Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 16 5139
hydrocarbon receptor deficient MCF-7 cells. Br. J. Cancer 2003, 88,
refluxing aqueous KOH followed by air oxidation as previously
described,10 were heated under reflux in toluene (20 mL) containing
PPh3 (0.185 g, 0.71 mmol) and p-TsOH (2 mg) for 3 days. After the
mixture was cooled, solvent was removed in vacuo and the benzothia-
zoles were purified by column chromatography (EtOAc/hexane, 1:4).
1H NMR data for disulfides (8a-i) are given in Supporting Informa-
tion. Microanalytical data and spectroscopic properties for benzothia-
zoles 9a-j in given in Supporting Information.
General Method B for the Synthesis of o-Bromobenzanil-
ides (11a-r). Substituted benzoyl chloride (10 mmol) was added
to a mixture of 4- or 5-fluoro-2-bromoaniline (10a,b, 10 mmol),
triethylamine (11 mmol), and 4-dimethylaminopyridine (2 mmol)
in CH2Cl2 (20 mL), and the mixture was stirred at room temperature
for 18 h. The mixture was diluted with further dichloromethane
(30 mL), then washed with 1 M HCl (50 mL), and the aqueous
fraction was extracted with dichloromethane (50 mL). The com-
bined organic layers were dried (MgSO4), filtered, and concentrated
in vacuo. The crude product benzanilides were checked for purity
(1H NMR) and then used directly in the next step.
599–605.
(7) Chua, M.-S.; Kashiyama, E.; Bradshaw, T. D.; Stinson, S. F.; Brantley,
E.; Sausville, E. A.; Stevens, M. F. G. Role of CYP1A1 in modulation
of antitumor properties of the novel agent 2-(4-amino-3-methylphe-
nyl)benzothiazole (DF 203, NSC 674495) in human breast cancer cells.
Cancer Res. 2000, 60, 5196–5203.
(8) Brantley, E.; Trapani, V.; Alley, M. C.; Hose, C. D.; Bradshaw, T. D.;
Stevens, M. F. G.; Sausville, E. A.; Stinson, S. F. Fluorinated 2-(4-
amino-3-methylphenyl)benzothiazoles induce CYP1A1 expression,
become metabolized, and bind to macromolecules in sensitive human
cancer cells. Drug Metab. Dispos. 2004, 32, 1392–1401.
(9) Kashiyama, E.; Hutchinson, I.; Chua, M-S.; Stinson, S. F.; Phillips,
L. R.; Kaur, G.; Sausville, E. A.; Bradshaw, T. D.; Westwell, A. D.;
Stevens, M. F. G. Antitumor benzothiazoles. 8. Synthesis, metabolic
formation, and biological properties of the C- and N-oxidation products
of antitumor 2-(4-aminophenyl)benzothiazoles. J. Med. Chem. 1999,
42, 4172–4184.
(10) Hutchinson, I.; Chua, M-Z.; Browne, H. L.; Trapani, V.; Bradshaw,
T. D.; Westwell, A. D.; Stevens, M. F. G. Antitumor benzothiazoles.
14. Synthesis and in vitro biological properties of fluorinated 2-(4-
aminophenyl)benzothiazoles. J. Med. Chem. 2001, 44, 1445–1455.
General Method C for the Synthesis of 2-Phenylbenzox-
azoles 12a-r. To a mixture of o-bromobenzanilide 11a-r (5 mmol),
copper(I) iodide (47.5 mg, 0.25 mmol), 1,10-phenanthroline (94 mg,
0.5 mmol), and cesium carbonate (2.45 g, 7.5 mmol) was added DME
(50 mL) at room temperature, under a nitrogen atmosphere. The
mixture was heated under reflux for 18 h and then allowed to cool to
room temperature. The mixture was diluted with water (100 mL) and
then CH2Cl2 (200 mL). The organic layer was extracted, then dried
(MgSO4), filtered, and concentrated in vacuo. The crude product was
purified by column chromatography (diethyl ether/petroleum ether) to
give the required substituted 2-arylbenzoxazole in 61-91% yields.
(11) Leong, C. O.; Suggitt, M.; Swaine, D. J.; Bibby, M. C.; Stevens,
M. F. G.; Bradshaw, T. D. In vitro, in vivo, and in silico analyses of
the antitumor activity of 2-(4-amino-3-methylphenyl)-5-fluoroben-
zothiazoles. Mol. Cancer Ther. 2004, 3, 1565–1575.
(12) Fichtner, I.; Monks, A.; Hose, C.; Stevens, M. F. G.; Bradshaw, T. D.
The experimental antitumor agents phortress and doxorubicin are
equiactive against human-derived breast carcinoma xenograft models.
Breast Cancer Res. Treat. 2004, 87, 97–107.
