Quinols as novel therapeutic agents. 7. Synthesis of antitumor 4-[1-(arylsulfonyl-1H-indol-2-yl)]-4-hydroxycyclohexa-2,5-dien-1-ones by Sonogashira reactions

Article abstract of DOI:10.1021/jm061163m

Interaction of 2-iodoaniline or 5-fluoro-2-iodoaniline with a range of arylsulfonyl chlorides affords sulfonamides that undergo Sonogashira couplings under thermal or microwave conditions with the alkyne 4-ethynyl-4- hydroxycyclohexa-2,5-dien-1-one follow

Full text of DOI:10.1021/jm061163m

J. Med. Chem. 2007, 50, 1707-1710
1707
Quinols As Novel Therapeutic Agents. 7.1 Synthesis of Antitumor
4-[1-(Arylsulfonyl-1H-indol-2-yl)]-4-hydroxycyclohexa-2,5-dien-1-ones by Sonogashira Reactions
Andrew J. McCarroll, Tracey D. Bradshaw, Andrew D. Westwell,† Charles S. Matthews, and Malcolm F. G. Stevens*
Centre for Biomolecular Sciences, School of Pharmacy, UniVersity of Nottingham, UniVersity Park, Nottingham,
Nottingham, NG7 2RD, United Kingdom
ReceiVed October 6, 2006
Interaction of 2-iodoaniline or 5-fluoro-2-iodoaniline with a range of arylsulfonyl chlorides affords
sulfonamides that undergo Sonogashira couplings under thermal or microwave conditions with the alkyne
4-ethynyl-4-hydroxycyclohexa-2,5-dien-1-one followed by cyclization to 4-[1-(arylsulfonyl-1H-indol-2-yl)]-
4-hydroxycyclo-hexa-2,5-dien-1-ones. This method allows for incorporation of a range of substituents into
the arylsulfonyl moiety, and compounds showed selective in vitro inhibition of cancer cell lines of colon
and renal origin, a feature of compounds bearing the quinol pharmacophore.
Scheme 1. Synthesis of 4-Substituted
Introduction
4-Hydroxycyclohexa-2,5-dien-1-onesa
Our interest in the generation of novel and structurally diverse
chemical oxidation products of bioactive phenols as potential
therapeutic agents with enhanced biological properties has led
to the discovery of 4-hydroxycyclohexa-2,5-dien-1-ones
(“quinols”) substituted with a heterocyclic fragment in the
4-position, a new pharmacophore in anticancer drug develop-
ment. The prototypic benzothiazole-substituted quinol 1 dis-
played selective antitumor activity against colon, renal, and
breast cancer cell lines,2 and by a combination of biochemical
and biophysical methods we have identified the redox homeo-
stasis-controlling protein thioredoxin (Trx) as a primary mo-
lecular target.3 As expected, this agent also perturbs signaling
events modulated by downstream Trx effectors (eg Hif-1R4 and
VEGF5) that have a major role in the tumor angiogenesis process
triggered by cellular hypoxia. Subsequently, we have identified
a second more potent series of indolyl-quinols 2, which maintain
the selectivity fingerprint against colon, renal, and breast cell
lines in vitro and show significant in vivo antitumor activity in
mice bearing human mammary MDA-MB-435, colon HCT-116,
and renal CAKI-1 xenografts.6
The original synthesis of 1 was achieved by a phenyliodonium
diacetate (or trifluoroacetate) oxidation of a precursor phenol,
2-(4-hydroxyphenyl)benzothiazole 3.2 A more versatile one-pot
synthesis of indoles 2 was accomplished by lithiation of a
1-(arylsulfonyl)indole 4 with n-butyllithium in THF at -78 °C,
followed by addition to 4,4-dimethoxycyclohexa-2,5-dien-1-one,
with subsequent acidic removal of the ketal protecting group
(Scheme 1).6 Both methods gave variable yields generally
<40%, and in some cases reactions failed to deliver isolable
products, probably because of stability issues in workup.
