Transition metals in organic synthesis - Part 83#: Synthesis and pharmacological potential of carbazoles

Article abstract of DOI:10.1007/s00044-007-9073-0

A series of carbazole derivatives with promising pharmacological properties has been prepared using either an iron-mediated or a palladium-catalyzed synthetic approach. The carbazole alkaloids carbazoquinocin C, carbazomadurin A and B, epocarbazolin A and

Full text of DOI:10.1007/s00044-007-9073-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2008) 17:374–385
DOI 10.1007/s00044-007-9073-0
ORIGINAL RESEARCH
Transition metals in organic synthesis - Part 83#:
Synthesis and pharmacological potential of carbazoles
Taylor A. Choi Æ Regina Czerwonka Æ Ronny Forke Æ
¨
¨
Anne Jager Æ Jan Knoll Æ Micha P. Krahl Æ
Tilo Krause Æ Kethiri R. Reddy Æ Scott G. Franzblau Æ
¨
Hans-Joachim Knolker
Received: 17 October 2007 / Accepted: 20 November 2007 / Published online: 10 January 2008
¨
Ó Birkhauser Boston 2007
Abstract A series of carbazole derivatives with promising pharmacological
properties has been prepared using either an iron-mediated or a palladium-catalyzed
synthetic approach. The carbazole alkaloids carbazoquinocin C, carbazomadurin A
and B, epocarbazolin A and B, neocarazostatin B, and carquinostatin A are anti-
oxidants acting as free-radical scavengers. Thus, they represent potential lead
compounds for the development of novel drugs against diseases initiated by oxygen-
derived free radicals. Initiated by the first naturally occurring carbazole alkaloids
with antituberculosis (anti-TB) activity, clausine K and micromeline, a study on the
structure–activity relationships for anti-TB-active carbazole derivatives has been
carried out. The 6-oxygenated carbazoles glycozoline and glycozolinine show
antibiotic activity towards several microorganisms. The 7-oxygenated carbazole
siamenol exhibits anti-HIV activity.
Introduction
#
Part 82: (Forke et al., 2007)
A broad structural range of carbazole alkaloids with useful biological activities
has been isolated from nature (Chakraborty and Roy, 1991; Chakraborty 1993;
¨
Knolker and Reddy, 2002; Knolker 2005). Because of the pharmacological potential
of these natural products, several research groups have developed diverse synthetic
¨
¨
strategies (Chakraborty and Roy, 1991; Chakraborty 1993; Knolker and Reddy,
¨
¨
T. A. Choi Á R. Czerwonka Á R. Forke Á A. Jager Á J. Knoll Á M. P. Krahl Á
¨
T. Krause Á K. R. Reddy Á H.-J. Knolker (&)
¨
Department Chemie, Technische Universitat Dresden, Bergstrasse 66, 01069 Dresden, Germany
e-mail: hans-joachim.knoelker@tu-dresden.de
T. A. Choi Á S. G. Franzblau
Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S.
Wood St., MC 964, Chicago, IL 60612-7231, USA

