schonberg and Aziz [39] in 300 mL of H2SO4 (1 M) at 60 ꢁC. To
this solution 20 mL of potassium dichromate solution (0.3 M) was
added dropwise so that the temperature remained between 60 and
70 ꢁC. Immediately a white precipitate was formed, which was
filtered off after stirring the reaction for an additional 2 h, washed
and recrystallized from methanol/water to give 6-formyl-7-
hydroxy-5-methoxy-2-methyl-4H-[1]benzopyran-4-one (52, 71%).
Without any further characterization 52 was used for the next step.
According to Gammill and Nash [40] 52 (4.7 g, 20.1 mmol) was
dissolved in 34 mL of NaOH (1 M) and on cooling 12 mL of a H2O2
solution (10 M) were added dropwise. The reaction mixture was
stirred for 2-3 h at room temperature. After completion it was
acidified with HCl (3 M) and extracted with ethyl acetate
(3 ꢂ 50 mL). The pooled ethyl acetate phases were dried over
Na2SO4 and the solvent was evaporated to give 6,7-dihydroxy-5-
methoxy-2-methyl-4H-[1]benzopyran-4-one (53, 86%). For identi-
a light yellow oily residue; 1H NMR (DMSO-d6)
d: 2.02–2.15 (m, 4H,
4-O–CH2–(CH2)2–CH2–O–C6H5), 4.12 (t, 2H, 3J ¼ 6.4 Hz, 4-O–
(CH2)3–CH2–O–C6H5), 4.20 (t, 2H, 3J ¼ 6.1 Hz, 4-O–CH2–(CH2)3–O–
C6H5), 6.70 (dd,1H, 3J ¼ 7.7 Hz, 5J ¼ 0.5 Hz, H-5 or H-7), 6.89 (dd,1H,
3J ¼ 2.2 Hz, 5J ¼ 0.7 Hz, H-3), 6.92–7.00 (m, 3H, H-20, H-40 and H-60),
7.15–7.35 (m, 4H, H-5 or H-7, H-6, H-30, H-50), 7.56 (d, 1H,
3J ¼ 2.2 Hz, H-2); 13C NMR (DMSO-d6)
d: 25.39, 66.93, 67.59, 103.80,
104.16, 104.57, 114.37, 117.16, 120.33, 125.11, 129.36, 144.36, 152.46,
155.55, 158.53; MS (EI) m/z 282 [Mþ] (12), 149 (88), 134 (23), 107
(100), 94 (9), 77 (46), 65 (8), 55 (54), 51 (17), 41 (7); Anal. calcd for
C18H18O3: C, 76.57; H, 6.43; found: C, 76.42; H, 6.73.
5.3.21. 4-(4-Phenoxybutoxy)-5H-furo[3,2-g][1]benzopyran-5-one
(51)
In a first step according to Spath and Gruber [37] 4-methoxy-7-
methyl-5H-furo[3,2-g][1]benzopyran-5-one (46, visnagin, 5 g,
21.7 mmol) was refluxed for 15 min in 500 mL of KOH (0.2 M). After
cooling 75 mL H2SO4 (0.4 M) were added and the precipitate was
filtered off. The precipitate was recrystallized from methanol/water
(60:40) to give 5-acetyl-4-methoxybenzofuran-6-ole (47, visnagi-
none, yield: 83%). For identification 1H NMR data were recorded: 1H
fication 1H NMR data were recorded: 1H NMR (DMSO-d6)
d: 2.24 (s,
3H, 2-CH3), 3.71 (s, 3H, 5-OCH3), 5.90 (s, 1H, H-8), 6.62 (s, 1H, H-3),
9.47 (s, 2H, 6-OH and 7-OH). According to Gammill and Nash [40]
53 (3.84 g, 17.3 mmol) was then dissolved in 86.5 mL DMF and
K2CO3 (5.19 g, 34.6 mmol) was added. A solution of dibromo-
methane (3.31 g, 19.03 mmol) in DMF (63 mL) was added dropwise
under nitrogen atmosphere. Afterwards the reaction mixture was
stirred at 95 ꢁC for 4 h. K2CO3 was removed and solvent was
evaporated. The remaining residue was dissolved in diethyl ether
and extracted three times with NaOH (0.25 M). The diethyl ether
was evaporated and the residue was purified by MPLC (cyclo-
hexane/ethyl acetate (3:2)) to give 2-methyl-6,7-methylenedioxy-
5-methoxy-4H-[1]-benzopyran-4-one (54, 35.4%). For identifica-
NMR (DMSO-d6) d: 2.54 (s, 3H, 5-COCH3), 4.12 (s, 3H, 4-OCH3), 6.71
(s, 1H, H-7), 7.18 (d, 1H, 3J ¼ 2 Hz, H-3), 7.82 (d, 1H, 3J ¼ 3 Hz, H-2),
11.77 (s, 1H, 6-OH). In a next step according to Abdel-Rahman et al.
