Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 24 7245
and plotted as absorbance at 560 nm versus concentration in
µM. The Schiff base quinoline derivative and its copper complex
did not generate high levels of H2O2 (Figure 2A in Supporting
Information). The standard H2O2 curve was plotted as shown
in Figure 2B in Supporting Information. At 10 µM, copper
derivative 2 shows an almost 2-fold lowered absorbance than
(8) Adams, J.; Behnke, M.; Chen, S.; Cruikshank, A. A.; Dick, L. R.;
Grenier, L.; Klunder, J. M.; Ma, Y. T.; Plamondon, L.; Stein, R. L.
Potent and selective inhibitors of the proteasome: dipeptidyl boronic
acids. Bioorg. Med. Chem. Lett. 1998, 8, 333-338.
(9) Lightcap, E. S.; McCormack, T. A.; Pien, C. S.; Chau, V.; Adams,
J.; Elliott, P. Proteasome inhibition measurements: clinical applica-
tion. J. Clin. Chem. 2000, 46, 673-683.
(
(
(
10) Elofsson, M.; Splittgerber, U.; Myung, J.; Mohan, R.; Crews, C. M.
Towards subunit-specific proteasome inhibitors: synthesis and evalu-
ation of peptide R1, â1-epoxyketones. Chem. Biol. 1999, 6, 811-
10 µM H2O2 as indicated by the plot in Figure 2A in Supporting
Information. Thus, induction of apoptosis by these compounds
in LNCaP cells is not through oxidative stress but through
inhibition of the proteasome-ubiquitin pathway, resulting in
the induction of apoptosis in LNCaP prostate cancer cells as
shown by our results.
822.
11) Lynas, J. F.; Harriott, P.; Healy, A.; Mckarvey, M. A.; Walker, B.
Inhibitors of the chymotrypsin-like activity of proteasome based on
di- and tri-peptidyl R-keto aldehydes (glyoxals). Bioorg. Med. Chem.
Lett. 1998, 8, 373-378.
12) Lum, R. T.; Nelson, M. G.; Joly, A.; Horsma, A. G.; Lee, G.; Meyer,
S. M.; Wick, M. M.; Schow, S. R. Selective inhibition of the
chymotrypsin-like activity of the 20S proteasome by 5-methoxy-1-
indanone dipeptide benzamides. Bioorg. Med. Chem. Lett. 1998, 8,
Conclusions
Nitrogen heterocyclic compounds have been used widely in
the pharmaceutical industry, medicine, and agriculture for their
biological activity because of their antimicrobial, antipyretic,
anti-inflammatory, and anticancer properties. We have described
the synthesis and structural characterization of novel copper
quinoline-2-carboxaldehyde complexes. These synthesized Schiff
base compounds are different with respect to their various
functional groups attached to the quinoline ligand. The cytotoxic
activity is also affected by the nature of the side chains at
position C2, and our in vitro findings show that these compounds
have high antiproliferative activity against prostate cancer cell
lines PC-3 and LNCaP. Furthermore, these compounds are
capable of inducing apoptosis in prostate cancer cells without
oxidative stress, as indicated by the H2O2 assay. The highest
cytotoxic activity was observed for the copper complex 2 that
inhibited chymotrypsin-like proteasome activity in intact prostate
LNCaP cancer cells. Our study strongly suggests that the
strategies adopted in modifying the parent ligand with introduc-
tion of cytotoxic thiocarbonyl side chains enhance the antitumor
property with subsequent lowering of IC50 values. Furthermore,
the Schiff base copper complex 2 can inhibit the proteasome
and induce apoptosis as shown by PARP cleavage in prostate
tumor LNCaP cells. In conclusion, the present work indicates
that introduction of a thiocarbonyl group at the C2 position in
the quinoline moiety upon copper complexation leads to
generation of a potent anticancer agent that can be used for
targeting the ubiquitin-proteasome pathway for the treatment
of prostate cancer.
2
09-214.
(
13) Loidi, G.; Groll, M.; Musiol, H. J.; Huber, R.; Moroder, L. Bivalency
as a principle for proteasome inhibition. Proc. Natl. Acad. Sci. U.S.A.
1999, 96, 5418-5422.
14) Stein, R. L.; Ma, Y. T.; Brand, S. Inhibitors of the 26s proteolytic
complex and the 20S proteasome contained therein. U.S. Patent 5,-
(
693,617, December 2, 1997.
(15) Daniel, K. G.; Chen, D.; Harbach, R. H.; Guida, W. C.; Dou, Q. P.
Organic copper complexes as a new class of proteasome inhibitors
and apoptosis inducers in human cancer cells. Biochem. Pharmacol.
2004, 67, 1139-1151.
(
16) Daniel, K. G.; Chen, D.; Orlu, S.; Cui, Q. C.; Miller, F. R; Dou, Q.
P. Clioquinol and pyrrolidine dithiocarbamate complex with copper
to form proteasome inhibitors and apoptosis inducers in human breast
cancer cells. Breast Cancer Res. 2005, 7, R897-R908.
(
17) Habib, F. K.; Dembinski, T. C.; Stitch, S. R. The zinc and copper
content of blood leucocytes and plasma from patients with benign
and malignant prostates. Clin. Chim. Acta 1980, 10, 329-335.
