New Water-Soluble Duocarmycin Derivatives
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 4 675
Location for the Site of Thermally Induced Strand Breakage and
Analysis of DNA Sequence Specificity. Biochemistry 1985, 24,
6228-6237. (c) Tang, M. S.; Lee, C. S.; Doisy, R.; Ross, L.;
Needham-VanDevanter, D. R.; Hurley, L. H. Recognition and
Repair of the CC-1065-(N3-adenine)-DNA Adduct by the UVRABC
Nuclease. Biochemistry 1988, 27, 893-901.
terial is available free of charge via the Internet at
http://pubs.acs.org.
Refer en ces
(1) (a) Takahashi, I.; Takahashi, K.; Ichimura, M.; Morimoto, M.;
Asano, K.; Kawamoto, I.; Tomita, F.; Nakano, H. Duocarmycin
A, a New Antibiotic from Streptomyces. J . Antibiot. 1988, 41,
1915-1917. (b) Yasuzawa, T.; Iida, T.; Muroi, K.; Ichimura, M.;
Takahashi, K.; Sano, H. Structure of Duocarmycins, Novel
Antitumor Antibiotics Produced by Streptomyces sp. Chem.
Pharm. Bull. 1988, 36, 3728-3731. (c) Ichimura, M.; Muroi, K.;
Asano, K.; Kawamoto, I.; Tomita, F.; Morimoto, M.; Nakano, H.
DC89-A1, A New Antibiotic from Streptomyces. J . Antibiot. 1988,
41, 1285-1288. (d) Ogawa, T.; Ichimura, M.; Katsumata, S.;
Morimoto, M.; Takahashi, K. New Antitumor Antibiotics, Duo-
carmycin B1 and B2. J . Antibiot. 1989, 42, 1299-1301. (e)
Ichimura, M.; Ogawa, T.; Takahashi, K.; Kobayashi, E.; Kawa-
moto, I.; Yasuzawa, T.; Takahashi, I.; Nakano, H. Duocarmycin
SA, a New Antitumor Antibiotic from Streptomyces sp. J .
Antibiot. 1990, 43, 1037-1038. (f) Ichimura, M.; Ogawa, T.;
Katumata, S.; Takahashi, K.; Takahashi, I.; Nakano, H. Duo-
carmycins, New Antitumor Antibiotics Produced by Streptomy-
ces; Producing Organisms and Improved Production. J . Antibiot.
1991, 44, 1045-1053. (g) Yasuzawa, T.; Saitoh, Y.; Ichimura,
M.; Takahashi, I.; Sano, H. Structure of Duocarmycin SA, a
Potent Antitumor Antibiotic. J . Antibiot. 1991, 44, 445-447. (h)
Yasuzawa, T.; Muroi, K.; Ichimura, M.; Takahashi, I.; Taka-
hashi, K.; Sano, H.; Saitoh, Y. Duocarmycins, Potent Antitumor
Antibiotics by Streptomyces sp. Structure and Chemistry. Chem.
Pharm. Bull. 1995, 43, 378-391.
(2) Gomi, K.; Kobayashi, E.; Miyoshi, K.; Ashizawa, T.; Okamoto,
A.; Ogawa, T.; Katsumata, S.; Mihara, A.; Okabe, M.; Hirata,
T. Anticellular and Antitumor Activity of Duocarmycins, Novel
Antitumor Antibiotic. J pn. J . Cancer Res. 1992, 52, 113-120.
(3) A number of reviews on the duocarmycins are available from
the following: (a) Boger, D. L. Duocarmycins: A New Class of
Sequence Selective DNA Minor Groove Alkylating Agents.
CHEMTRACTS: Org. Chem. 1991, 4, 329-349. (b) Boger, D.
L. The Duocarmycins: Synthesis and Mechanistic Studies. Acc.
Chem. Res. 1995, 28, 20-29. (c) Boger, D. L.; J ohnson, D. S.
CC-1065 and Duocarmycins: Unraveling the Keys to A New
Class of Naturally Derived DNA Alkylating Agents. Proc. Natl.
Acad. Sci. U.S.A. 1995, 92, 3642-3649. (d) Boger, D. L.; J ohnson,
D. S. CC-1065 and the Duocarmycins: Understanding their
Biological Function through Mechanistic Studies. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1438-1474.
(7) (a) Nagamura, S.; Asai, A.; Kanda, Y.; Kobayashi, E.; Gomi, K.;
Saito, H. Synthesis and Antitumor Activity of Duocarmycin
Derivatives: Modification of Segment A Duocarmycin B2. Chem.
Pharm. Bull. 1996, 44, 1723-1730. (b) Kobayashi, E.; Okamoto,
A.; Asada, M.; Okabe, M.; Nagamura, S.; Asai, A.; Saito, H.;
Gomi, K.; Hirata T. Characteristics of Antitumor Activity of KW-
2189, a Novel Water-soluble Derivative of Duocarmycin, Against
Murine and Human Tumors. Cancer Res. 1994, 54, 2404-2410.