[38] 47 (4.12 g, 20 mmol) and N,N-dimethylformamide dimethyla-
cetal (DMFDMA) were refluxed in 50 mL of toluene for 3 h. The
solvent was evaporated and the resulting residue was washed with
petroleum ether and recrystallized from ethanol to give 1-(4-
methoxy-6-hydroxybenzofuran-5-yl)-3-dimethylamino-2-propen-
1-one (48, 65%). Without further characterization 48 (3.38 g,
12.9 mmol) was refluxed in glacial acetic acid for 5 h. After adding
ice the solution was alkalized with a solution of NH4OH (7 M). The
forming precipitate was filtered off and recrystallized from ethanol
to give 4-methoxy-5H-furo[3,2-g][1]benzopyran-5-one (49, yield:
80%). The spectroscopic data were in accordance with literature
[38]. In a next step 49 (865 mg, 4 mmol) was demethylated with
tion 1H NMR data were recorded: 1H NMR (DMSO-d6)
d: 2.26 (s, 3H,
2-CH3), 3.87 (s, 3H, 5-OCH3), 5.98 (s, 1H, H-8), 6.16 (s, 2H, –O–CH2–
O–), 6.90 (s, 1H, H-3). In a next step 54 (850 mg, 3.63 mmol) was
demethylated with boron tribromide (347 mL, 3.6 mmol) according
to procedure C. The crude compound was purified by MPLC
(cyclohexane/ethyl acetate (1:1)) to give 5-hydroxy-2-methyl-6,7-
methylenedioxy-4H-[1]benzopyran-5-one (55, 85%) as a yellowish
powder: mp 174 ꢁC; 1H NMR (DMSO-d6)
d
: 2.37 (s, 3H, 2-CH3), 6.15
(s, 2H, H-20), 6.23 (s, 1H, H-8), 6.78 (s, 1H, H-3), 12.84 (s, 1H, 5-OH).
13C NMR (DMSO-d6)
: 19.75, 89.41, 102.64, 106.27, 107.86, 129.29,
141.02, 152.99, 153.65, 167.99, 182.39; MS (EI) m/z 220 [Mþ] (100),
boron tribromide (385 mL, 4 mmol) according to procedure C. The
crude compound was recrystallized from methanol/water (5:1) to
give 4-hydroxy-5H-furo[3,2-g][1]benzopyran-5-one (50, 98%). For
d

1850
S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
191 (10), 162 (54), 134 (29), 122 (8), 119 (8), 78 (28), 69 (22), 66 (22),
53 (29), 43 (23); HRMS calcd for C11H9O5 [M þ H]þ 221.0450, found
221.0444.
(520 mg, 2 mmol) was demethylated with boron tribromide (96 mL,
1 mmol) according to procedure C. The crude compound was
purified by MPLC (toluene/methanol (50:1)) to give 8-hydroxy-5-
methoxy-4-methylpsoralen (62, 43%). Without any further char-
acterization 62 (370 mg, 1.5 mmol), CsF-Celite (1.39 g, 6.75 mmol)
and 4-PBB (688 mg, 3 mmol) were reacted in a final step according
to general procedure A to give 5-methoxy-4-methyl-8-(4-phenox-
ybutoxy)psoralen (63, 149 mg, 25%) as a white solid: mp 76 ꢁC; 1H
5.3.23. 2-Methyl-6,7-methylenedioxy-5-(4-phenoxybutoxy)-4H-
[1]benzopyran-4-one (56)
Compound 55 (238 mg, 1.08 mmol), 4-PBB (495 mg, 2.16 mmol)
and 430 mg (3.12 mmol) K2CO3 in 15 mL of dried acetone were
reacted according to general procedure B. The crude product was
purified by MPLC (cyclohexane/ethyl acetate (4:1)) to give 56
NMR (CDCl3) d: 2.03–2.11 (m, 4H, 8-O–CH2–(CH2)2–CH2–O–C6H5),
2.63 (s, 3H, 4-CH3), 4.06 (s, 3H, 5-OCH3), 4.09 (t, 2H, 3J ¼ 6.0 Hz, 8-
O–(CH2)3–CH2–O–C6H5), 4.40 (t, 2H, 3J ¼ 6.1 Hz, 8-O–CH2–(CH2)3–
O–C6H5), 6.11 (s, 1H, H-3), 6.89–6.92 (m, 3H, H-200, H-400 and H-600),
6.94 (d,1H, 3J ¼ 2.3 Hz, H-40), 7.23–7.29 (m, 2H, H-300 and H-500), 7.59
(80 mg, 20%) as a yellow solid: mp 83.5 ꢁC; 1H NMR (DMSO-d6)
d:
1.82–2.00 (m, 4H, 5-O–CH2–(CH2)2–CH2–O–C6H5), 2.31 (s, 3H, 2-
CH3), 4.07 (t, 2H, 3J ¼ 6.2 Hz, 5-O–(CH2)3–CH2–O–C6H5), 4.20 (t, 2H,
3J ¼ 6.0 Hz, 5-O–CH2–(CH2)3–O–C6H5), 6.01 (s, 1H, H-8), 6.17 (s, 2H,
H-20), 6.92–6.98 (m, 4H, H-3, H-200, H-400 and H-600), 7.27–7.35 (m,
3
(d, 1H, J ¼ 2.3 Hz, H-50); 1H,1H-NOESY (CDCl3): cross-peaks: 2.63/
4.06, 2.63/6.11, 4.06/6.94, 6.94/7.59; 13C NMR (DMSO-d6)
d: 23.26,
2H, H-300 and H-500); 13C NMR (DMSO-d6)
d: 19.05, 25.17, 26.03,
25.22, 26.20, 61.27, 66.91, 73.09, 105.47, 108.72, 112.97, 114.34,
116.59, 120.28, 127.02, 129.34, 143.58, 146.19, 148.67, 154.09, 158.53,
158.95; MS (EI) m/z 394 [Mþ] (5), 246 (9), 231 (21), 203 (7), 149
(100), 107 (69), 79 (10), 77 (23), 65 (6), 55 (23); Anal. calcd for
C23H22O6: C, 70.04; H, 5.62; found: C, 70.25; H, 5.80.