Med Chem Res (2008) 17:374–385
375
¨
2002; Knolker 2005; Kawasaki and Sakamoto, 1994; Moody 1994; Hibino and
Sugino, 1995; Kirsch 2001; Lemster and Pindur, 2002; Agarwal et al., 2005;
Agarwal et al., 2006). We have described two highly efficient approaches using
either an iron-mediated or a palladium-catalyzed construction of the carbazole
¨
¨
framework (Knolker and Reddy, 2002; Knolker 2005; Agarwal et al., 2005;
Agarwal et al., 2006). Both routes offer the advantage of functionalized building
blocks, which can be combined by exploitation of transition-metal-mediated or
catalyzed coupling reactions. Therefore, our synthetic strategy leads to highly
convergent and short-step total syntheses of natural products and has been applied to
structure–activity studies. In the present paper, we emphasize some recent
achievements along these lines.
Results and Discussion
The carbazoquinocins, e.g., carbazoquinocin C, have been isolated from Strepto-
myces violaceus 2448-SVT2 (Tanaka et al., 1995). Our approach, using a palladium
(II)-catalyzed oxidative cyclization as a key step, provides a simple four-step route
¨
to carbazoquinocin C (Scheme 1) (Knolker et al., 2002).
Regioselective addition of aniline (1) to 2-methoxy-3-methyl-1,4-benzoquinone
(2) afforded the anilinobenzoquinone 3. Treatment with catalytic amounts of
palladium (II) acetate in the presence of cupric acetate as reoxidant led to 3-
methoxy-2-methylcarbazole-1,4-quinone (4). Addition of heptylmagnesium chlo-
ride gave the carbazolequinol 5, which on treatment with acid provided
carbazoquinocin C (6) in four steps and 39% overall yield. Carbazoquinocin C
shows a strong inhibition of lipid peroxidation induced by free radicals (Tanaka
et al., 1995).
The carbazomadurins A and B have been isolated from the microorganism
Actinomadura madurae 2808-SV1 (Kotoda et al., 1997). On screening for 5-
lipoxygenase inhibitors, the structurally related epocarbazolins A and B were found
in the actinomycete strain Streptomyces anulatus T688-8 (Nihei et al., 1993). A
common approach to these natural products has been developed by sequential
∆
1
2
3
4
5
6
Scheme 1 Palladium-catalyzed synthesis of carbazoquinocin C

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application of three different palladium-catalyzed cross-coupling reactions
¨
¨
¨
¨
(Scheme 2) (Knolker and Knoll, 2003; Knoll and Knolker, 2006).
Palladium (0)-catalyzed Buchwald–Hartwig coupling of the aryl triflate 7 with
the arylamine 8 afforded the N,N-diarylamine 9. The subsequent palladium (II)-
mediated oxidative cyclization provided the pentasubstituted carbazole skeleton 10.
Change of the protecting groups led to the disilyl ether 11. Introduction of the
appropriate side chain at C-1 by a palladium (0)-catalyzed Stille coupling with the
alkenylstannanes 12a and 12b afforded the 1-alkenylcarbazoles 13. Reduction of the
methyl esters gave the benzylic alcohols 14 as crucial intermediates for both classes
of compounds. Removal of the silyl protecting groups provided carbazomadurin A
¨
(15a) and carbazomadurin B (15b) (Knolker and Knoll, 2003; Knoll and Knolker,
2006). Conversion of the disilyl ethers 14 to the trisilyl-protected intermediates 16
¨
¨
¨
Scheme 2 Palladium-catalyzed synthesis of the carbazomadurins and epocarbazolins

Med Chem Res (2008) 17:374–385
377
followed by epoxidation with dimethyldioxirane and desilylation afforded racemic
¨
¨
epocarbazolin A (17a) and epocarbazolin B (17b) (Knoll and Knolker, 2006).
The carbazomadurins A and B exhibit a strong neuronal cell protecting activity
against L-glutamate-induced cell death. The epocarbazolins A and B are potent
inhibitors of rat 5-lipoxygenase (epocarbazolin A: IC50 = 2.4 lM; epocarbazolin B:
IC50 = 2.6 lM) (Nihei et al., 1993).
Neocarazostatin B has been isolated from the culture of Streptomyces sp. strain
GP 38 (Kato et al., 1991). The structurally related carquinostatin A, obtained from
Streptomyces exfoliatus 2419-SVT2, represents the corresponding ortho-quinone
derivative (Shin-ya et al., 1993; Grammel et al., 1998). Using the iron-mediated
carbazole construction, a straightforward synthesis of both alkaloids has been
developed; moreover, the absolute configuration of neocarazostatin B could be
assigned (Scheme 3) (Czerwonka et al., 2006).
Reaction of the iron complex salt 18 with the arylamine 19 in air resulted in
electrophilic substitution in situ followed by oxidative cyclization to the tricarbon-
yliron-coordinated dihydrocarbazole 20. Aromatization with demetalation and
subsequent electrophilic bromination afforded the 6-bromocarbazole 21. Nickel-
mediated prenylation and removal of the acetyl protecting groups from compound
22 provided (R)-(–)-neocarazostatin B (23). Oxidation with cerium (IV) ammonium
Scheme 3 Iron-mediated synthesis of (R)-(–)-neocarazostatin B and carquinostatin A