(c) Asai, A.; Nagamura, S.; Saito, H. A Novel Property of
Duocarmycin and its Analogues for Covalent Reaction with DNA.
J . Am. Chem. Soc. 1994, 116, 4171-4177. (d) Nagamura, S.;
Kobayashi, E.; Gomi, K.; Saito, H. Studies on the Active
Metabolite (DU-86) of KW-2189, a Novel Derivative of Duocar-
mycin. Bioorg. Med. Chem. Lett. 1996, 6, 2147-2150.
(8) Nagamura, S.; Kanda, Y.; Kobayashi, E.; Gomi, K.; Saito, H.
Synthesis and Antitumor Activity of Duocarmycin Derivatives.
Chem. Pharm. Bull. 1995, 43, 1530-1535.
(9) A direct relationship between solvolysis stability and in vitro
cytotoxic potency with the more stable agents exhibiting the
more potent activity is demonstrated. (a) Boger, D. L.; Ishizaki,
T. Resolution of A CBI Precursor and Incorporation into the
Synthesis of (+)-CBI, (+)-CBI-CDPI1, (+)-CBI-CDPI2: Enhanced
Functional Analogues of (+)-CC-1065. A Critical Appraisal of a
Proposed Relationship between Electrophile Reactivity, DNA
Binding Properties, and Cytotoxic Potency. Tetrahedron Lett.
1990, 31, 793-796. (b) Boger, D. L.; Mesini, P.; Tarby, C. M.
Chemical and Structural Comparison of N-Boc-CBQ and N-Boc-
CBI: Identification and Structural Origin of an Unappreciated
but Productive Stability of the CC-1065 and Duocarmycin SA
Alkylation Subunits. J . Am. Chem. Soc. 1994, 116, 6461-6462.
(c) Boger, D. L.; McKie, J . A.; Han, N.; Taby, C. M.; Riggs, H.
W.; Kitos, P. A. A Hammett Correlation for CC-1065 and
Duocarmycin Analogues: Magnitude of Substituent Electronic
Effects on Functional Reactivity. Bioorg. Med. Chem. Lett. 1996,
6, 659-664. (d) Boger, D. L.; Goldberg, J .; McKie, J . A. A
Comparative Study of the Solvolysis Reactivity, Regioselectivity,
and Stereochemistry of the Duocarmycin A and SA Alkylation
Subunits. Bioorg. Med. Chem. Lett. 1996, 6, 1955-1960. (e)
Boger, D. L.; Boyce, C.; J ohnson, D. S. pH Dependence of the
Rate of DNA Alkylation for (+)-Duocarmycin SA and (+)-CBI-
TMI. Bioorg. Med. Chem. Lett. 1997, 7, 233-238.
(4) (a) Sugiyama, H.; Hosoda, M.; Saito, I.; Asai, A.; Saito, H.
Covalent Alkylation of DNA with Duocarmycin A. Identification
of Abasic Site Structure. Tetrahedron Lett. 1990, 31, 7197-7200.
(b) Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H. Synthesis and
Preliminary Evaluation of Agents Incorporating the Phama-
cophore of the Duocarmycin/Pyrindamycin Alkylation Subunit:
Identification of the CC-1065/Duocarmycin Common Pharma-
cophore. J . Org. Chem. 1990, 55, 4499-4502. (c) Boger, D. L.;
Ishizaki, T.; Zarrinmayeh, H.; Munk, S. A.; Kitos, P. A.;
Suntornwat, O. Duocarmycin-Pyrindamycin DNA Alkylation
Properties and Identification, Synthesis, and Evaluation of
Agents Incorporating the Pharmacophore of the Duocarmycin-
Pyrindamycin Alkylation Subunit. Identification of the CC-1065-
Duocarmycin Common Pharmacophore. J . Am. Chem. Soc. 1990,
112, 8961-8971. (d) Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H.
Isolation and Characterization of the Duocarmycin-adenine DNA
Adduct. J . Am. Chem. Soc. 1991, 113, 6645-6649. (e) Sugiyama,
H.; Ohmori, K.; Chan, K. L.; Hosoda, M.; Asai, A.; Saito, H.;
Saito, I. A Novel Guanine N3 Alkylation by Antitumor Antibiotic
Duocarmycin A. Tetrahedron Lett. 1993, 34, 2179-2182. (f)
Boger, D. L.; J ohnson, D. S.; Yun, W. (+)- and ent-(-)-Duocar-
mycin SA and (+)- and ent-(-)-N-Boc-DSA DNA Alkylation
Properties. Alkylation Site Models that Accommodate the Offset
AT-rich Adenine N3 Alkylation Selectivity of the Enantiomeric
Agents. J . Am. Chem. Soc. 1994, 116, 1635-1656.