66.98, 72.95, 93.48, 102.33, 110.55, 112.42, 114.34, 120.23, 129.31,
135.77, 139.08, 152.16, 154.16, 158.55, 163.37, 175.53; MS (EI) m/z
368 [Mþ] (3), 275 (100), 233 (80), 220 (71), 162 (22), 149 (24), 107
(52), 77 (61), 65 (20), 55 (35); Anal. calcd for C21H20O6: C, 68.47; H,
5.47; found: C, 68.73; H, 5.69.
5.3.26. 4-(4-Phenoxybutoxy)furo[2,3-b]quinoline (71)
5.3.24. 2,6-Dihydro-8-methyl-5-(4-phenoxybutoxy)pyrano[3,2-
g][1]benzopyran-2,6-dione (59)
According to Morel et al. [42] iodomethane (4.47 mL, 71.8 mmol)
was added to a premixed solution of 2,4-dihydroquinoline (64,
2.98 g, 17.95 mmol) and silver carbonate (15 g, 53.85 mmol) in
50 mL of anhydrous hexane. The greenish solution was stirred for 3
days at room temperature in the dark. Afterwards ethyl acetate was
added in order to dilute the sluggish mixture. The grey solution was
filtrated through Celite and concentrated under vacuum. The crude
residue was purified by flash chromatography (pentane/ethyl
acetate (19:1)) to give 2,4-dimethoxyquinoline (65, montanine,
1.36 g, 40%) as white needles. According to Bhoga et al. [43] n-
butyllithium (6.72 mL, 10.75 mmol, 1.6 M solution in hexane) was
added dropwise at ꢀ10 ꢁC to a solution of 65 (1.13 g, 5.97 mmol) in
15 mL of anhydrous diethyl ether. The orange solution was main-
tained at this temperature for 45 min and 0.69 mL of anhydrous
DMF (8.96 mmol) in 3 mL of diethyl ether was added. The reaction
mixture was stirred at 0 ꢁC for 30 min and at room temperature for
another 45 min. During this time, the red solution turned light pink.
The mixture was subsequently hydrolyzed (20 mL of water; color
turned from pink to yellow) and extracted with diethyl ether
(3 ꢂ 20 mL). The combined organic extracts were washed with
brine, dried over MgSO4 and finally concentrated under vacuum.
The crude residue was purified by flash chromatography (pentane/
ethyl acetate (19:1)) to give 2,4-dimethoxyquinoline-3-carbalde-
hyde (66, 699.4 mg, 54%) as a white solid. In a next step 9.47 mL of
a solution of potassium tert-butoxide in THF (1 M) was added to
In a first step 46 was converted into 52 as described for 55. In
a second step according to Atta et al. [41] a mixture of 52 (7.2 g,
30.8 mmol) and methoxycarbonylmethylene-triphenylphosphor-
ane (10.3 g, 30.8 mmol) in 500 mL of toluene was refluxed for 6 h.
After evaporation of the solvent under vacuum the remaining
residue was purified by MPLC (CH2Cl2/ethyl acetate (10:1)) to give
2,6-dihydro-5-methoxy-8-methylpyrano[3,2-g][1]benzopyran-
2,6-dione (57, 25%). The structure was confirmed by 1H NMR: 2.34
(s, 3H, 8-CH3), 3.90 (s, 3H, 5-OCH3), 6.15 (d, 1H, 4J ¼ 0.8 Hz, H-7),
6.49 (d, 1H, 3J ¼ 9.8 Hz, H-3), 7.35 (d, 1H, 5J ¼ 0.5 Hz, H-10), 8.15 (dd,
1H, 3J ¼ 9.8 Hz, 5J ¼ 0.5 Hz, H-4). In a next step 57 (290 mg,
1.12 mmol) was demethylated with boron tribromide (139
1.44 mmol) according to procedure C to give 2,6-dihydro-5-
hydroxy-8-methylpyrano[3,2-g][1]benzopyran-2,6-dione (58,
91%). For characterization 1H NMR data were recorded: 1H NMR
(DMSO-d6) : 2.44 (s, 3H, 8-CH3), 6.38–6.41 (m, 2H, H-3 and H-7),
mL,
d
7.04 (s, 1H, H-10), 8.09 (d, 1H, 3J ¼ 9.6 Hz, H-4), 13.94 (s, 1H, 5-OH).
