Modified Quinolones as Antitumoral Acridones
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 12 2143
Characteristics and Physiological Significance of Major DNA
Topoisomerases. Antimicrob. Agents Chemother. 1989, 33, 2027-
2033. (f) Wang, J . C. DNA Topoisomerases. Annu. Rev. Biochem.
1996, 65, 635-692.
Topoisomerase II: Influence of the C-8 Fluorine Group. Anti-
microb. Agents Chemother. 1992, 36, 751-756. (c) Elsea, S. H.;
Osheroff, N.; Nitiss, J . L. Cytotoxicity of Quinolones toward
Eukaryotic Cells. J . Biol. Chem. 1992, 267, 13150-13153.
(11) (a) Chu, D. T. W.; Fernandes, P. B.; Claiborne, A. K.; Shen, L.
L.; Pernet, A. G. Structure-activity Relationship in Quinolone
Antibacterials: Design, Synthesis and Biological Activities of
Novel Isothiazoloquinolone. Drugs Exp. Clin. Res. 1988, 14, 379-
383. (b) Kohlbrenner, W. E.; Wideburg, N.; Weigl, D.; Saldivar,
A.; Chu, D. T. W. Introduction of Calf-thymus Topoisomerase
II-mediated Breakage by the Antibacterial Isothiazoloquinolones
A-65281 and A-65282. Antimicrob. Agents Chemother. 1992, 36,
81-86. (c) Chu, D. T. W. Isothiazoloquinolones: Antibacterial
and Antineoplastic Agents. Drugs Future 1992, 17, 1101-1109.
(12) (a) Chu, D. T. W.; Hallas, R.; Clement, J . J .; Alder, J .; McDonald,
E.; Plattner, J . J . Synthesis and Antitumor Activities of Quin-
olone Antineoplastic Agents. Drugs Exptl. Clin. Res. 1992, XVIII,
275-282. (b) Clement, J . J .; Burres, N.; J arvis, K.; Chu, D. T.
W.; Swinirski, J .; Alder, J . Biological Characterization of a Novel
Antitumor Quinolone. Cancer Res. 1995, 55, 830-835.
(13) (a) Cecchetti, V.; Fravolini, A.; Schiaffella, F.; Tabarrini, O.;
Zhou, W.; Pagella, P. G. 1,4-Benzothiazine-2-carboxylic Acid
1-Oxides as Analogues of Antibacterial Quinolones [1]. J . Het-
erocycl. Chem. 1992, 29, 375-382. (b) Cecchetti, V.; Fravolini,
A.; Fringuelli, R.; Schiaffella, F.; Lorenzini, M. C.; Tabarrini,
O. 4H-1-Benzothiopyran-4-one-3-carboxylic Acids and 3,4-Dihy-
dro-2H-isothiazolo[5,4-b][1]benzothiopyran-3,4-diones as Quin-
olone Antibacterial Analogues. J . Heterocycl. Chem. 1993, 30,
1143-1148.
(14) (a) Cecchetti, V.; Clementi, S.; Cruciani, G.; Fravolini, A.;
Pagella, P. G.; Savino, A.; Tabarrini, O. 6-Aminoquinolones: A
New Class of Quinolone Antibacterials? J . Med. Chem. 1995,
38, 973-982. (b) Cecchetti, V.; Fravolini, A.; Lorenzini, M. C.;
Tabarrini, O.; Terni, P.; Xin, T. Studies on 6-Aminoquinolones:
Synthesis and Antibacterial Evaluation of 6-Amino-8-methyl-
quinolones. J . Med. Chem. 1996, 39, 436-445.
(15) (a) Huges, G. K.; Lahey, F. N.; Price, J . R.; Webb, L. J . Alkaloids
of the Australian Rutaceae. Nature 1948, 162, 223-224. (b)
Svoboda, G. H.; Poore, G. A.; Simpson, P. J .; Bodor, G. B.
Alkaloids of Acronychia baueri. I. Isolation of the Alkaloids and
a Study of the Antitumor and Other Biological Properties of
Acronycine. J . Pharm. Sci. 1966, 55, 758-768. (c) Gout, P. W.;
Dunn, B. P.; Beer, C. T. Effect of Acronycine on Nucleic Acid
Synthesis and Population Growth in Mammalian Tumor Cell
Cultures. J . Cell. Physiol. 1971, 78, 127-138. (d) Schneider, J .;
Evans, E. L.; Grunberg, E.; Fryer, R. I. Synthesis and Biological
Activity of Acronycine Analogues. J . Med. Chem. 1972, 15, 266-
270.
(16) (a) Wu, T.-S.; Furukawa, H. Structure of Four New Acridone
Alkaloids from Glycosmis citrifolia (Willd.) Lindl. Heterocycles
1982, 19, 1047-1051. (b) Su, T. L.; Ko¨hler, B.; Chou, T.-C.; Chun,
M. W.; Watanable, K. A. Synthesis of the Acridone Alkaloids
Glyfoline and Congeners. Structure-Activity Relationship Stud-
ies of Cytotoxic Acridones. J . Med. Chem. 1992, 35, 2703-2710.
