Synthesis and antitumor activity of duocarmycin derivatives: A-ring pyrrole compounds bearing cinnamoyl groups

Journal of Medicinal Chemistry

Volumn 40, Issue 6, 1997, Pages 972-979

  Nagamura, Satoru ^a   Asai, Akira ^a   Amishiro, Nobuyoshi ^a   Kobayashi, Eiji ^a   Gomi, Katsushige ^a   Saito, Hiromitsu ^a  

^a KYOWA HAKKO KOGYO CO LTD   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

CINNAMIC ACID DERIVATIVE; DU 86; DUOCARMYCIN A; DUOCARMYCIN B2; DUOCARMYCIN DERIVATIVE; PIBROZELESIN; RACHELMYCIN; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CONTROLLED STUDY; DOSE RESPONSE; DRUG STRUCTURE; DRUG SYNTHESIS; HELA CELL; HUMAN; HUMAN CELL; INTRAVENOUS DRUG ADMINISTRATION; MOLONEY MURINE SARCOMA ONCOVIRUS; MOUSE; NONHUMAN; SARCOMA; STOMACH TUMOR; STRUCTURE ACTIVITY RELATION; UTERINE CERVIX CARCINOMA;

ANIMALS; ANTIBIOTICS, ANTINEOPLASTIC; CELL DIVISION; CINNAMATES; DRUG SCREENING ASSAYS, ANTITUMOR; HELA CELLS; HUMANS; INDOLES; MAGNETIC RESONANCE SPECTROSCOPY; MICE; MOLECULAR STRUCTURE; NEOPLASMS, EXPERIMENTAL; PYRROLIDINONES;

EID: 0030998113     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9606094     Document Type: Article

References (57)