Without further purification 58 (180 mg, 0.74 mmol), 4-PBB
(336.8 mg, 1.47 mmol) and K2CO3 (306.4 mg, 2.22 mmol) in 30 mL
of dried DMF (120 ꢁC) were reacted according to general procedure
B. The crude product was purified by MPLC (dichloromethane/ethyl
acetate (200:1)) to give 59 (27 mg, 9%) as white crystals: mp 120–
124 ꢁC; 1H NMR (DMSO-d6)
d: 1.90–2.01 (m, 4H, 5-O–CH2–(CH2)2–
CH2–O–C6H5), 2.35 (s, 3H, 8-CH3), 4.06 (t, 2H, 3J ¼ 6.1 Hz,
5-O–(CH2)3–CH2–O–C6H5), 4.10 (t, 2H, 3J ¼ 6.3 Hz, 5-O–CH2–
(CH2)3–O–C6H5), 6.15 (s, 1H, H-7), 6.48 (d, 1H, 3J ¼ 9.8 Hz, H-3),
6.89–6.94 (m, 3H, H-20, H-40 and H-60), 7.24–7.30 (m, 2H, H-30 and
H-50), 7.36 (s, 1H, H-10), 8.14 (d, 1H, 3J ¼ 9.8 Hz, H-4); 13C NMR
methoxymethyltriphenylphosphonium
chloride
(3.35 g,
9.47 mmol) in 29 mL of anhydrous diethyl ether. This homogeneous
mixture was stirred at room temperature for 1 h. Compound 66
(1.03 g, 4.74 mmol) in 13 mL of dry THF was then added and the
resulting red solution was stirred overnight. Afterwards the organic
solvents were evaporated and the crude residue was directly
purified by flash chromatography (pentane/ethyl acetate (9:1)) to
give 2,4-dimethoxy-3-(2-methoxyethyenyl)quinoline (67, 1.14 g,
98%) as a 6:1 (E/Z) mixture as a white solid. The spectroscopic data
were in accordance with literature [44]. In a next step 67 (1.9 g,
7.75 mmol) was treated with 30 mL of HCl (5.5 M), refluxed for
45 min and then carefully quenched with NaHCO3. The extraction
of the neutral solution with diethyl ether (3 ꢂ 30 mL) gave 2-
(DMSO-d6) d: 19.27, 25.23, 26.16, 67.07, 76.29, 100.81, 110.94, 111.24,
113.95, 114.37, 115.31, 120.31, 129.35, 138.67, 156.09, 158.53, 158.86,
158.94, 164.91, 175.19; MS (EI) m/z 392 [Mþ] (15), 299 (42), 257 (85),
244 (43), 229 (34), 149 (53), 107 (95), 79 (33), 77 (83), 55 (100);
HRMS calcd for C23H20O6 [M]þ 392.1260, found 392.1252.
5.3.25. 5-Methoxy-4-methyl-8-(4-phenoxybutoxy)psoralen (63)
According to Atta et al. [41] 5-acetyl-4,7-dimethoxybenzofuran-
6-ole (60, 1.36 g, 5.76 mmol) and methoxycarbonylmethylene-tri-
phenylphosphorane (1.93 g, 5.76 mmol) were refluxed in 96 mL
dried toluene for 3 h. After cooling to room temperature the
precipitate was filtered off and recrystallized from toluene to give
5,8-dimethoxy-4-methylpsoralen (61, yield: 85%). The spectro-
scopic data were in accordance with literature [41]. In a next step 61
hydroxy-4-methoxy-3-quinolineacetaldehyde (68) as
a crude
orange-brown residue (w50%), which was treated without any
further purification with 30 g of polyphosphoric acid. The resulting
sluggish mixture was heated at 125 ꢁC for 5 h, poured into water,
neutralized carefully with NaHCO3 and extracted with chloroform.
The resulting residue was subsequently purified by flash

S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
1851
chromatography (pentane/ethyl acetate (7:3)) to give 4-methox-
5.4. Electrophysiology
yfuro[2,3-b]quinoline (69, dictamnine, 418.4 mg, 27% overall yield
for the 2 steps) as a white powder. The melting point (131 ꢁC; Lit.