(17) (a) Yamashita, Y.; Kawada, S.; Nakano, H. Biochem. Pharmacol.
1990, 39, 737-744. (b) Barnes, S.; Peterson, G. T. Biochemical
Targets of the Isoflavone Genistein in Tumor Cell Lines. Proc.
Soc. Exp. Biol. Med. 1995, 208, 103-108. (c) Markovits, J .;
Linassier, C.; Fosse, P.; Couprie, J .; Pierre, J .; J aquemin-Sablon,
A.; Saucier, J . M.; Le Pecq, J . B.; Larsen, A. K. Inhibitory Effects
of the Tyrosine Kinase Inhibitor Genistein on Mammalia DNA
Topoisomerase II. Cancer Res. 1989, 49, 5111-5117. (d) Con-
stantinou, A.; Kiguchi, K.; Huberman, E. Induction Differentia-
tion and DNA Strand Breakage in Human HL-60 and K-562
Leukemia Cells by Genistein. Cancer Res. 1990, 50, 2618-2624.
(e) McCabe, M. J ., J r.; Orrenius, S. Genistein Induces Apoptosis
in Immature Human Thymocytes by Inhibiting Topoisomerase-
II. Biochem. Biophys. Res. Commun. 1993, 194, 944-950. (f)
Capranico, G.; Palumbo, M.; Tinelli, S.; Mabilia, M.; Pozzan, A.;
Zunino, F. Conformational Drug Determinants of the Sequence
Specifity of Drug-Stimulated Topoisomerase II DNA Cleavage.
J . Mol. Biol. 1994, 235, 1218-1230.
(3) Morrison, A.; Cozzarelli, N. R. Contacts between DNA Gyrase
and its Binding Site on DNA: Features of Symmetry and
Asymmetry Revealed by Protection from Nucleases. Proc. Natl.
Acad. Sci. U.S.A. 1981, 78, 1416-1420.
(4) (a) Huff, A. C.; Kreuzer, K. N. Evidence for a Common Mecha-
nism of Action for Antitumor and Antibacterial Agents That
Inhibit Type II DNA Topoisomerases. J . Biol. Chem. 1990, 265,
20496-20505. (b) Insaf, S. S.; Danks, M. K.; Witiak, D. T. A
Structure-Function Analyses of DNA Topoisomerase II Inhibi-
tors. Curr. Med. Chem. 1996, 3, 437-466.
(5) (a) Gellert, M.; Mizuuchi, K.; O’Dea, M. H.; Itoh, T.; Tomizawa,
J . I. Nalidixic Acid Resistance: A Second Genetic Character
Involved in DNA Gyrase Activity. Proc. Natl. Acad. Sci. U.S.A.
1977, 74, 4772-4776. (b) Sugino, A.; Peebles, C. L.; Cozzarelli,
N. R.; Kreuzer, K. N. Mechanism of Action of Nalidixic Acid:
Purification of Escherichia coli nalA Gene Prodrug and its
Relationship to DNA Gyrase and
a
Novel Nicking-closing
Enzyme. Proc. Natl. Acad. Sci. U.S.A. 1977, 74, 4767-4771. (c)
Quinolone Antimicrobial Agents, 2nd ed.; Wolfson, J . S., Hooper,
D. C., Eds.; American Society for Microbiology: Washington, DC,
1989. (d) Shen, L. L.; Chu, D. T. W. Type II DNA Topoisomerases
as Antibacterial Targets. Curr. Pharm. Des. 1996, 2, 195-208.
(6) (a) Lock, R. B.; Ross, W. E. DNA Topoisomerases in Cancer
Therapy. Anti-Cancer Drug Des. 1987, 2, 151-154. (b) Liu, L.
F. DNA Topoisomerases Poisons as Antitumor Drugs. Annu. Rev.
Biochem. 1989, 58, 351-375. (c) Zwelling, L. A. Topoisomerase
II as a Target of Antileukemia Drugs: a Review of Controversial
Areas. Hematol. Pathol. 1989, 3, 101-112. (d) Schneider, E.;
Hsiang, Y. H.; Liu, L. F. DNA Topoisomerases as Anticancer
Drug Targets. Adv. Pharmacol. 1990, 21, 149-183. (e) Bodley,
A.; Liu, L. F.; Israel, M.; Seshadri, R.; Silber, R.; Potmesil, M.
In DNA Topoisomerases in Cancer; Oxford University Press:
New York, 1991; pp 283-298. (f) Capranico, G.; Binaschi, M.;
Borgnetto, M. E.; Zunino, F.; Palumbo, M. A Protein-Mediated
Mechanism for the DNA Sequence-specific Action of Topo-
isomerase II Poisons. TiPS 1997, 18, 323-329.
(7) (a) Kreuzer, K. N.; Cozzarelli, N. R. Escherichia coli Mutants
Thermosensitive for Deoxyribonucleic Acid Gyrase Subunit A:
Effects on Deoxyribonucleic Acid Replication, Transcription, and
Bacteriophage Growth. J . Bacteriol. 1973, 140, 425-435. (b)
Shen, L. S. Molecular Mechanisms of DNA Gyrase Inhibition
by Quinolone Antibacterials. Adv. Pharmacol. 1994, 29A, 285-
304. (c) Shen, L. L.; Chu, D. T. W. Type II Topoisomerases as
Antibacterial Targets. Curr. Pharm. Des. 1996, 2, 195-208.