Accordingly, we sought an alternative synthetic methodology
to increase the range of quinols available for biological
evaluation as well as to identify agents with better solubility
properties than the original series 2.
a Reagents and conditions: (a) [bis(trifluoroacetoxy)iodo]benzene, TEMPO,
in MeCN/H2O; (b) n-BuLi, THF, -78 °C, 4,4-dimethoxy-2,5-cyclohexadien-
1-one, then 10% aq. AcOH.
they reported the addition of copper acetylides to o-thallated
anilides, with the subsequent cyclization mediated by palladium
chloride.8 In 1988, Sakamoto et al. described a significant
advance in the one-pot Sonogashira synthesis of indoles from
2-iodoanilines and alkynes activated by electron-withdrawing
substituents on the amino group.9 Since then, a substantial body
of work has been carried out on related reactions, and the subject
has been covered in several reviews.10 Methods have been
developed for conducting indole syntheses on polymer supports
by Zhang et al., where an arylsulfonyl group activates the amine
and also acts as a traceless linker.11 Kabalka adapted Sono-
gashira conditions to secure indole formation on alumina under
microwave conditions, and the sulfonamide was the most
successful activating group;12 also, Sakamoto showed that the
reaction could be performed using mono- or bismesylated
iodoanilines in the reaction when TBAF was used as base.13
One possible reason for the limited use of the sulfonamide
activating/protecting group in palladium(0)-mediated syntheses
is the difficulty of its removal once the reaction is complete.
However, as our past work has shown that the arylsulfonyl
moiety actually enhances activity in indolyl-quinols 2,6 our new
strategy was to react N-arylsulfonyl-2-iodoanilines with an
alkynyl-substituted quinol under Sonogashira conditions.
The use of transition metallic reagents, such as copper
acetylides, in the construction of an indole ring from 2-iodoa-
nilines dates back to the 1960s.7 Taylor and McKillop were the
first to use palladium chemistry in this type of synthesis when
* To whom correspondence should be addressed. Phone: (44) 115 951
3414. Fax: (44) 115 951 3412. E-mail: malcolm.stevens@nottingham.ac.uk.
† Current address: Welsh School of Pharmacy, Cardiff University,
Redwood Building, King Edward VII Avenue, Cardiff, CF10 3XF, U.K.
10.1021/jm061163m CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/08/2007

1708 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 7
Brief Articles
Scheme 2. Synthesis of Indol-2-yl-substituted 4-Hydroxycyclohexa-2,5-dien-1-onesa
a Reagents and conditions: (a) pyridine/THF, 25 °C; (b) (i-Pr)2NH, tetrakis(triphenylphosphine)palladium, CuI, DMAC, H2O, 100 °C, 100W MW; (c) 8i,
Me3SnOH, DCE, 120 °C, 100W MW; (d) as (c) from 8j.
Table 1. Yields and Melting Points of Products of Sonogashira
Reactions
because the halogen substituents provide additional sites for
palladium(0)-mediated couplings. The reactions also proceeded
yield
(%)
m.p. °C
(lit.)
yield
(%)
m.p. °C
(lit.)
in 10 min under thermal conditions at 100 °C (or in some cases
at 80 °C) with similar yields, but the microwave conditions were
more convenient for small-scale reactions.
8a
49
170-172
8h
28
64.5 (dec)
(170-172)a
The indolyl-quinols as a class are only poorly soluble in water
and we were interested to prepare agents with appended polar
groups which might impart more tractable pharmaceutical
properties. Hydrolysis of the esters 8i,j to yield the correspond-
ing propionic acids 8m,n could not be accomplished under basic
saponification conditions without degradation of the quinol
moiety. A method modified from that described by Nicolaou,17
involving application of excess trimethyltin hydroxide in 1,2-
dichloroethane (DCE) for 0.5 h at 120 °C under microwave
conditions, was successfully employed to effect hydrolysis of
methyl esters 8i,j to the corresponding propanoic acids 8m,n.
8b
8c
44
45
185-187b
8i
8j
20
48
137-138
129.5-130.5
159-161
(159-161)a
226-228 (dec)
109-115 (dec)
95-105 (dec)
213-215
8d
8e
8f
38
27
23
10
10
24
14
32
70
173-174 (dec)
170 (dec)
201-202
96.5-103
12a
12b
14
8g
a Reference 6. b This compound was reported in ref 6, but no mp was
recorded.