132 ꢁC [45]) and the spectroscopic data were in accordance with
literature [43]. In a next step 0.22 mL of isopropylthiol were added
to a solution of sodium hydride (258 mg, 6.4 mmol) in 4 mL of
anhydrous DMF and stirred for 10 min. Afterwards a solution of 69
(183.4 mg, 0.92 mmol) in 4 mL DMF was added dropwise. This
reaction mixture was heated under reflux for 4 h, cooled down to
room temperature, neutralized at 0 ꢁC with HCl (2 M) and extracted
with diethyl ether. The combined organic extracts were subse-
quently washed with brine, dried over Na2SO4 and concentrated
under vacuum. The crude product was purified by flash chroma-
tography (pentane/ethyl acetate (5:5)) to give nordictamnine (70,
40.8 mg, 24%) as a white solid. In a last step KHCO3 (152 mg,
1.10 mmol) and 4-PBB (78 mg, 0.34 mmol) were added to a solution
of 70 (40.8 mg, 0.22 mmol) in 3 mL of 2-butanone. The mixture was
heated under reflux for 25 h, cooled down to 5 ꢁC (ice bath) and
carefully quenched with HCl (1 M). The aqueous solution was
extracted with diethyl ether and the combined organic extracts
were subsequently washed with brine, dried over Na2SO4 and
concentrated under vacuum. The crude product was purified by
flash chromatography (pentane/ethyl acetate (4:6)) to give 71
The inhibition of Kv1.3 was determined by whole-cell patch-
clamp on L929 cells stably expressing Kv1.3 with a holding
potential of ꢀ80 mV [17]. The currents were recorded in normal
Ringer solution (160 mM NaCl, 4.5 mM KCl, 2 mM CaCl2, 1 mM
MgCl2, 10 mM HEPES, pH 7.4, 290–310 mOsm) with an internal
pipette solution containing 145 mM KF, 2 mM MgCl2, 10 mM
HEPES, 10 mM EGTA (pH 7.2, 290–310 mOsm). Depolarizing pulses
to 40 mV were applied every 45 s for 500 ms. Kv1.5 currents were
recorded from MEL-C88 cells. IC50 values were determined by
fitting the reduction of area under the current curve to the Hill
equation.
Acknowledgements
The authors thank Mr. Bjo¨rn Henke for excellent technical
assistance. This research was funded by R21NS53426 from NIH (to
H.W.).
References
[1] K.G. Chandy, H. Wulff, C. Beeton, M. Pennington, G.A. Gutman, M.D. Cahalan,
Potassium channels as targets for specific immunomodulation, Trends Phar-
macol. Sci. 25 (2004) 280–289.
[2] H. Wulff, P.A. Calabresi, R. Allie, S. Yun, M. Pennington, C. Beeton, K.G. Chandy,
The voltage-gated Kv1.3 Kþ channel in effector memory T cells as new target
for MS, J. Clin. Invest. 111 (2003) 1703–1713.
[3] C. Beeton, H. Wulff, N.E. Standifer, P. Azam, K.M. Mullen, M.W. Pennington,
A. Kolski-Andreaco, E. Wei, A. Grino, D.R. Counts, P.H. Wang, C.J. Leehealey,
B.S. Andrews, A. Sankaranarayanan, D. Homerick, W.W. Roeck, J. Tehranzadeh,
K.L. Stanhope, P. Zimin, P.J. Havel, S. Griffey, H.G. Knaus, G.T. Nepom,
G.A. Gutman, P.A. Calabresi, K.G. Chandy, Kv1.3 channels are a therapeutic
target for T cell-mediated autoimmune diseases, Proc. Natl. Acad. Sci. U.S.A.
103 (2006) 17414–17419.
[4] H. Rus, C.A. Pardo, L. Hu, E. Darrah, C. Cudrici, T. Niculescu, F. Niculescu,
K.M. Mullen, R. Allie, L. Guo, H. Wulff, C. Beeton, S.I. Judge, D.A. Kerr,
H.G. Knaus, K.G. Chandy, P.A. Calabresi, The voltage-gated potassium channel
Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis
brain, Proc. Natl. Acad. Sci. U.S.A. 102 (2005) 11094–11099.
[5] G.C. Koo, J.T. Blake, A. Talento, M. Nguyen, S. Lin, A. Sirotina, K. Shah,
K. Mulvany, D. Hora Jr., P. Cunningham, D.L. Wunderler, O.B. McManus,
R. Slaughter, R. Bugianesi, J. Felix, M. Garcia, J. Williamson, G. Kaczorowski,
N.H. Sigal, M.S. Springer, W. Feeney, Blockade of the voltage-gated potassium
channel Kv1.3 inhibits immune responses in vivo, J. Immunol. 158 (1997)
5120–5128.
[6] C. Beeton, M.W. Pennington, H. Wulff, S. Singh, D. Nugent, G. Crossley,
I. Khaytin, P.A. Calabresi, C.Y. Chen, G.A. Gutman, K.G. Chandy, Targeting
effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for
therapy of autoimmune diseases, Mol. Pharmacol. 67 (2005) 1369–1381.
[7] C. Beeton, J. Barbaria, P. Giraud, J. Devaux, A. Benoliel, M. Gola, J. Sabatier,
D. Bernard, M. Crest, E. Beraud, Selective blocking of voltage-gated Kþ chan-
nels improves experimental autoimmune encephalomyelitis and inhibits T cell
activation, J. Immunol. 166 (2001) 936–944.
