C. O. Puentes et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3654–3657
3657
Table 2
2. Teodori, E.; Dei, S.; Martelli, C.; Scapecchi, S. Curr. Top. Med. Chem. 2010, 10,
1715.
Inhibition of ABC transporters by reference compounds and the tariquidar analogues
9a–f, 10a–f determined in the calcein-AM (ABCB1) and Hoechst 33342 (ABCG2)
microplate assay unless otherwise indicated
3. Fruttero, R.; Crosetti, M.; Chegaev, K.; Guglielmo, S.; Gasco, A.; Berardi, F.; Niso,
M.; Perrone, R.; Panaro, M. A.; Colabufo, N. A. J. Med. Chem. 2010, 53, 5467.
4. Avendano, C.; Menendez, J. C. Med. Chem. Rev. 2004, 1, 419.
5. Baumert, C.; Hilgeroth, A. Anti-Cancer Agents Med. Chem. 2009, 9, 415.
6. Müller, H.; Pajeva, I. K.; Globisch, C.; Wiese, M. Bioorg. Med. Chem. 2008, 16,
2456.
7. Colabufo, N. A.; Berardi, F.; Cantore, M.; Perrone, M. G.; Contino, M.; Inglese, C.;
Niso, M.; Perrone, R.; Azzariti, A.; Simone, G. M.; Paradiso, A. Bioorg. Med. Chem.
2008, 16, 3732.
8. Pleban, K.; Ecker, G. F. Mini-Rev. Med. Chem. 2005, 5, 153.
9. Varma, M. V. S.; Ashokraj, Y.; Dey, C. S.; Panchagnula, R. Pharmacol. Res. 2003,
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10. Ahmed-Belkacem, A.; Pozza, A.; Macalou, S.; Pérez-Victoria, J. M.; Boumendjel,
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J. A.; Templeton, D.; Charlton, P. Cancer Res. 2001, 6, 749.
Compd
ABCB1 IC50 (nM)
ABCG2 IC50 (nM)
Tariquidar
Elacridar
9a
9b
9c
9d
9e
9f
223 8a
193 18a
>50,000
>1000
>100,000
>50,000
>100,000
>50,000
>29000a
>10000a
>50,000
>100,000
>50,000
>50,000
526 85b
127 41b
>5000
>100,000
>50,000
>50,000
6200
>50,000
59 11b
172 45b,e
183 32
390 57g
130 29
508 191j
10ac
10bd
10cf
10d
10eh
10fi
a
Ref. 15: data from flow cytometric calcein-AM assay.
Ref. 15: data from flow cytometric mitoxantron assay (% maximal inhibitory
b
effect, relative to fumitremorgine c): IC50 values (% max. effect), Tariquidar:
916 197 nM (39%), Elacridar 250 45 nM (46%), 10a: 60 10 nM (56%); 10b:
179 35 nM (25%).
17. Planting, A. S. T.; Sonneveld, P.; Gaast, A. v. d.; Sparreboom, A.; Burg, M. E. L. v.
d.; Luyten, G. P. M.; Leeuw, K. d.; Boer-Dennert, M. d.; Wissel, P. S.; Jewell, R. C.;
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König, B.; Buschauer, A. J. Med. Chem. 2009, 52, 1190.
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Q.-H. Appl. Radiat. Isot. 2010, 68, 1098.
20. Hubensack, M.; Müller, C.; Höcherl, P.; Fellner, S.; Spruss, T.; Bernhardt, G.;
Buschauer, A. J. Cancer. Res. Clin. Oncol. 2008, 134, 597.
c
UR-ME22-1.
UR-ME19-2.
55% maximal inhibitory effect.
UR-COP77.
41% maximal inhibitory effect.
UR-COP78.
UR-COP134.
d
e
f
g
h
i
j
61% maximal inhibitory effect. 179 35 nM (25%).