Results and Discussion
Having achieved Sonogashira indole cyclizations on a small
scale under microwave conditions, the conversion of 6b to the
most potent indolyl-quinol 8b on a larger scale (20 mmol) was
investigated: a yield of 53% was obtained in just 10 min under
thermal conditions. Compound 8c was prepared similarly (72%
yield) from 6c. Yields of 8b,c by this process were superior to
that achieved in the lithiation/addition route.6
A series of 2-iodoanilines 6a-l activated by N-arylsulfonyl
residues was prepared from arylsulfonyl chlorides and 2-iodo-
aniline 5a or 5-fluoro-2-iodoaniline 5b in pyridine. In a model
experiment, the reaction between N-(2-iodophenyl)benzene-
sulfonamide 6a and phenylacetylene gave 1-benzenesulfonyl-
2-phenylindole in a satisfactory 70% yield employing conditions
reported by Kotschy [Pd/C catalyst, copper iodide, diisopropyl-
amine base in dimethylacetamide (DMAC) containing 5%
water].14 However, this approach, and use of other catalyst/
solvent combinations, to pilot reactions between 6a-c and
4-ethynyl-4-hydroxycyclohexa-2,5-dien-1-one 7 (prepared by
addition of ethynylmagnesium bromide to 4,4-dimethoxycyclo-
hexa-2,5-dienone)15,16 gave only poor yields of products 8a-c.
After considerable experimentation, it was found that use of
the homogeneous catalyst tetrakis(triphenylphosphine)palladium
and copper iodide in a diisopropylamine/aqueous DMAC
medium at 100 °C afforded indoles 8a-g in only 10 min with
microwave irradiation (Scheme 2, Table 1); again, yields were
generally low possibly because of losses sustained during
isolation. These standardized conditions were used to prepare
indolyl-quinols bearing aliphatic side chains 8h-j, but disap-
pointingly, the halo-substituted N-(2-iodophenyl)benzenesulfon-
amides 6k,l failed to furnish isolable quinols 8k,l presumably
The 3-pyridosulfonyl-activated iodoaniline 9 was successfully
cyclized to 10 (24%) using homogeneous catalyst with micro-
wave activation. The preparation of 5- and 6-azaindoles bearing
the quinol group was also investigated. The desired ami-
noiodopyridine starting materials were not commercially avail-
able and were prepared by ortho-lithiation/iodination of pi-
valoylated aminopyridines with subsequent acid hydrolysis.18
Surprisingly, addition of the arylsulfonyl group to 3-iodo-4-
aminopyridine was unsuccessful under the normal conditions,
so the sulfonamide 11a was prepared using KOH and a phase-
transfer catalyst in DCM. Cyclization of the activated iodopy-
ridylamines 11a,b with alkyne 7 to the 5- and 6-azaindolyl-
quinols 12a,b, respectively, was achieved under microwave
conditions although yields of these isolated aza-analogs were
only modest (<35%). The dansyl-substituted indole 14, which
was required as a potential fluorescent probe to explore

Brief Articles
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 7 1709
Table 2. Activity of Compounds in the NCI In Vitro 60-Cell Panela
within a tight range at δ 6.32-6.37, and H-2 of the indole at δ
6.74-6.90, as a doublet with a small (∼ 0.5 Hz) coupling
constant.