(20.1 mg, 27%): mp 101–102 ꢁC; 1H NMR (500 Hz, CDCl3)
d: 2.14 (m,
2H) and 2.21 (m, 2H) (4-O–CH2–(CH2)2–CH2–O–C6H5), 4.13 (t, 2H,
3J ¼ 6.0 Hz, 4-O–(CH2)3–CH2–O–C6H5), 4.79 (td, 2H, 3J ¼ 6.0 Hz,
3
4J ¼ 1.6 Hz, 4-O–CH2–(CH2)3–O–C6H5), 6.93 (t, 2H, J ¼ 7.8 Hz, H-20
3
and H-60), 6.97 (t, 1H, J ¼ 7.4 Hz, H-40), 7.03 (m, 1H, H-3), 7.30 (m,
2H, H-30 and H-50), 7.45 (t, 1H, 3J ¼ 7.4 Hz, H-6), 7.63 (d, 1H,
3J ¼ 3 Hz, H-2), 7.70 (td, 1H, 3J ¼ 7.4 Hz, 4J ¼ 1.6 Hz, H-7), 8.03 (d, 1H,
3J ¼ 8.5 Hz, H-5), 8.29 (d, 1H, 3J ¼ 8.0 Hz, H-8); MS (FAB) m/z 334
[M þ H]þ (75), 333 [Mþ] (15), 186 (37), 154 (45), 149 (100), 136 (55);
HRMS calcd for C21H20NO3 [M þ H]þ 334.1445, found 334.1443.
5.3.27. 9-(4-Phenoxybutyl)furo[2,3-b]quinolin-4(9H)-one (72)
For synthesis see compound 71. The crude product was purified
by flash chromatography (pentane/ethyl acetate (4:6)) to give 72
(yield: 5%): mp 105 ꢁC; 1H NMR (500 Hz, CDCl3)
d: 1.95 (quint, 2H,
3J ¼ 7.5 Hz, N–(CH2)2–CH2–CH2–O–C6H5), 2.14 (quint, 2H,
3J ¼ 6.0 Hz, N–CH2–CH2–(CH2)2–O–C6H5), 4.06 (t, 2H, 3J ¼ 6 Hz, N–
(CH2)3–CH2–O–C6H5), 4.56 (t, 2H, 3J ¼ 6 Hz, N–CH2–(CH2)3–O–
C6H5), 6.91 (d, 2H, 3J ¼ 7.8 Hz, H-20 and H-60), 6.89 (t, 1H, 3J ¼ 7.5 Hz,
H-40), 7.16 (swide, 1H, H-3), 7.32–7.27 (m, 3H, H-2, H-30 and H-50),
7.41 (t, 1H, 3J ¼ 7.5 Hz, H-6), 7.57 (d, 1H, 3J ¼ 8.3 Hz, H-8), 7.70 (t, 1H,
3J ¼ 7 Hz, H-7), 8.62 (d, 1H, 3J ¼ 8 Hz, H-5); HRMS calcd for
C21H20NO3 [M þ H]þ 334.1443, found 334.1439.
[8] C. Beeton, H. Wulff, J. Barbaria, O. Clot-Faybesse, M. Pennington, D. Bernard,
M.D. Cahalan, K.G. Chandy, E. Beraud, Selective blockade of T lymphocyte Kþ
channels ameliorates experimental autoimmune encephalomyelitis, a model
for multiple sclerosis, Proc. Natl. Acad. Sci. U.S.A. 98 (2001) 13942–13947.
[9] P. Valverde, T. Kawai, M.A. Taubman, Selective blockade of voltage-gated
potassium channels reduces inflammatory bone resorption in experimental
periodontal disease, J. Bone Miner. Res. 19 (2004) 155–164.
[10] K.G. Chandy, H. Wulff, C. Beeton, P.A. Calabresi, G.A. Gutman,
M.W. Pennington, Kv1.3 potassium channel: physiology, pharmacology and
therapeutic indications, in: D.J. Triggle, M. Gopalakrishnan, D. Rampe,
W. Zheng (Eds.), Voltage-gated Ion Channels as Drug Targets, Wiley-VCH,
Weinheim, 2006, pp. 214–274.
5.3.28. 4-(4-Phenoxybutoxy)-7H-furo[3,2-g]chromene-7-thione
(73)
PAP-1 (2, 500 mg, 1.43 mmol) was dissolved in 20 mL of anhy-
drous toluene. The resulting solution was refluxed and Lawesson’s
reagent (3.86 g, 9.24 mmol) was added at the start of the reaction
and again after 10 h. After 20 h the solution was concentrated in
vacuo. Purification of the crude product by flash chromatography
(pentane/ethyl acetate (7:3)) gave 73 (36 mg, 15%) as an orange
powder: mp 126–127 ꢁC; 1H NMR (500 MHz, CDCl3)
d: 2.04 (m, 2H,
[11] H. Wulff, C. Beeton, K.G. Chandy, Potassium channels as therapeutic targets for
autoimmune disorders, Curr. Opin. Drug Discov. Dev. 6 (2003) 640–647.
[12] K.H. Bohuslavizki, E. Koppenhofer, W. Hansel, W.D. Moller, A new approach for
the treatment of demyelinating diseases? J. Neuroimmunol. 20 (1988) 251–
252.
[13] K.H. Bohuslavizki, W. Hansel, A. Kneip, E. Koppenhofer, E. Niemoller,
K. Sanmann, Mode of action of psoralens, benzofurans, acridones and
coumarins on the ionic currents in intact myelinated nerve fibres and its
significance in demyelinating diseases, Gen. Physiol. Biophys. 13 (1994) 309–
328.