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Med Chem Res (2008) 17:374–385
nitrate converted (R)-(–)-neocarazostatin B (23) into carquinostatin A (24).
Neocarazostatin B is a potent inhibitor of the free-radical-induced lipid peroxidation
in rat brain homogenate (IC50 = 0.39 lM) and was much more efficient than other
well-known antioxidants (Kato et al., 1991). Carquinostatin A is also an efficient
antioxidant and shows neuronal cell protecting activity against L-glutamate-induced
cell death (Shin-ya et al., 1993).
7-Methoxy-O-methylmukonal has been isolated from the roots of Murraya
siamensis (Ruangrungsi et al., 1990). Clausine O has been found in the root bark of
the Chinese medicinal plant Clausena excavata (Wu et al., 1999). Clausine H
(clauszoline-C) and clausine K (clauszoline-J) have been obtained from the stem
bark of the same plant (Wu et al., 1996; Ito et al., 1996; 1997). Moreover, clausine
K has also been obtained from the roots of Clausena harmandiana (Yenjai et al.,
2000). The pharmacological potential initiated us to develop a simple iron-mediated
approach to the 2,7-dioxygenated carbazole alkaloids (Scheme 4) (Kataeva et al.,
2005).
Electrophilic substitution of 3-methoxy-4-methylaniline (26) by reaction with the
2-methoxy-substituted iron complex salt 25 afforded the iron complex 27. Iron-
mediated arylamine cyclization followed by aromatization provided 2,7-dimethoxy-
3-methylcarbazole (28), which served as relay to the subsequent carbazole alkaloids
having the same substitution pattern. Oxidation with 2,3-Dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) led to 7-methoxy-O-methylmukonal (29) and subsequent
ether cleavage gave clausine O (30). Further oxidation of the aldehyde 29 to the
methyl ester afforded clausine H (31), which on ester cleavage provided clausine K
(32). Clausine H (clauszoline-C) exhibits antiplasmodial activity against Plasmo-
dium falciparum (IC50 = 5.5–10.7 lg mL-1) (Yenjai et al., 2000). Clausine K
(clauszoline-J) shows weak antimycobacterial activity against Mycobacterium
Scheme 4 Iron-mediated synthesis of 2,7-dioxygenated carbazole alkaloids

Med Chem Res (2008) 17:374–385
379
tuberculosis H37Ra (MIC90 = 100 lg mL-1 = 369 lM) (Sunthitikawinsakul et al.,
2003).
Glycozoline and glycozolinine (glycozolinol) were isolated first from Glycosmis
pentaphylla (Chakraborty 1966; Mukherjee et al., 1983; Bhattacharyya et al., 1984).
Glycomaurrol has been found in the stem bark of Glycosmis mauritiana (Kumar
et al., 1989). Eustofoline-D, isolated from the root bark of Murraya euchrestofolia
(Ito and Furukawa, 1990), has an unprecedented furo[2,3-c]carbazole framework
¨
and is one of only four natural furocarbazoles currently known (Frohner et al., 2004;
Knolker and Reddy, 2005). 3-Formyl-6-methoxycarbazole and methyl 6-methoxyc-
¨
arbazole-3-carboxylate have been isolated from the roots of Clausena lansium (Li
et al., 1991). An antituberculosis bioassay-directed fractionation of the stem bark
extract of Micromelum hirsutum led to the isolation of micromeline along with 3-
formyl-6-methoxycarbazole (Ma et al., 2005). Using the palladium-catalyzed
synthesis we gained access to a whole series of 6-oxygenated carbazole alkaloids
(Scheme 5) (Forke et al., 2007).
Palladium (0)-catalyzed coupling of p-bromoanisole (33) with p-toluidine (34)
and subsequent palladium (II)-catalyzed oxidative cyclization of the resulting N,N-
diarylamine 35 provided glycozoline (36). Glycozoline (36) was then used as relay
Scheme 5 Palladium-catalyzed synthesis of 6-oxygenated carbazole alkaloids