(8) (a) Hussy, P.; Maass, G.; Tu¨mmler, B.; Grosse, F.; Schomburg,
U. Effect of 4-Quinolones and Novobiocin on Calf Thymus DNA
Polymerase a Primase Complex, Topoisomerase I and II, and
Growth of Mammalian Lymphoblasts. Antimicrob. Agents
Chemother. 1986, 29, 1073-1078. (b) Oomori, Y.; Yasue, T.;
Aoyama, H.; Hirai, K.; Suzue, S.; Yokota, T. Effects of Fleroxacin
on HeLa Cell Functions and Topoisomerase II. J . Antimicrob.
Chemother. 1988, 22 (Suppl. D), 91-97. (c) Hoshino, K.; Sato,
K.; Une, T.; Osada, Y. Inhibitory Effects of Quinolones on DNA
Gyrase of Escherichia coli and Topoisomerase II of Calf Thymus.
Antimicrob. Agents Chemother. 1989, 33, 1818-1818. (d) Barrett,
J . F.; Gootz, T. D.; McGuirk, P. R.; Farrel, C. A.; Sokolowski, S.
A. Use of in Vitro Topoisomerase II Assay for Studying Quin-
olone Antibacterial Agents. Antimicrob. Agents Chemother. 1989,
33, 1697-1703. (e) Gootz, T. D.; Osheroff, N. Quinolones and
Eukaryotic Topoisomerases. In Quinolone Antimicrobial Agents,
2nd ed.; Hooper, D. C., Wolfson, J . S., Eds.; American Society
for Microbiology: Washington, DC, 1993; pp 139-160.
(9) (a) Barret, J . F.; Gootz, T. D.; McGuirk, P. R.; Farrel, C. A.;
Sokolowski, S. A. Use In Vitro Topoisomerase II Assay for
Studying Quinolone Antibacterial Agents. Antimicrob. Agents
Chemother. 1989, 33, 1697-1703. (b) Wentland, M. P.; Lesher,
G. Y.; Reuman, M.; Pilling, G. M.; Saindane, M. T.; Perni, R. B.;
Eisseinstat, M. A.; Weaver, J . D., III; Sing, B.; Rake, J . B.;
Coughlin, S. A. Relationship of Structure of Bridged (2,6-
Dimethyl-4-pyridinyl)quinolones to Mammalian Topoisomerase
II Inhibition. Bioorg. Med. Chem. Lett. 1993, 3, 1711-1716. (c)
Wentland, M. P.; Lesher, G. Y.; Reuman, M.; Gruett, M. D.; Sing,
B.; Aldous, S. C.; Dorff, P. H.; Rake, J . B.; Coughlin, S. A.
Mammalian Topoisomerase II Inhibitory Activity of 1-Cyclopro-
pyl-6,8-difluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-
3-quinolinecarboxylic Acid and Related Derivatives. J . Med.
Chem. 1993, 36, 2801-2809.
(10) (a) Robinson, M. J .; Martin, B. A.; Gootz, T. D.; McGuirk, P. R.;
Maynhian, M.; Sutcliffe, J . A.; Osheroff, M. Effects of Quinolone
Derivatives on Eukaryotic Topoisomerase II, a Novel Mechanism
for Enhancement of Enzyme Mediated DNA Cleavage. J . Biol.
Chem. 1991, 266, 14585-14592. (b) Robinson, M. J .; Martin, B.
A.; Gootz, T. D.; Mcguirk, P. R.; Osheroff, N. Effect of Novel
Fluoroquinolones on the Catalytic Activities of Eukaryotic
(18) Radl, S.; Kova`rova`, L. Preparation of Some Substituted 9,10-
Dihydro-1-hydroxy-9-Oxoacridine Derivatives. Collect. Czech.
Chem. Commun. 1992, 57, 212-215.
(19) Nocentini, G.; Barzi, A. A Predictive Screening Model for in Vitro
Selection of Agents with Potential Antitumor Activity. Arzneim.-
Forsch./ Drug Res. 1995, 45 (II), 1306-1311.
(20) Goldstein, H.; Schaaf, E. 5-Nitro- and 3-Nitro-2,4-dichlorobenzoic
Acids. Helv. Chim. Acta 1957, 40, 1187-1188.
(21) Methods for Dilution Antimicrobial Susceptibility Tests for
Bacteria Grown Aerobically; Approved Standard M7-A3; Na-
tional Committee for Clinical Laboratory Standards (NC-
CCLS): Villanova, PA, 1993.
(22) (a) Scudiero, D. A.; Shoemaker, R. H.; Paull, K. D.; Monks, A.;
Tierney, S.; Nofriger, T. H.; Cunens, M. J .; Seniff, D.; Boyd, M.
R. Evaluation of a Soluble Tetrazolium/formazan Assay for Cell
Growth and Drug Sensitivity in Culture Using Human and other