4-O–(CH2)2–CH2–CH2–O–C6H5), 2.11 (m, 2H, 4-O–CH2–CH2–
(CH2)2–O–C6H5), 4.08 (t, 2H, 3J ¼ 5.8 Hz, 2H, 4-O–(CH2)3–CH2–O–
C6H5), 4.57 (t, 2H, 3J ¼ 6.0 Hz, 4-O–CH2–(CH2)3–O–C6H5), 6.89 (d,
3
2H, J ¼ 7.1 Hz, H-20 and H-60), 6.98 (m, 1H, H-3), 7.08 (d, 1H,
3J ¼ 9.5 Hz, H-6), 7.30–7.26 (m, 4H, H-9, H-30, H-40, H-50), 7.62 (d,1H,
3J ¼ 3.0 Hz, H-2), 7.88 (d, 1H, 3J ¼ 9 Hz, H-5); 13C NMR (CDCl3)
d:
25.9, 26.9, 67.0, 72.5, 93.7, 105.2, 108.5, 113.9, 114.4, 120.8, 125.6,
129.5, 130.7, 145.4, 148.9, 154.9, 158.4, 158.7, 183.2, 198.1; MS (ESþ)
m/z 367 [M þ H]þ (8), 366 (40), 218 (12), 174 (20), 149 (90), 107
(100); HRMS calcd for C21H18O4S [Mþ] 366.0926, found 366.0921.
[14] H. Wulff, H. Rauer, T. During, C. Hanselmann, K. Ruff, A. Wrisch, S. Grissmer,
W. Haensel, Alkoxypsoralens, novel nonpeptide blockers of Shaker-type Kþ
channels: synthesis and photoreactivity, J. Med. Chem. 41 (1998) 4542–4549.

1852
S.B. Bodendiek et al. / European Journal of Medicinal Chemistry 44 (2009) 1838–1852
[15] H.K. Bohuslavizki, C. Hinck-Kneip, A. Kneip, E. Koppenhofer, A. Reimers,
Reduction of MS-related scotoma by new class of potassium channel
blockers from Ruta graveolens, Neuroophthalmology 13 (1993) 191–198.
[16] J. Vennekamp, H. Wulff, C. Beeton, P.A. Calabresi, S. Grissmer, W. Hansel,
K.G. Chandy, Kv1.3 blocking 5-phenylalkoxypsoralens: a new class of immu-
nomodulators, Mol. Pharmacol. 65 (2004) 1364–1373.
[17] A. Schmitz, A. Sankaranarayanan, P. Azam, K. Schmidt-Lassen, D. Homerick,
W. Hansel, H. Wulff, Design of PAP-1, a selective small molecule Kv1.3 blocker,
for the suppression of effector memory T cells in autoimmune diseases, Mol.
Pharmacol. 68 (2005) 1254–1270.
[18] L.E. Pereira, F. Villinger, H. Wulff, A. Sankaranarayanan, G. Raman, A.A. Ansari,
Pharmacokinetics, toxicity, and functional studies of the selective Kv1.3
channel blocker 5-(4-phenoxybutoxy)psoralen in rhesus macaques, Exp. Biol.
Med. (Maywood) 232 (2007) 1338–1354.
[28] K. Yamamoto, M. Jikei, K. Miyatake, J. Katoh, H. Nishide, E. Tsuchida, Sulfide
bond formation for the synthesis of poly(thioarylene) through oxidation of
sulfur chloride with aromatics, Macromolecules 27 (1994) 4312–4317.
[29] J.A. Lamberton, J.R. Price, Alkaloids of the Australian Rutaceae: Acronychia
baueri. IV. Alkaloids present in the leaves, Aust. J. Chem. 6 (1953) 66–77.
[30] H. Ishii, Alkaloids of Rutaceous plants. XIV. Syntheses of some hydrogenated
derivatives of skimmianine, Yakugaku Zasshi 81 (1961) 248–253.
[31] A. Schonberg, N. Badran, Khellin from visnagin, J. Am. Chem. Soc. 73 (1951)
2960–2961.
[32] V.K. Ahluwalia, K.K. Arora, C. Prakash, Selective Claisen migration in chro-
mones. A convenient synthesis of the linear furanochromones desmethox-
yvisnagin, norvisnagin, and visnagin, Gazz. Chim. Ital. 111 (1981) 103–107.
[33] T. Dubuffet, A. Loutz, G. Lavielle, An efficient large scale synthesis of coumarins
a
by
a dealkylative boron-mediated ring closure of 3-(ortho-methoxyar-
[19] P. Azam, A. Sankaranarayanan, D. Homerick, S. Griffey, H. Wulff, Targeting
yl)propenoic esters, Synth. Commun. 29 (1999) 929–936.
effector memory
T
cells with the small molecule Kv1.3 blocker PAP-1
[34] N.M.F.S.A. Cerqueira, A.M.F. Oliveira-Campos, P.J. Coelho, L.H. Melo De Car-
valho, A. Samat, R. Guglielmetti, Synthesis of photochromic dyes based on
annulated coumarin systems, Helv. Chim. Acta 85 (2002) 442–450.
[35] G. Kneen, P.J. Maddocks, A convenient synthesis of 4-hydroxybenzo(b)furan,
(karanjol), Synth. Commun. 16 (1986) 1635–1640.
suppresses allergic contact dermatitis, J. Invest. Dermatol. 127 (2007) 1419–
1429.