21. General procedure for SPS of tariquidar analogues 9. A polypropylene 2.0-mL
fritted syringe was charged with 50 mg of Wang resin (1.1 mmol/g loading)
and the resin was swollen in 1 mL of DMF during 1 h. The resin was transferred
to an eppendorf tube and a mixture of 7-carboxyisatoic anhydride (57 mg,
0.27 mmol, 5 equiv) and DMAP (19 mg, 0.16 mmol, 3 equiv) in 1 mL of DMF
was added. The resin was heated at 98 °C overnight, then transferred to a
polypropylene 2.0-mL syringe and washed three times with 5% AcOH/DCM,
DCM, MeOH, DMF and DCM. The syringe was fritted and a solution of DIPEA
this class of ABCG2 inhibitors due to high conversion efficiency in
all reaction steps resulting in good to high yields. In particular,
intrinsic difficulties in solution chemistry, due to low solubility
of intermediates and target molecules, were circumvented.
Compounds 10c,e are among the most potent and selective
ABCG2 modulators reported so far. The increased solubility and
ABCG2 inhibitory efficacy of these compounds is very promising
with respect to the development of pharmacological tools for
in vivo proof-of-concept studies, provided that the drug-like prop-
erties can be further improved. Thereby, automated parallel solid
phase synthesis resulting in larger substance libraries should be
helpful to optimize the lead structures.
(47 lL, 0.27 mmol, 5 equiv) in DCM was added and the resin was shaken
during 5 min, after that, quinoline-2- or -6-carbonyl chloride (freshly prepared,
52 mg, 0.27 mmol, 5 equiv) was added and the resin was shaken at room
temperature during 12 h, washed three times with DCM, MeOH, DMF, MeOH
and DMF (this coupling was repeated once more). The resin was cooled down
and a solution of DIPEA (95 lL, 0.55 mmol, 10 equiv) and HBTU (102 mg,
0.27 mmol, 5 equiv) in 1 mL of DMF was added, the resin was shaken for 2 min
and compound 5, 6 or 7 (0.27 mmol, 5 equiv) was added. The resin was shaken
at room temperature for 24 h and then washed three times with DCM, MeOH
and DMF. Cleavage: the resin was dried under vacuum and a mixture of TFA/
DCM/TES 1:1:0.05 was added (1 mL). The resin was shaken for 1 h, the cleavage
cocktail was collected and the content of the syringe was washed two times
with fresh 50% TFA in DCM (this procedure was repeated once more).
Combined washes were evaporated and residual oil was washed with fresh
diethyl ether, the precipitated solid was filtered and dried. General procedure
for the esterification of compounds 9. The carboxylic acid derivative (1 equiv)
Acknowledgments
The authors are grateful to Maria Beer-Krön for excellent tech-
nical assistance. C.O.P. thanks the German Academic Exchange Ser-
vice (DAAD) for a graduate fellowship. Financial support from the
University of Regensburg and the Deutsche Forschungsgemeins-
chaft (GRK 760) is acknowledged.
was dissolved in 3 mL of
a
mixture PhH/MeOH 2:1 and
trimethylsilyldiazomethane solution (2 M in diethyl ether) was added
dropwise until no evolution of N2 was observed. The reaction was stirred
during 1 h at room temperature. The solvent was evaporated and the solid was
purified by flash chromatography (CHCl3/MeOH 5% or 10%).
22. Clark, A. S.; Deans, B.; Stevens, M. F. G.; Tisdale, M. J.; Wheelhouse, R. T.; Denny,
B. J.; Hartley, J. A. J. Med. Chem. 1995, 38, 1493.
23. Bobbit, J. M.; Roy, D. N.; Marchand, A.; Allen, C. W. J. Org. Chem. 1967, 32, 2225.
24. Snow, A. W.; Foos, E. E. Synthesis 2003, 509.
25. Klinkhammer, W.; Müller, H.; Globisch, C.; Pajeva, I. K.; Wiese, M. Bioorg. Med.
Chem. 2009, 17, 2524.
Supplementary data
Supplementary data associated with this article can be found, in
26. Höcherl, P. Ph.D. Thesis, Universität Regensburg, June 2010, <http://epub.uni-
References and notes
27. Kühnle, M. Ph.D. Thesis, Universität Regensburg, February 2010, <http://
1. Colabufo, N. A.; Berardi, F.; Perrone, M. G.; Capparelli, E.; Cantore, M.; Inglese,
C.; Perrone, R. Curr. Top. Med. Chem. 2010, 10, 1703.