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to all the other 6-oxygenated carbazole alkaloids. Ether cleavage gave glycozolinine
(glycozolinol) (37). Regioselective bromination of 37 at C-5 followed by nickel-
mediated prenylation provided glycomaurrol (38). Annulation of the furan ring at
glycozolinine (37) led to eustifoline-D (39). Oxidation of glycozoline (36) using
DDQ afforded 3-formyl-6-methoxycarbazole (40). Further selective oxidation
(aldehyde to ester) provided methyl 6-methoxycarbazole-3-carboxylate (41).
Bromination of 40 to 5-bromo-3-formyl-6-methoxycarbazole (42) followed by
ether cleavage and nickel-mediated prenylation gave micromeline (43). Glycozoline
and glycozolinine (glycozolinol) are antibiotics, with glycozolinine showing much
stronger antibiotic activity (Chakraborty et al, 1975). Antimycobacterial activity
against the Mycobacterium tuberculosis strain H37Rv was reported for 3-formyl-6-
methoxycarbazole (MIC90 = 15.6 lg mL-1 = 69 lM) and micromeline (MIC90
=
31.5 lg mL-1 = 113 lM) (Ma et al., 2005).
The organic extract of the plant Murraya siamensis, collected in Thailand, has
been reported to exhibit anti-HIV activity. Siamenol has been isolated in a bioassay-
guided fractionation of this extract (Meragelman et al., 2000). More recent
investigations of the Chinese medicinal plant Clausena excavata led to the isolation
of clauszoline-K, clausine C (clauszoline-L), clausine M, and clausine N (Wu et al.,
1999; Wu et al., 1996; Ito et al., 1997). A straightforward synthetic route to the 7-
oxygenated carbazole alkaloids has been realized by using the palladium-catalyzed
approach (Scheme 6) (Krahl et al., 2006).
Palladium (0)-catalyzed amination of p-bromotoluene (45) with m-anisidine (44)
to the N,N-diarylamine 46 followed by palladium(II)-catalyzed oxidative cycliza-
tion led to 7-methoxy-3-methylcarbazole (47) (Fig. 1) (Krahl et al., 2006), which
served as a relay to 7-oxygenated carbazole alkaloids. Regioselective bromination at
Scheme 6 Palladium-catalyzed synthesis of 7-oxygenated carbazole alkaloids

Med Chem Res (2008) 17:374–385
381
C-6, cleavage of the methyl ether and nickel-mediated prenylation afforded
siamenol (48). Oxidation of 47 with DDQ led to clauszoline-K (49) (Fig. 2) [crystal
data for clauszoline-K (49): C14H11NO2, M = 225.24, orthorhombic, space group:
3
Pbca, a = 7.163(1), b = 13.245(1), c = 22.516(2) A, V = 2136.2(4) A , Z = 8,
˚
˚
qcalc = 1.401 g cm-3, l = 0.095 mm-1, T = 198(2) K, k = 0.71073 A, h
˚
range = 3.08–35.00°; reflections collected: 69965, independent: 4709 (Rint
=
0.0282). The structure was solved by direct methods and refined by full-matrix
least-squares on F2; R1 = 0.0457, wR2 = 0.1193 [I [ 2r(I)]. CCDC-633273
contains the supplementary crystallographic data for this structure. These data
can be obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif. Further oxidation led to clausine C
(clauszoline-L) (50) (Fig. 3) (Krahl et al., 2006). Ether cleavage of clausine C (50)
afforded clausine M (51), while ester cleavage gave clausine N (52). Siamenol
showed HIV inhibition in the XTT-tetrazolium assay (EC50 = 2.6 lg mL-1
(Meragelman et al., 2000).
)
Based on the reports of naturally occurring carbazole alkaloids with inhibiting
activity against M. tuberculosis (Sunthitikawinsakul et al., 2003; Ma et al., 2005),
we started a project to investigate the structure–activity relationships for this class
of compounds (Choi et al., 2006). The present study provides further data on the
Fig. 1 Crystal structure of 7-methoxy-3-methylcarbazole (47), CCDC-609679
Fig. 2 Crystal structure of clauszoline-K (49), CCDC-633273