mean GI50 mean LC50
most sensitive cell lines
cmpd
(µM)
(µM)
(LC50, µM)b,c
1
0.23d
0.039d
0.016d
0.11
3.39
2.95
2.24
7.24
HCT-116 (0.43), RXF393 (0.58)
HCT-116 (0.03), CAKI-1 (0.05)
HCT-116 (<0.01), ACNH (0.02)
HCT-116 (<0.01), LOX IMVI (<0.01),
ACHN (0.04)
Biological Results and Discussion
8a
8b
8c
The growth-inhibitory activities of new quinols were initially
monitored in a preliminary screen comprising a panel of human
colon (HCT-116 and HT29), breast (MCF-7 and MDA 468),
and nonsmall cell lung (A549) cancer cell lines in 72 h drug
exposure MTT assays. The most sensitive cell line was colon
HCT-116, giving IC50 values over a 10-fold range (0.03-0.2
µM); the least sensitive cell line was A549 (IC50 values 0.5-4
µM) with the other cell lines of intermediate sensitivity (data
not shown). Activities of new indolyl-quinols were compared
with those of lead structures in the U.S. National Cancer Institute
(NCI) in vitro 60-cell panel.19 With the exception of the
propanoic acids 8m,n, the mean GI50 values (Table 2) were in
the range 0.1-0.68 µM, but new compounds were less potent
than the previously synthesized indolyl-quinols 8a,b (mean GI50
0.039 and 0.016 µM, respectively). Because of the tight range
of activities, it was not possible to discern a meaningful
structure-activity relationship in this series, but clearly, the
presence of the 6-F substituent in 8b confers high potency at
the GI50 level. The mean potencies and pattern of selectivities
at the LC50 level were similar across the series of compounds
with colon (HCT-116) and renal cells lines (ACNH, CAKI-1,
and RXF-393) being particularly sensitive, a feature of this novel
class of agents bearing the quinol pharmacophore.2,6 This
selectivity is a property of compounds of the quinol class that
inhibit the thioredoxin signaling pathway.3 However, conversion
of the propionate esters 8i,j to more polar propanoic acids 8m,n
was accompanied by an overall loss of in vitro activity,
especially against the normally sensitive cell lines. Possibly,
introduction of a residue charged at physiological pH has an
adverse effect on cellular penetration, although this has not been
investigated.
8d
8i
8j
0.19
0.68
0.50
7.58
22.9
10.5
HCT-116 (0.295), ACHN (0.60)
HCT-116 (0.02), SK-MEL-5 (0.60)
HCT-116 (0.72), LOX IMVI (0.81),
BT-549 (0.74)
8m
8n
10
12a
12b
2.34
2.5
0.41
0.34
0.17
23.4
29.5
14.1
13.8
5.75
e
e
HCT-116 (0.29)
HCT-116 (0.93), CAKI-1 (0.47)
HCT-116 (<0.01), LOX IMVI (0.06),
ACHN (0.05)
14
0.19
13.2
A498 (0.06), ACHN (0.41)
a For definitions of GI50 and LC50, see ref 19. b Cell lines with LC50
<
1 µM. c Cancer cell line origin: HCT-116 (colon); RXF 393, CAKI-1,
ACHN and A498 (renal); LOX IMVI and SK-MEL-5 (melanoma); BT-
549 (breast). d Data from ref 6. e No cell lines with LC50 < 1 µM.
Scheme 3. Synthesis of 4-Substituted
4-Hydroxycyclohexa-2,5-dien-1-ones with Additional Hetero
Atoms and Benzene Ringsa
In summary, we have shown that Sonogashira coupling
chemistry can be employed to construct a new series of indolyl
quinols 8b-j, which show selective in vitro activities especially
against cancer cells of colon, renal, and melanoma origin.
However, new compounds prepared by this route were less
potent than other congeners in this series.6
Experimental Section
Melting points were recorded on a Stuart Scientific SMP3
apparatus and are uncorrected. IR spectra were recorded on a Perkin-
Elmer Spectrum One FT-IR. Mass spectra were recorded on a
Micromass LCT spectrometer using electrospray. NMR spectra
were recorded on a Bruker Avance 400 instrument at 400.13 MHz
(1H) and 100.62 MHz (13C) in [2H6]DMSO) or CDCl3; coupling
constants are in Hz. Merck silica gel 60 (40-60 µM) was used for
column chromatography. 2-Iodoaniline was purchased from Avo-
cado and recrystallized from hexane prior to use, and 5-fluoro-2-
iodoaniline was purchased from Lancaster and used as received.