[20] H. Wulff, M. Pennington, Targeting effector memory T-cells with Kv1.3
blockers, Curr. Opin. Drug Discov. Dev. 10 (2007) 438–445.
[21] T. Ohta, Y. Mori, C. Noda, T. Aoki, Furoquinolines. XX. Alkaloids of the leaves of
Ruta graveolens and synthesis of dihydrokokusaginine, Chem. Pharm. Bull. 8
(1960) 377–379.
[22] I. Butenschon, K. Moller, W. Hansel, Angular methoxy-substituted furo- and
pyranoquinolinones as blockers of the voltage-gated potassium channel Kv1.3,
J. Med. Chem. 44 (2001) 1249–1256.
[23] A.J. Harvey, J.B. Baell, N. Toovey, D. Homerick, H. Wulff, A new class of blockers
of the voltage-gated potassium channel Kv1.3 via modification of the 4- or 7-
position of khellinone, J. Med. Chem. 49 (2006) 1433–1441.
[24] J.B. Baell, R.W. Gable, A.J. Harvey, N. Toovey, T. Herzog, W. Hansel, H. Wulff,
Khellinone derivatives as blockers of the voltage-gated potassium channel
Kv1.3: synthesis and immunosuppressive activity, J. Med. Chem. 47 (2004)
2326–2336.
[25] W.A. Schmalhofer, J. Bao, O.B. McManus, B. Green, M. Matyskiela,
D. Wunderler, R.M. Bugianesi, J.P. Felix, M. Hanner, A.-R. Linde-Arias,
C.G. Ponte, L. Velasco, G. Koo, M.J. Staruch, S. Miao, W.H. Parsons, K. Rupprecht,
R.S. Slaughter, G.J. Kaczorowski, M.L. Garcia, Identification of a new class of
inhibitors of the voltage-gated potassium channel, Kv1.3, with immunosup-
pressant properties, Biochemistry 18 (2002) 7781–7794.
[26] J.P. Felix, R.M. Bugianesi, W.A. Schmalhofer, R. Borris, M.A. Goetz,
O.D. Hensens, J.M. Bao, F. Kayser, W.H. Parsons, K. Rupprecht, M.L. Garcia,
G.J. Kaczorowski, R.S. Slaughter, Identification and biochemical characteriza-
tion of a novel nortriterpene inhibitor of the human lymphocyte voltage-gated
potassium channel, Kv1.3, Biochemistry 38 (1999) 4922–4930.
[27] J.C. Lee, Y. Choi, An improved method for preparation of carboxylic esters
using CsF-celite/alkyl halide/CH3CN combination, Synth. Commun. 28 (1998)
2021–2026.
[36] C. Bonini, G. Cristiani, M. Funicello, L. Viggiani, Facile entry to 4- and 5-hydrox-
ybenzofuran and to their amino derivatives, Synth. Commun. 36 (2006) 1983–1990.
[37] E. Spath, W. Gruber, Natural chromones. II. Constitution of visnagin (from
Ammi visnaga), Ber. Dtsch. Chem. Ges. 74B (1941) 1492–1500.
[38] A.-R.H. Abdel-Rahman, E.M. Keshk, E.M. El-Telbani, Linearly fused furo-
chromones by intramolecular enaminone reactions, Z. Naturforsch., B: Chem.
Sci. 57 (2002) 557–562.
[39] A. Schonberg, G. Aziz, Furochromones and coumarins. VI. Demethylation of
xantotoxin, khellin and khellol with aniline hydrochloride and magnesium
iodide, Am. J. Chem. Soc. 75 (1953) 3265–3266.
[40] R.B. Gammill, S.A. Nash, Oxymetallation of khellin. Solvomercuration, osmy-
lation, and palladium-catalyzed oxidation of the furan ring in khellin. The
synthesis of highly oxygenated chromones and 2-substituted furochromones,
J. Org. Chem. 51 (1986) 3116–3123.
[41] S.M.S. Atta, T.S. Hafez, M.R. Mahran, Organophosphorus chemistry. 25. The
utilization of Wittig reagents in lactone ring formation. Application to the
synthesis of linear furocoumarins and pyranocoumarins, Phosphorus, Sulfur
Silicon Relat. Elem. 80 (1993) 109–116.
[42] A.F. Morel, E.L. Larghi, M.M. Selvero, Mild, efficient and selective silver
carbonate-mediated O-alkylation of 4-hydroxy-2-quinolones. Synthesis of
2,4-dialkoxyquinolines, Synlett (2005) 2755–2758.
[43] U. Bhoga, R.S. Mali, S.R. Adapa, New synthesis of linear furoquinoline alkaloids,
Tetrahedron Lett. 45 (2004) 9483–9485.
[44] N.S. Narasimhan, R.S. Mali, Synthetic application of lithiation reactions. VI. New
synthesis of linear furoquinoline alkaloids, Tetrahedron 30 (1974) 4153–4157.
[45] M.F. Grundon, N.J. McCorkindale, Synthesis of g-fagarine and dictamnine,
Chem. Ind. (London, United Kingdom) (1956) 1091–1092.