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Med Chem Res (2008) 17:374–385
Fig. 3 Crystal structure of clausine C (clauszoline-L) (50), CCDC- 609678
anti-TB activity of carbazole derivatives (Table 1). Minimum inhibitory concen-
tration (MIC90) values for inhibition of M. tuberculosis H37Rv were determined
using the microplate alamar blue assay (MABA) (Collins and Franzblau, 1997;
Pauli et al., 2005). Rifampin (rifampicin) and isoniazid were used as positive
Table 1 Antituberculosis activity, cytotoxicity, and selectivity indices of carbazole derivatives
a
MIC90
b
IC50
c
Compound
Name
SI
4
3-methoxy-2-methylcarbazole-1,4-quinone
6-bromocarbazole derivative
2,7-dimethoxy-3-methylcarbazole
7-methoxy-O-methylmukonal
clausine O
8
[128
25
[16
0.5
–
21
28
29
30
32
36
37
39
40
41
42
43
47
48
49
50
51
52
RMP
INH
a
55
[128
[128
89
[128
96
\0.8
1.3
\0.2
–
114
25
clausine K (clauszoline-J)
glycozoline
[128
[128
123
–
glycozolinine (glycozolinol)
eustifoline-D
57
0.5
–
[128
99
[128
[128
[128
78
3-formyl-6-methoxycarbazole
methyl 6-methoxycarbazole-3-carboxylate
5-bromo-3-formyl-6-methoxycarbazole
micromeline
[1.3
[4.0
\0.6
–
32
[128
[128
[128
22
–
7-methoxy-3-methylcarbazole
siamenol
–
–
15
0.7
–
clauszoline-K
[128
[128
19
–
clausine C (clauszoline-L)
clausine M
–
–
35
1.8
–
clausine N
[128
0.09
0.4
–
rifampin (rifampicin)
isoniazid
105
[128
1167
[320
Minimum inhibitory concentration (lM) against M. tuberculosis H37Rv in the MABA assay.
b
Cytotoxicity on Vero cells. Both values are means of three replicate experiments; [128 indicates
values higher than the maximum concentration applied.
c
Selectivity index: SI = IC50/MIC90

Med Chem Res (2008) 17:374–385
383
controls in the assay and solvent as negative control. All compounds were tested for
in vitro cytotoxicity toward Vero cells (African green monkey kidney cells) (Pauli
et al., 2005; Falzari et al., 2005). The MIC90 value found for natural clausine K
(clauszoline-J) (32) (369 lM) (Sunthitikawinsakul et al., 2003) was much higher
than the highest concentration applied in our assay (128 lM). Moreover, a different
strain of M. tuberculosis (H37Ra) was used in that assay. The MIC90 reported for
natural micromeline (43) (113 lM) (Ma et al., 2005) was in the range of the highest
concentration used herein. This may explain why no anti-TB activity was found for
clausine K (32) and micromeline (43) in the present study. However, a weak anti-
TB activity described for natural 3-formyl-6-methoxycarbazole (40) (MIC90 = 69
lM) (Ma et al., 2005) could be confirmed. The promising antituberculosis activity
of 3-methoxy-2-methylcarbazole-1,4-quinone (4) (Choi et al., 2006) was confirmed
as well. Also methyl 6-methoxycarbazole-3-carboxylate (41) exhibited anti-TB
activity and was nontoxic for the mammalian cell line. Some other compounds
screened in this study showed weak anti-TB activity but were found to be cytotoxic
at the same time: the 6-bromocarbazole derivative 21, clausine O (30), glycozol-
inine (glycozolinol) (37), siamenol (48), and clausine M (51).
In conclusion, carbazoles represent a novel class of potential anti-TB drug
candidates. Further structural modifications of the identified hits for improvement of
the efficacy are in progress.
Acknowledgement We are grateful to the European Funds for Regional Development and the State of
Saxony (EFRE project 4212/06-08) for financial support of our research. We would also like to thank
JADO Technologies, Dresden, for their support.
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