General Method A: Preparation of Arylsulfonamides. A
solution of an arylsulfonyl chloride (10 mmol) and 2-iodoaniline
5a or 5-fluoro-2-iodoaniline 5b (10 mmol) in pyridine (4 mL) and
tetrahydrofuran (4 mL) was stirred overnight at 25 °C. The mixture
was concentrated under reduced pressure, and the products were
purified either by recrystallization from aqueous ethanol or by
column chromatography (hexane/ethyl acetate, 3/1).
a Reagents and conditions: (a) 7, (i-Pr)2NH, tetrakis(triphenylphos-
phine)palladium, CuI, DMAC, H2O, 100 °C, 100W MW.
biological mechanisms in this series, but which also has the
structural requirements for bioactivity in its own right (see Table
2), was similarly prepared from the dansyl-activated iodoaniline
13 (70%; Scheme 3).
Certain indolyl-quinols (8f-h and 10) showed evidence of
instability and gave substantial (M-H2O + H)+ ions in their
HRMS (ES) spectra; they also gave unreliable CHN analytical
data. However, all the indolyl-quinol series showed characteristic
absorptions in their 1H NMR spectra. The (exchangeable) 4-OH
proton absorbs at δ 5.11-5.56, the cyclohexadienone 3-CH
General Method B: Preparation of Indolyl-quinols. To a 10
mL microwave vial containing a magnetic stirrer bar was added
4-ethynyl-4-hydroxycyclohexa-2,5-dienone 7 (0.39 g, 2.9 mmol),
an activated 2-iodoaniline (2.5 mmol), DMAC (2.5 mL), diisopro-
pylamine (0.5 mL), and water (0.1 mL). Nitrogen gas was gently

1710 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 7
Brief Articles
(5) Mukherjee, A.; Westwell, A. D.; Bradshaw, T. D.; Stevens, M. F.
G.; Carmichael, J.; Martin, S. G. Cytotoxic and antiangiogenic activity
of AW464 (NSC 706704), a novel thioredoxin inhibitor: An in vitro
study. Br. J. Cancer 2005, 92, 350-358.
bubbled through for 10 min, and then tetrakis(triphenylphosphine)-
palladium (160 mg, 0.15 mmol) and copper iodide (48 mg, 0.25
mmol) were added. The vial was sealed, shaken, and heated at 100
°C (100 W) for 10 min under microwave conditions. The cooled
mixture was diluted with DCM/water (200 mL, 1/1). The aqueous
layer was extracted with DCM, and the combined organic layers
were dried and concentrated. The residue was passed through a
pad of silica (hexane/ethyl acetate, 1/1) and purified further by
column chromatography and/or recrystallization with aqueous
ethanol.
3-{4-[2-(4-Hydroxy-1-oxocyclohexa-2,5-dienyl)-1H-indol-1-yl-
sulfonyl]-phenyl}propanoic Acid 8m. A mixture of ester 8i (0.132
g) and trimethyltin hydroxide (0.30 g) in 1,2-dichloroethane (3 mL)
was heated in a sealed vial under microwave conditions at 120 °C
for 0.5 h. The cooled mixture was filtered, concentrated in vacuo,
and purified by column chromatography (EtOAc) to yield the
propanoic acid 8m (0.05 g, 39%), mp 193-194 °C.
(6) Berry, J. M.; Bradshaw, T. D.; Fichtner, I.; Ren, R. ; Schwalbe, C.
H.; Wells, G.; Chew, E.-H.; Stevens, M. F. G.; Westwell, A. D.
Quinols as novel therapeutic agents. 2. 4-(1-arylsulfonylindol-2-yl)-
4-hydroxycyclohexa-2,5-dien-1-ones and related agents as potent and
selective antitumor agents. J. Med. Chem. 2005, 48, 639-644.
Stevens, M. F. G.; Westwell, A. D.; Poole, T. D.; Wells, G.; Berry,
J. M. 4-(1-(Sulfonyl)-1H-indol-2-yl)-4-(hydroxy)-cyclohexa-2,5-di-
enone compounds and analogs thereof as therapeutic agents. Inter-
national Publication Number WO 2004/056361 A1, 2004.