1. (a) Takahashi, I.; Takahashi, K.; Ichimura, M.; Morimoto, M.; Asano, K.; Kawamoto, I.; Tomita, F.; Nakano, H. Duocarmycin A, A New Antibiotics from Streptomyces. J. Antibiot. 1988, 41, 1915-1917.
2. (b) Yasuzawa, T.; Iida, T.; Muroi, K.; Ichimura, M.; Takahashi, K.; Sano, H. Structures of Duocarmycins, Novel Antitumor Antibiotics Produced by Streptomyces sp. Chem. Pharm. Bull. 1988, 36, 3728-3731.
3. (c) Ichimura, M.; Muroi, K.; Asano, K.; Kawamoto, I.; Tomita, F.; Morimoto, M.; Nakano, H. DC-89A1, A New Antibiotics from Streptomyces. J. Antibiot. 1988, 41, 1285-1288.
4. (d) Ogawa, T.; Ichimura, M.; Katsumata, S.; Morimoto, M.; Takahashi, K. New Antitumor Antibiotics, Duocarmycin B1 and B2. J. Antibiot. 1989, 42, 1299-1301.
5. (e) Ichimura, M.; Ogawa, T.; Takahashi, K.; Kobayashi, E.; Kawamoto, I.; Yasuzawa, T.; Takahashi, I.; Nakano, H. Duocarmycin SA, A New Antitumor Antibiotic from Streptomyces sp. J. Antibiot. 1990, 43, 1037-1038.
6. (f) Yasuzawa, T.; Saitoh, Y.; Ichimura, M.; Takahashi, I.; Sano, H. Structure of Duocarmycin SA, A Potent Antitumor Antibiotic. J. Antibiot. 1991, 44, 445-447.
7. (g) Ichimura, M.; Ogawa, T.; Katsumata, S.; Takahashi, K.; Takahashi, I.; Nakano, H. Duocarmycins, New Antibiotics Produced by Streptomyces; Producing Organisms and Improved Production. J. Antibiot. 1991, 44, 1045-1053.
8. (h) Yasuzawa, T.; Muroi, K.; Ichimura, M.; Takahashi, I.; Ogawa, T.; Takahashi, K.; Sano, H; Saitoh, Y. Duocarmycins, Potent Antitumor Antibiotics by Streptomyces sp. Structures and Chemistry. Chem. Pharm. Bull. 1995, 43, 378-391.
9. (a) Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H. Synthesis and Preliminary Evaluation of Agents Incorporating the Pharmacophore of the Duocarmycin/Pyrindamycin Alkylation Subunit: Identification of the CC-1065/Duocarmycin Common Pharmacophore. J. Org. Chem. 1990, 55, 4499-4502.
10. (b) 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.
11. (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.
12. (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.
13. (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.
14. (f) Boger, D. L.; Johnson, D. S.; Yun, W. (+)- and ent-(-)-Duocarmycin 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.
15. (a) Hanka, L. J.; Dietz, A.; Gerpheide, S. A.; Kuentzel, S. L.; Martin, D. G. CC-1065 (NSC-298223), A New Antitumor Antibiotic. Production, in vitro Biological Activity, Microbiological Assay, and Taxonomy of the Producing Microorganism. J. Antibiot. 1978, 31, 1211-1217.
16. (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.
17. (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.
18. (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.
19. (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 Location for the Site of Thermally Induced Strand Breakage and Analysis of DNA Sequence Specificity. Biochemistry 1985, 24, 6228-6237.
20. (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 -(NS-Adenine)-DNA Adduct by the UVRABC Nuclease. Biochemistry 1988, 27, 893-901.
21. 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 Antibiotics. Jpn. J. Cancer Res. 1992, 83, 113-120.
22. (6) 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: Synthetic and Mechanistic Studies. Acc. Chem. Res. 1995, 28, 20-29. (c) Boger, D. L.; Johnson, D. S. CC-1065 and the 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.; Johnson, D. S. CC-1065 and the Duocarmycins: Understanding Their Biological Function through Mechanistic Studies. Angew. Chem., Int. Ed. Engl. 1996, 35, 1438-1474.
23. 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: Synthetic and Mechanistic Studies. Acc. Chem. Res. 1995, 28, 20-29. (c) Boger, D. L.; Johnson, D. S. CC-1065 and the 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.; Johnson, D. S. CC-1065 and the Duocarmycins: Understanding Their Biological Function through Mechanistic Studies. Angew. Chem., Int. Ed. Engl. 1996, 35, 1438-1474.
24. 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: Synthetic and Mechanistic Studies. Acc. Chem. Res. 1995, 28, 20-29. (c) Boger, D. L.; Johnson, D. S. CC-1065 and the 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.; Johnson, D. S. CC-1065 and the Duocarmycins: Understanding Their Biological Function through Mechanistic Studies. Angew. Chem., Int. Ed. Engl. 1996, 35, 1438-1474.
25. 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: Synthetic and Mechanistic Studies. Acc. Chem. Res. 1995, 28, 20-29. (c) Boger, D. L.; Johnson, D. S. CC-1065 and the 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.; Johnson, D. S. CC-1065 and the Duocarmycins: Understanding Their Biological Function through Mechanistic Studies. Angew. Chem., Int. Ed. Engl. 1996, 35, 1438-1474.
26. Nagamura, S.; Kanda, Y.; Kobayashi, E.; Gomi, K.; Saito, H. Synthesis and Antitumor Activity of Duocarmycin Derivatives. Chem. Pharm. Bull. 1995, 43, 1530-1535.
27. 2: Enhanced Functional Analogs 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 Analogs: 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.
28. 2: Enhanced Functional Analogs 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 Analogs: 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.
29. 2: Enhanced Functional Analogs 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 Analogs: 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.
30. 2: Enhanced Functional Analogs 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 Analogs: 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.