(13) Hutchinson, I.; Jennings, S. A.; Vishnuvajjala, B. R.; Westwell, A. D.;
Stevens, M. F. G. Antitumor benzothiazoles. 16. Synthesis and
pharmaceutical properties of antitumor 2-(4-aminophenyl)benzothia-
zole amino acid prodrugs. J. Med. Chem. 2002, 45, 744–747.
(14) Mathis, C. A.; Wang, Y.; Holt, D. P.; Huang, G. F.; Debnath, M. L.;
Klunk, W. E. Synthesis and evaluation of 11C-labeled 6-substituted
2-arylbenzothiazoles as amyloid imaging agents. J. Med. Chem. 2003,
46, 2740–2754.
(15) Price, J. C.; Klunk, W. E.; Lopresti, B. J.; Lu, X.; Hoge, J. A.; Ziolko,
S. K.; Holt, D. P.; Meltzer, C. C.; DeKosty, S. T.; Mathis, C. A. Kinetic
modelling of amyloid binding in humans using PET imaging and
Pittsburgh compound-B. J. Cereb. Blood Flow Metab. 2005, 25, 1528–
1547.
(16) Henriksen, G.; Hauser, A. I.; Westwell, A. D.; Yousefi, B. H.;
Schwaiger, M.; Drzezga, A.; Wester, H.-J. Metabolically stabilized
benzothiazoles for imaging of amyloid plaques. J. Med. Chem. 2007,
50, 1087–1089.
(17) Mortimer, C. G.; Wells, G.; Crochard, J.-P.; Stone, E. L.; Bradshaw,
T. D.; Stevens, M. F. G.; Westwell, A. D. Antitumor benzothiazoles.
26. 2-(3,4-Dimethoxyphenyl)-5-fluorobenzothiazole (GW 610, NSC
721648), a simple fluorinated 2-arylbenzothiazole, shows potent and
selective inhibitory activity against lung, colon, and breast cancer cell
lines. J. Med. Chem. 2006, 49, 179–185.
(18) Stevens, M. F. G.; McCall, C. J.; Lelieveld, P.; Alexander, P.; Richter,
A.; Davies, D. E. Structural studies on bioactive compounds. 23.
Synthesis of polyhydroxylated 2-phenylbenzothiazoles and a com-
parison of their cytotoxicities and pharmacological properties with
genistein and quercetin. J. Med. Chem. 1994, 37, 1689–1695.
(19) Wang, M.; Gao, M.; Mock, B. H.; Miller, K. D.; Sledge, G. W.;
Hutchins, G. D.; Zheng, Q.-H. Synthesis of carbon-11 labeled
fluorinated 2-arylbenzothiazoles as novel potential PET cancer imaging
agents. Bioorg. Med. Chem. 2006, 14, 8599–8607.
(20) Kadri, H.; Matthews, C. S.; Bradshaw, T. D.; Stevens, M. F. G.;
Westwell, A. D. Synthesis and antitumour evaluation of novel
2-phenylbenzimidazoles. J. Enzyme Inhib. Med. Chem., in press.
(21) Evindar, G.; Batey, R. A. Parallel synthesis of a library of benzoxazoles
and benzothiazoles using ligand-accelerated copper-catalysed cycliza-
tions of ortho-halobenzanilides. J. Org. Chem. 2006, 71, 1802–1808.
(22) Hutchinson, I.; Stevens, M. F. G.; Westwell, A. D. The regiospecific
synthesis of 5- and 7-monosubstituted and 5,6-disubstituted 2-aryl-
benzothiazoles. Tetrahedron Lett. 2000, 41, 425–428.
(23) Fried, K. W.; Bazzi, R.; Lopez, W. L.; Corsten, C.; Schramm, K.-W.;
Bell, D. R.; Rozman, K. K. Relationship between aryl hydrocarbon
receptor-affinity and the induction of EROD activity by 2,3,7,8-
tetrachlorinated phenothiazine and derivatives. Toxicol. Appl. Phar-
macol. 2007, 224, 147–155.
(24) Merchant, M.; Krishnan, V.; Safe, S. Mechanism of action of alpha-
naphthoflavone as an Ah receptor antagonist in MCF-7 human breast
cancer cells. Toxicol. Appl. Pharmacol. 1993, 120, 179–185.
Acknowledgment. We thank the European Association for
Cancer Research (EACR) for the award of the Travel Fellowship
(to S.A.), and the Algerian Government for the award of a Ph.D.
studentship (to H.K.). Part of this work was supported by a
Program Grant to the Cancer Research U.K. Experimental
Cancer Chemotherapy Research Group (University of Notting-
ham),andadditionalsupportfromPharminoxLtd.isacknowledged.
Supporting Information Available: Spectroscopic and analyti-
cal data for new compounds and intermediate structures; microana-
lytical data (CHN) for new compounds; details on cell culture,
growth inhibitory assay, cell cycle analyses, aryl hydrocarbon
receptor binding assay, uptake/stability studies; two figures showing
depletion of 5 from nutrient media and effect of R-naphthoflavone
on growth and viability of MCF-7 and MDA 468 cells. This material
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