(7) Castro, C. E.; Gaughan, E. J.; Owsley, D. C. Indoles, benzofurans,
phthalides, and tolanes via copper(I) acetylides. J. Org. Chem. 1966,
31, 4071-4078.
(8) Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H.; McKillop, A.
Thallium in organic synthesis. 68. A convenient synthesis of
2-phenylindoles from anilides. Tetrahedron Lett. 1985, 26, 5963-
5966.
3-{4-[6-Fluoro-2-(4-hydroxy-1-oxocyclohexa-2,5-dienyl)-1H-
indol-1-ylsulfonyl]phenyl}propanoic Acid 8n. Similarly prepared
from 8j and trimethyltin hydroxide, followed by recrystallization
from hexane/EtOAc, was the propanoic acid 8n as white crystals
(65%), mp 70-71 °C.
(9) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T.; Yamanaka, H.
Condensed heteroaromatic ring-systems. 13. One-step synthesis of
2-substituted 1-methyl-sulfonylindoles from N-(2-halophenyl)-
methanesulfonamides. Chem. Pharm. Bull. 1988, 36, 1305-1308.
(10) Cacchi, S.; Fabrizi, G. Synthesis and functionalization of indoles
through palladium-catalyzed reactions. Chem. ReV. 2005, 105, 2873-
2920. Kirsch, G.; Hesse, S.; Comel, A. Synthesis of five- and six-
membered heterocycles through palladium-catalyzed reactions. Curr.
Org. Synth. 2004, 1, 47-63. Battistuzzi, G.; Cacchi, S.; Fabrizi, G.
The aminopalladation/reductive elimination domino reaction in the
construction of functionalized indole rings. Eur. J. Org. Chem. 2002,
2671-2681. Cacchi, S.; Fabrizi, G.; Parisi, L. M. Nitrogen-containing
heterocycles via palladium-catalyzed reaction of alkynes with organic
halides or triflates. Heterocycles 2002, 58, 667-682. Larock, R. C.
Palladium-catalyzed annulation of alkynes. Topics in Organometallic
Chemistry 2005, 14, 147-182. Larock, R. C. Palladium-catalyzed
annulation. J. Organomet. Chem. 1999, 576, 111-124.
(11) Zhang, H.-C.; Ye, H.; Moretto, A. F.; Brumfield, K. K.; Maryanoff,
B. E. Facile solid-phase construction of indole derivatives based on
a traceless, activating sulfonyl linker. Org. Lett. 2000, 2, 89-92.
(12) Kabalka, G. W.; Wang, L.; Pagni, R. M. Sonogashira coupling and
cyclization reactions on alumina: A route to aryl alkynes, 2-substituted-
benzo[b]furans and 2-substituted-indoles. Tetrahedron 2001, 57,
8017-8028.
(13) Suzuki, N.; Yasaki, S.; Yasuhara, A.; Sakamoto, T. Convenient indole
synthesis from 2-iodoanilines and terminal alkynes by the sequential
Sonogashira reaction and the cyclization reaction promoted by
tetrabutylammonium fluoride (TBAF). Chem. Pharm. Bull. 2003, 51,
1170-1173.
(14) Novak, Z.; Szabo, A.; Repasi, J.; Kotschy, A. Sonogashira coupling
of aryl halides catalyzed by palladium on charcoal. J. Org. Chem.
2003, 68, 3327-3329.
(15) Pelter, A.; Elgendy, S. M. A. Phenolic oxidations with phenyliodo-
nium diacetate. J. Chem. Soc., Perkin Trans. 1 1993, 1891-1896.
Fleck, A. E.; Hobart, J. A.; Morrow, G. W. Mixed quinone
monoketals via iodobenzene diacetate oxidation. Synth. Commun.
1992, 22, 179-187.
(16) Tran-Huu-Dau, M.-E.; Wartchow, R.; Winterfeldt, E.; Wong, Y. S.
New cyclohexadienone derivatives: Preparation and chiral discrimi-
nation in high-pressure Diels-Alder cycloadditions. Chem. Eur. J.
2001, 7, 2349-2369.