(5) (a) Hanka, L. J .; Dietz, A.; Gerpheide, S. A.; Kuentzel, S. L.;
Martin, D. G. CC-1065 (NSC-298223), a New Antitumor Anti-
biotic. Production, in vitro Biological Activity, Microbiological
Assays, and Taxonomy of the Producing Microorganism. J .
Antibiot. 1978, 31, 1211-1217. (b) Martin, D. G.; Chidester, C.
G.; Duchamp, D. J .; Mizsak, S. A. Structure of CC-1065 (NSC-
298223), a New Antitumor Antibiotic. J . Antibiot. 1980, 33, 902-
903. (c) Reynolds, V. L.; McGovren, J . P.; Hurley, L. H. The
Chemistry, Mechanism of Action and Biological Properties of CC-
1065, a Potent Antitumor Antibiotic. J . Antibiot. 1986, 39, 319-
334.
(10) (a) Nagamura, S.; Kobayashi, E.; Gomi, K.; Saito, H. Synthesis
and Antitumor Activity of Duocarmycin Derivatives: A-ring
Pyrrole Analogues of Duocarmycin B2. Bioorg. Med. Chem. 1996,
4, 1379-1391. (b) Ogasawara, H.; Nishio, K.; Takeda, Y.;
Ohmori, T.; Kubota, N.; Funayama, Y.; Ohira, T.; Kuraishi, Y.;
Isogai, Y.; Saijo, N. A Novel Antitumor Antibiotics, KW-2189 is
Activated by Carboxyl Esterase and Induces DNA Strand Breaks
in Human Small Cell Lung Cancer Cells. J pn. J . Cancer Res.
1994, 54, 418-425. (c) Okamoto, A.; Asai, A.; Saito, H.; Okabe,
M.; Gomi, K. Differential Effect of Duocarmycin A and its Novel
Derivatives DU-86 on DNA Strand Breaks in HeLa S3 Cells. J pn.
J . Cancer Res. 1994, 85, 1304-1311. (d) Ogasawara, H.; Nishio,
K.; Kanzawa, F.; Lee, Y. S.; Funayama, Y.; Ohmori, T.; Kuraishi,
Y.; Isogai, Y.; Saijo, N. Intracellular Carboxyl Esterase Activity
is A Determinant of Cellular Sensitivity to the Antineoplastic
Agent KW-2189 in Cell lines Resistant to Cisplatin and CPT-
11. J pn. J . Cancer Res. 1995, 55, 124-129. (e) Ogasawara, H.;
Nishio, K.; Ishida, T.; Arioka, H.; Fukuoka, K.; Saijo, N. In vitro
Enhancement of Antitumor Activity of a Water-soluble Duocar-
mycin Derivative, KW-2189, by Caffeine-mediated DNA-repair
Inhibition in Human Lung Cancer Cells. J pn. J . Cancer Res.
1997, 88, 1033-1037.
(11) (a) Chidester, C. G.; Krueger, W. C.; Mizsak, S. A.; Duchamp,
D. J .; Martin, D. G. The Structure of CC-1065,
a Potent
Antitumor Agent, and its Binding to DNA. J . Am. Chem. Soc.
1981, 103, 7629-7635. (b) Warpehoski, M. A.; Gebnard, I.; Kelly,
R. C.; Krueger, W. C.; Li, L. H.; McGovren, J . P.; Prairie, M. D.;
Wicnienski, N.; Wierenga, W. Stereoelectronic Factors Influenc-
ing the Biological Activity and DNA Interaction of Synthetic
Antitumor Agents Modeled on CC-1065. J . Med. Chem. 1988,
31, 590-603. (c) Boger, D. L.; Tun, W. Role of the CC-1065 and
Duocarmycin N2 Substituent: Validation of A Direct Relation-
ship Between Solvolysis Chemical Stability and in vitro Biologi-
cal Potency. J . Am. Chem. Soc. 1994, 116, 5523-5524.
(12) Asai, A.; Nagamura, S.; Kobayashi, E.; Gomi, K.; Saito, H.
Syntesis and Antitumor Activity of Novel Duocarmycin Deriva-
tives. Bioorg. Med. Chem. Lett. 1996, 6, 1215-1220.
(13) Nagamura, S.; Asai, A.; Amishiro, N.; Kobayashi, E.; Gomi, K.;
Saito, H. Synthesis and Antitumor Activity of Duocrmycn
Derivatives: A-ring Pyrrole Compounds Bearing Cinnamoyl
Groups. J . Med. Chem. 1997, 40, 972-979.
(6) (a) Hurley, L. H.; Reynolds, V. L.; Swenson, D. H.; Petzold, G.
L.; Scahill, T. A. Reaction of the Antitumor Antibiotic CC-1065
with DNA: Structure of A DNA Adduct with DNA Sequence
Specificity. Science 1984, 226, 843-844. (b) Reynolds, V. L.;
Molineaux, I. J .; Kaplan, D. J .; Swensen, D. H.; Hurley, L. H.
Reaction of the Antitumor Antibiotic CC-1065 with DNA.