A molecular model for DNA cross-linking by the antitumor agent azinomycin B

Journal of Medicinal Chemistry

Volumn 43, Issue 15, 2000, Pages 2783-2788

  Alcaro, Stefano ^a   Coleman, Robert S ^b  

^a UNIVERSITY MAGNA GRAECIA OF CATANZARO   (Italy)

^b OHIO STATE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; AZINOMYCIN B; UNCLASSIFIED DRUG;

ALKYLATION; ANTINEOPLASTIC ACTIVITY; ARTICLE; COMPUTER SIMULATION; CYTOTOXICITY; DNA CROSS LINKING; DNA DETERMINATION; DNA SEQUENCE; DRUG CONFORMATION; DRUG POTENCY; GENE TARGETING; PROTEIN CONFORMATION; RECEPTOR BINDING; STREPTOMYCES; SYNTHESIS; SYSTEM ANALYSIS;

ANTI-BACTERIAL AGENTS; ANTIBIOTICS, ANTINEOPLASTIC; CROSS-LINKING REAGENTS; DNA; GLYCOPEPTIDES; INTERCALATING AGENTS; MODELS, MOLECULAR; NAPHTHALENES; PEPTIDES;

EID: 0034721193     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm990362l     Document Type: Article

References (31)

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4. Azinomycin B is identical to carzinophilin A, an antitumor agent isolated in 1954 from Streptomyces sahachiroi: Hata, T.; Koga, F.; Sano, Y.; Kanamori, K.; Matsumae, A.; Sugawara, R.; Hoshi, T.; Shimi, T.; Ito, S.; Tomizawa, S. Carzinophilin. A New Tumor Inhibitory Substance Produced by Streptomyces. I. J. Antibiot. Ser. A. 1954, 7, 107-112.
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10. Coleman, R. S.; Kong, J.-S.; Richardson, T. E. Synthesis of Naturally Occurring Antitumor Agents: Stereocontrolled Synthesis of the Azabicyclic Ring System of the Azinomycins. J. Am. Chem. Soc. 1999, 121, 9088-9095. Coleman, R. S.; Richardson, T. E.; Carpenter, A. J. Synthesis of the Azabicyclic Core of the Azinomycins: Introduction of Differentiated trans-Diol by Crotylstannane Addition to Serinal. J. Org. Chem. 1998, 63, 5738-5739. Coleman, R. S.; Kong, J.-S. Stereocontrolled Synthesis of the Fully Elaborated Aziridine Core of the Azinomycins. J. Am. Chem. Soc. 1998, 120, 3538-3529. Coleman, R. S.; Carpenter, A. J. Synthesis of the Aziridino[1,2-α]pyrrolidine Substructure of the Antitumor Agents Azinomycin A and B. J. Org. Chem. 1992, 57, 5813-5815.
11. Coleman, R. S.; Kong, J.-S.; Richardson, T. E. Synthesis of Naturally Occurring Antitumor Agents: Stereocontrolled Synthesis of the Azabicyclic Ring System of the Azinomycins. J. Am. Chem. Soc. 1999, 121, 9088-9095. Coleman, R. S.; Richardson, T. E.; Carpenter, A. J. Synthesis of the Azabicyclic Core of the Azinomycins: Introduction of Differentiated trans-Diol by Crotylstannane Addition to Serinal. J. Org. Chem. 1998, 63, 5738-5739. Coleman, R. S.; Kong, J.-S. Stereocontrolled Synthesis of the Fully Elaborated Aziridine Core of the Azinomycins. J. Am. Chem. Soc. 1998, 120, 3538-3529. Coleman, R. S.; Carpenter, A. J. Synthesis of the Aziridino[1,2-α]pyrrolidine Substructure of the Antitumor Agents Azinomycin A and B. J. Org. Chem. 1992, 57, 5813-5815.
12. Coleman, R. S.; Kong, J.-S.; Richardson, T. E. Synthesis of Naturally Occurring Antitumor Agents: Stereocontrolled Synthesis of the Azabicyclic Ring System of the Azinomycins. J. Am. Chem. Soc. 1999, 121, 9088-9095. Coleman, R. S.; Richardson, T. E.; Carpenter, A. J. Synthesis of the Azabicyclic Core of the Azinomycins: Introduction of Differentiated trans-Diol by Crotylstannane Addition to Serinal. J. Org. Chem. 1998, 63, 5738-5739. Coleman, R. S.; Kong, J.-S. Stereocontrolled Synthesis of the Fully Elaborated Aziridine Core of the Azinomycins. J. Am. Chem. Soc. 1998, 120, 3538-3529. Coleman, R. S.; Carpenter, A. J. Synthesis of the Aziridino[1,2-α]pyrrolidine Substructure of the Antitumor Agents Azinomycin A and B. J. Org. Chem. 1992, 57, 5813-5815.
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16. While there is no experimental evidence that the azinomycin naphthoate moiety intercalates in DNA, the similarity with established intercalating naphthalene systems suggests that this mode of binding is potentially operable. See, for example: Gao, X.; Stassinopoulos, A.; Gu, J.; Goldberg, I. H. NMR Studies of the Post-Activated Neocarzinostatin Chromophore-DNA Complex. Conformational Changes Induced in Drug and DNA. Bioorg. Med. Chem. 1995, 3, 795-809.
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18. MAB = monoalkylation aziridine bottom; MAT = monoalkylation aziridine top; MEB = monoalkylation epoxide bottom; MET = monoalkylation epoxide top; AB-ET = aziridine bottom epoxide top cross-link.
19. As proposed by Arnott and implemented in MacroModel. See: Arnott, S.; Campbell-Smith, P.; Chandresekharan, P. CRC Handbook of Biochemistry; CRC Press: Boca Raton, FL, 1976; Vol. 2.
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21. 5 This raises the nontrivial issue of the relevance of the present modeling work using canonical B-DNA to experimental results using a short and probably noncanonical sequence. While we cannot address the conformation of the 6-mer used by Saito and co-workers, in related experimental studies we have confirmed the regioselectivity proposed in the our present modeling work under conditions where a 15-mer DNA target is expected exists in the B-form (Coleman, R. S.; Perez, R. J. Unpublished work).
22. All calculations were performed on SGI Impact R10000 or O2 computers using the programs MacroModel v. 5.5 (Columbia University, New York, 1996) and Spartan v. 5.0 (Wavefunction, Inc., Irvine, CA, 1995).
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28. 2 at 1.3 Å Resolution. J. Med. Chem. 1999, 42, 536-540.
29. It is not possible for the drug to intercalate within the base triplet that undergoes cross-linking because the maximum C21 to C10 distance of azinomycin B is ≈ 9.5 Å compared to the N7 to N7 distance of 11.6 Å with an intercalation site placed in a d(GCT) B-form sequence.
30. In the vast majority of X-ray crystal structures of molecules intercalated in duplex DNA, the center of the intercalating agent and the center of the upper and lower base pairs (measured from the four glycosidic nitrogens) are nearly coincident. The fixed distance approximated this coincidence.
31. It is geometrically impossible for the naphthalene to be intercalated and the epoxide to alkylate the distal purine base.