Larger Scale Preparation of 4-(1-Benzenesulfonyl-6-fluoro-
1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dien-1-one 8b Under Ther-
mal Conditions. Nitrogen gas was bubbled through a stirred
mixture of N-(5-fluoro-2-iodophenyl)benzenesulfonamide 6b (7.56
g, 20 mmol), 4-ethynyl-4-hydroxy-cyclohexa-2,5-dienone (7, 3.12
g), diisopropylamine (4 mL), DMAC (20 mL), and water (0.8 mL)
for approximately 10 min, and then tetrakis(triphenyl-phosphine)-
palladium(0) (1.28 g) and copper(I) iodide (0.384 g) were added.
The flask was sealed with a subaseal containing a needle to relieve
pressure, the mixture was heated at 80 °C for 10 min and then
allowed to cool, and the products were partitioned in DCM/water
(1/1). The organic layer was dried (MgSO4) and concentrated, and
the residue was passed through a short silica plug with EtOAc.
Column chromatography (hexane/ethyl acetate, 3/1) yielded the
indolyl-quinol 8b as white crystals, recrystallized from EtOH (4.08
g, 53%), identical (1H NMR) to the sample prepared previously.6
Similarly, on the same scale, 4-hydroxy-4-[1-(toluene-p-sul-
fonyl)-1H-indol-2-yl]cyclohexa-2,5-dien-1-one 8c was prepared
(72%) from 6c and 7 under thermal conditions.
Acknowledgment. This research was supported by Cancer
Research U.K.
Supporting Information Available: Spectroscopic properties
1
(IR, H NMR, and 13C NMR) for sulfonamides 6a-l, 9, 11a,b,
and 13 and for quinols 8a-j, 8m,n, 10, 12a,b, and 14. CHN
elemental analytical data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Lion, C. J.; Matthews, C. S.; Bradshaw, T. D.; Wells, G.; Stevens,
M. F. G.; Westwell, A. D. Antitumour properties of fluorinated
benzothiazole-substituted hydroxycyclohexa-2,5-dienones (“quinols”).
Bioorg. Med. Chem. Lett. 2006, 16, 5005-5008.
(2) Wells, G.; Berry, J. M.; Bradshaw, T. D.; Burger, A. M.; Seaton,
A.; Wang, B.; Westwell, A. D.; Stevens, M. F. G. 4-Substituted
4-hydroxycyclohexa-2,5-dien-1-ones with selective activities against
colon and renal cancer cell lines. J. Med. Chem. 2003, 46, 532-
541.
(3) Bradshaw, T. D.; Matthews, C. S.; Cookson, J.; Chew, E-H.; Shah,
M.; Bailey, K.; Monks, A.; Harris, E.; Westwell, A. D.; Wells, G.;
Laughton, C. A.; Stevens, M. F. G. Elucidation of thioredoxin as a
molecular target for antitumor quinols. Cancer Res. 2005, 65, 3911-
3919.
(4) Jones, D. T.; Pugh, C. W.; Wigfield, S.; Stevens, M. F. G.; Harris,
A. L. Novel thioredoxin inhibitors paradoxically increase hypoxia-
inducible factor-R expression but decrease functional transcriptional
activity, DNA binding, and degradation. Clin. Cancer Res. 2006, 12,
5384-5394.
(17) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B. S.
A mild and selective method for the hydrolysis of esters with
trimethyltin hydroxide. Angew. Chem., Int. Ed. 2005, 44, 1378-1382.
(18) Estel, L.; Marsais, F.; Queguiner, G. Metalation/Srn1 coupling in
heterocyclic synthesissA convenient methodology for ring func-
tionalization. J. Org. Chem. 1988, 53, 2740-2744. Mazeas, D.;
Guillaumet, G.; Viaud, M.-C. Synthesis of new melatoninergic ligands
including azaindole moiety. Heterocycles 1999, 50, 1065-1080.
(19) Boyd, M. R.; Paull, K. D. Some practical considerations and
applications of the National Cancer Institute in vitro anticancer drug
discovery screen. Drug DeV. Res. 1995, 34, 91-109.
JM061163M