18) El-Sonbati, A. Z.; Al-Shihri, A.; El-Bindary, A. A. Stereochemistry
containing heterocyclic aldehyde. Part XI. Novel ligational behavior
of quinoline as chelate ligand toward transition metal ion. Spectro-
chim. Acta, Part A 2004, 60, 1763-1768.
(
(
19) Geary, W. J. The use of conductivity measurements in organic
solvents for the characterization of coordination compounds. Coord.
Chem. ReV. 1971, 7, 81-122.
(20) Lever, A. B. P. Inorganic Electronic Spectroscopy, 2nd ed.;
Elsevier: New York, 1984.
21) Figgis, B. N.; Hitchman, M. A. Ligand Field Theory and Its
Application, 1st ed.; Wiley-VCH: New York, 2000; Chapter 10, pp
(
282-310.
(22) West, D. X.; Salberg, M. M.; Bain, G. A.; Liberta, A. E.; Valdes-
Martinez, J.; Fernandez-Ortega, S. J. Binuclear copper(II) complexes
of 5-nitrosalicylaldehyde N(3)-substituted thiosemicarbazones. Tran-
sition Met. Chem. 1996, 21, 206-212.
(23) West, D. X.; Yang, Y.; Klein, T. L.; Goldberg, K. I.; Liberta, A. E.;
Valdes-Martinez, J.; Toscano, R. A. Binuclear copper (II) complexes
of 2-hydroxyacetophenone 4N-substituted thiosemicarbazones. Poly-
hedron 1995, 14, 1681-1693.
(24) Kato, M.; Fanning, J. C.; Jonassen, H. B. Copper(II) complexes with
subnormal magnetic moments. Chem. ReV. 1964, 64, 99-128.
25) Reddy, K. H.; Sambasiva, P.; Babu, P. Synthesis, spectral studies
and nuclease activity of mixed ligand copper(II) complexes of
heteroaromatic semicarbazones/thiosemicarbazones and pyridine.
Inorg. Biochem. 1999, 77, 169-176.
(26) Wilkinson, G.; Gillard, R. D.; McCleverty, J. A. ComprehensiVe
Coordination Chemistry; Pergamon: Oxford, U.K., 1987; Vol. 3,
pp 1059-1127.
(27) Ronaid, D. H.; Mecabe, P. H. Infrared studies of chromones-I:
Carbonyl and hydroxyl regions. Tetrahedron 1969, 25, 5819-5837.
(28) El-shaaer, H. M.; Foltinova, P.; Lacova, M.; Chovancova, J.;
Stankovicova, H. Synthesis, antimicrobial activity and bleaching
effect of some reaction products of 4-oxo-4H-benzopyran-3-carbox-
aldehydes with aminobenzothiazoles and hydrazides. Farmaco 1998,
53, 224-232.
(29) Kumar, U. A.; Chandra, S. Semicarbazone and thiosemicarbazone
chromium(III) complexes. Transition Met. Chem. 1993, 18, 342-
344.
(30) Sonawane, P.; Chikate, R.; Kumbhar, A.; Padhye, S.; Doedens, R.
J. Inequivalent coordination of thiosemicarbazone ligands in cobalt-
(III) and chromium(III) complexes. Polyhedron 1994, 13, 395-401.
(31) Zhong-Lin, L.; Xiao, W.; Bei-Sheng, K.; Cheng-Yong, S.; Liu, J.
Chemistry of aroylhydrazones: bis-bipyridine ruthenium(II) com-
plexes with aroylhydrazone ligands containing ferrocenyl moiety. J.
Mol. Struct. 2000, 523, 133-141.
Supporting Information Available: Experimental details for
the determination of biological activity, spectral data, and elemental
analysis results for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(
References
(
1) Hochstrasser, M. Ubiquitin, proteasomes and the regulation of
intracellular protein degradation. Curr. Opin. Cell Biol. 1995, 7, 215-
223.
(
(
(
(
2) Clechanover, A. The ubiquitin-proteasome proteolytic pathway. Cell
1994, 79, 13-21.
3) Dou, Q. P.; Li, B. Proteasome inhibitors as potential novel anticancer
agents. Drug Resist. Updates 1999, 2, 215-223.
4) Adams, J. Potential for proteasome inhibition in the treatment of
cancer. Drug DiscoVery Today 2003, 8, 307-315.
5) Masse, C. E.; Morgan, A. J.; Adams, J.; Panek, J. S. Syntheses and
biological evaluation of (+)-lactacystin and analogs. Eur. J. Org.
Chem. 2000, 714, 2513-2528.
(
6) Koguchi, Y.; Kohno, J.; Nishio, M.; Takahashi, K.; Okuda, T.;
Ohnuki, T.; Komatsubara, S. TMC-86A, B and TMC-96, new
proteasome inhibitors from Streptomyces sp. TC 1084 and Saccha-
rothrix sp. TC 1094. I. Taxonomy, fermentation, isolation, and
biological activities. J. Antibiot. 2000, 53, 105-109.
(
7) Vinitsky, A.; Cardozo, C.; Sepp-Lorenzio, L.; Machaud, C.; Orlowski,
M. Inhibition of the proteolytic activity of the multicatalytic proteinase
complex (proteasome) by substrate-related peptidyl aldehydes. J. Biol.
Chem. 1994, 269, 29860-29866.