Thiol-mediated DNA alkylation by the novel antitumor antibiotic leinamycin

Journal of the American Chemical Society

Volumn 118, Issue 28, 1996, Pages 6802-6803

  Asai, Akira ^a   Hara, Mitsunobu ^a   Kakita, Shingo ^a   Kanda, Yutaka ^a   Yoshida, Mayumi ^a   Saito, Hiromitsu ^a   Saitoh, Yutaka ^a  

^a KYOWA HAKKO KOGYO CO LTD   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC ANTIBIOTIC; LEINAMYCIN;

ARTICLE; DNA ALKYLATION;

EID: 0029946861     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja960892w     Document Type: Article

References (15)

1. Hara, M.; Takahashi, I.; Yoshida, M.; Asano, K.; Kawamoto, I.; Morimoto, M.; Nakano, H. J. Antibiot. 1989, 42, 333-335.
2. Hara, M.; Asano, K.; Kawamoto, I.; Takiguchi, T.; Katumata, S.; Takahashi, K.; Nakano, H. J. Antibiot. 1989, 42, 1768-1774.
3. Hara, M.; Saitoh, Y.; Nakano, H. Biochemistry 1990, 29, 5676-5681.
4. Hirayama, N.; Matsuzawa, E. S. Chem. Lett. 1993, 11, 1957-1958.
5. Kanda, Y.; Fukuyama, T. J. Am. Chem. Soc. 1993, 115, 8451-8452.
6. 3, 35% from 1).
7. Sugiyama, H.; Fujiwara, T.; Ura, A.; Tashiro, T.; Yamamoto, K.; Kawanishi, S.; Saito, I. Chem. Res. Toxicol. 1994, 7, 673-683.
8. Sun, D.; Hansen, M.; Clement, J. J.; Hurley, L. H. Biochemistry 1993, 32, 8068-8074.
9. Lee, C.; Sun, D.; Kizu, R.; Hurley, L. H. Chem. Res. Toxicol. 1991, 4, 203-213.
10. Isolation of 3 from the aqueous reaction mixture resulted in low yields (< 10%) because of its lability which leads to 2. However, treatment of 1 with 2-ME and excess molar triethyl amine in 2-propen-1-ol unexpectedly resulted in the generation of sufficient amounts of 4 (yield: 68%) for spectroscopic characterization.
11. The details of conversion of 2, including DNA-cleavage activity in the absence of thiol will be reported elsewhere.
12. Regarding previously proposed oxathiolane intermediates: Stanwinski, J.; Thlein, M. J. Org. Chem. 1991, 56, 5169-5175.
13. Behroozi, S. J.; Kim, W.; Gates, K. S. J. Org. Chem. 1995, 60, 3964-3966. Gates et al. also showed some evidence which indicate the generation of an electrophilic oxathiolanone intermediate from thiol treated 1,3-dioxo-1,2-dithiolane heterocyclic compounds.
14. Behroozi, S. J.; Kim, W.; Dannaldson, J.; Gates, K. S. Biochemistry 1996, 35, 1768-1774. Gates et al. proposed that the mechanism of DNA-cleavage by dithiolane oxides is thiol-mediated generation of oxygen radicals from the results of their experimental system employing the simple dithiolane oxide compounds.
15. NOE experiments revealed the relative stereochemistry at C-6 and C-7 of 2c, 3, and 4a.