31. (a) Nagamura, S.; Asai, A.; Kanda, Y.; Kobayashi, E.; Gomi, K.; Saito, H. Synthesis and Antitumor Activity of Duocarmycin Derivatives: Modification of Segment A of Duocarmycin B2. Chem. Pharm. Bull. 1996, 44, 1723-1730.
32. (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.
33. (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.
34. (a) Nagamura, S.; Kobayashi, E.; Gomi, K.; Saito, H. Synthesis and Antitumor Activity of Duocarmycin Derivatives: A-ring Pyrrole Analogs of Duocarmycin B2. Bioorg. Med. Chem. 1996, 4, 1379-1391.
35. (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. Jpn. J. Cancer Res. 1994, 85, 418-425.
36. 3 Cells. Jpn. J. Cancer Res. 1994, 85, 1304-1311.
37. (d) Ogasawara, H.; Nishio, K.; Kanzawa, F.; Lee, Y.-S.; Funayama, Y.; Ohira, 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. Jpn. J. Cancer Res. 1995, 86, 124-129.
38. (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.
39. (b) Warpehoski, M. A.; Gebhard, I.; Kelly, R. C.; Krueger, W. C.; Li, L. H.; McGovren, J. P.; Prairie, M. D.; Wicnienski, N.; Wierenga, W. Stereoelectronic Factors Influencing the Biological Activity and DNA Interaction of Synthetic Antitumor Agents Modeled on CC-1065. J. Med. Chem. 1988, 31, 590-603.
40. (c) Boger, D. L.; Tun, W. Role of the CC-1065 and Duocarmycin N2 Substituent: Validation of a Direct Relationship between Solvolysis Chemical Stability and in Vitro Biological Potency. J. Am. Chem. Soc. 1994, 116, 5523-5524.
41. (a) Li, L. H.; Kelly, R. C.; Warpehoski, M. A.; McGovren, J. P.; Gebhard, I.; Dekoning, T. F. Adozelesin. A Selected Lead among Cyclopropylpyrroloindole Analogs of the DNA-binding Antibiotic, CC-1065. Invest. New Drugs 1991, 9, 137-148.
42. (b) Li, L. H.; Dekoning, T. F.; Kelly, R. C.; Krueger, W. C.; McGovren, J. P.; Pudbury, G. E.; Petzold, G. L.; Wallace, T. L.; Ouding, R. J.; Prairie, M. D.; Gebhard, I. Cytotoxicity and Antitumor Activity of Carzelesin, A Prodrug Cyclopropylpyrroloindole Analogue. Cancer Res. 1992, 52, 4904-4913.
43. Asai, A.; Nagamura, S.; Kobayashi, E.; Gomi, K.; Saito, H. Synthesis and Antitumor Activity of Novel Duocarmycin Derivatives. Bioorg. Med. Chem. Lett. 1996, 6, 1215-1220.
44. The importance of the C-5′ methoxy substituent of segment B in duocarmycins has been clearly defined. Boger, D. L.; Bollinger, B.; Johnson, D. S. Examination of the Role of the Duocarmycin SA Methoxy Substituents: Identification of the Minimum, Fully Potent DNA Binding Subunit. Bioorg. Med. Chem. Lett. 1996, 6, 2207-2210.
45. (a) Nagamura, S.; Kanda, Y.; Asai, A.; Kobayashi, E.; Gomi, K.; Saito, H. Wagner-Meerwein Rearrangement of Duocarmycins. Chem. Pharm. Bull. 1996, 44, 933-939.
46. (b) Berner, D.; Cox, D. P.; Dahn, H. On the Migration of a HOOC Group in a Wagner-Meerwein Rearrangement in Superacid Solution: Proof by Double Labeling with Carbon-13. J. Am. Chem. Soc. 1982, 104, 2631-2632.
47. Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K. A Convenient Method for the Synthesis of Carboxylic Esters. Chem. Lett. 1975, 1045-1048.
48. (17) The reduced intracellular permeability by charged molecules in this series has been previously discussed, and another related structure-activity relationship also has been reported. (a) Boger, D. L.; Yun, W.; Han, N.; Johnson, D. S. CC-1065 CBI Analogs: An Example of Enhancement of DNA Alkylation Efficiency through Introduction of Stabilizing Electrostatic Interactions. Bioorg. Med. Chem. 1995, 3, 611-621. (b) Boger, D. L.; Yun, W.; Han, N. 1,2,9,9a-Tetrahydrocyclopropa[c]benz[e]indol-4-one-(CBI) Analogs of CC-1065 and the Duocarmycins: Synthesis and Evaluation. Bioorg. Med. Chem. 1995, 3, 1429-1453.
49. The reduced intracellular permeability by charged molecules in this series has been previously discussed, and another related structure-activity relationship also has been reported. (a) Boger, D. L.; Yun, W.; Han, N.; Johnson, D. S. CC-1065 CBI Analogs: An Example of Enhancement of DNA Alkylation Efficiency through Introduction of Stabilizing Electrostatic Interactions. Bioorg. Med. Chem. 1995, 3, 611-621. (b) Boger, D. L.; Yun, W.; Han, N. 1,2,9,9a-Tetrahydrocyclopropa[c]benz[e]indol-4-one-(CBI) Analogs of CC-1065 and the Duocarmycins: Synthesis and Evaluation. Bioorg. Med. Chem. 1995, 3, 1429-1453.
50. (a) Nagamura, S.; Kobayashi, E.; Gomi, K.; Saito, H. Studies on the Active Metabolite (DU-86) of KW-2189, A Novel Derivative of Duocarmycin. Bioorg. Med. Chem. Lett. 1996, 6, 2147-2150.
51. (b) Details of the biological activity of duocarmycin SA will be reported else in the near future.
52. (a) McGovren, J. P.; Clarke, G. L.; Pratt, E. A.; Dekoning, T. F. Preliminary Toxicity Studies with the DNA-Binding Antibiotics, CC-1065. J. Antibiot. 1984, 37, 63-70.
53. (b) Warpehoski, M. A.; Harper, D. E.; Mitchell, M. A.; Monroe, T. J. Reversibility of the Covalent Reaction of CC-1065 and Analogues with DNA. Biochemistry 1992, 31, 2502-2508.
54. (c) Boger, D. L.; Yun, W. Reversibility of the Duocarmycin A and SA DNA Alkylation Reaction. J. Am. Chem. Soc. 1993, 115, 9872-9873.
55. (d) Asai, A.; Nagamura, S.; Saito, H.; Takahashi, I.; Nakano, H. The Reversible DNA-Alkylating of Duocarmycin and Its Analogues. Nucleoic Acids Res. 1994, 22, 83-93.
56. Geran, R. I.; Greenberg, N. H.; MacDonald, M. M.; Schumacher, A. M.; Abbott, B. J. Protocols for Screening Chemical Agents and Natural Products against Animal Tumors and Other Biological Systems. Cancer Chemother. Rep. 1972, 3, 1-103.
57. Inaba, M.; Kobayashi, T.; Tashiro, T.; Sakurai, Y.; Maruo, K.; Ohnishi, Y.; Ueyama, Y.; Nomura, T. Evaluation of Antitumor Activity in a Human Breast Tumor/Nude Mouse Model with a Special Emphasis on Treatment Dose. Cancer 1989, 64, 1577-1582.