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ZUSCHRIFTEN 3802 WILEY-VCH VerlagGmbH, D-69451 Weinheim, 2000 0044-8249/00/11220-3802 $ 17.50+.50/0 Angew. Chem. 2000, 112, Nr. 20 Chemical Synthesis and DNA Photocleavage of the Intercalator ± Carbohydrate Hybrid Moiety of the Neocarzinostatin Chromophore** Kazunobu Toshima,* Shigeki Takai, Yutaka Maeda, Ryusuke Takano, and Shuichi Matsumura Dedicated to Professor Kuniaki Tatsuta on the occasion of his 60th birthday The development of photochemical DNA-cleaving agents, which effectively cleave DNA by irradiation at a specific wavelength under mild conditions and without any additives such as metals and reducing agents, is very interesting from a chemical and biological standpoint and offers considerable potential in medicine. [1] Indeed, photodynamic therapy using a photosensitizing drug has recently emerged as a promising modality against cancer and allied diseases. [2] Sugiura et al. [3] first demonstrated the light-induced DNA cleavage by the antitumor enediyne antibiotic neocarzinostatin [4] and Hirama et al. [5] reported the photoinduced cycloaromatization of the neocarzinostatin chromophore (Scheme 1), which is respon- sible for the DNA-cleavage activity of neocarzinostatin. In O O O O O O O NHMe OH OH Me OH OMe Me O Scheme 1. Neocarzinostatin chromophore. this context, we anticipated that if the intercalator ± carbo- hydrate hybrid moiety of the neocarzinostatin chromophore, without its enediyne moiety, interacts with DNA and if the C O bond in the hybrid generates a photoexcited 3 (n-p*) radical-like [5] state by photoirradiation, then the intercalator ± carbohydrate hybrid moiety of the enediyne-free neocarzi- nostatin chromophore could be capable of DNA cleavage. Herein, we report the chemical synthesis and DNA-photo- cleavage properties of the intercalator ± carbohydrate hy- brids [6, 7] 1 and 2, which correspond to the intercalator and the carbohydrate moieties of the enediyne antibiotic, neocarzi- nostatin (Scheme 2). O O O NHMe OH OH Me OH OMe Me O O O O NHMe OH OH Me OH OMe Me O OMe OH OMe Me O O MeO O NHMe OH OH Me O MeO O NHMe OH OH Me 1 2 17 18 19 Scheme 2. The intercalator ± carbohydrate hybrids and their components. To confirm our hypothesis, we designed and synthesized 1 and 2, in which the aromatic and sugar moiety of the neocarzinostatin chromophore were linked by only an ethyl- ene glycol unit to each other. Compounds 1 and 2 are the anomers of each other. Their synthesis began with the [13] For recent synthetic advances from our laboratory in the area of O-linked glycopeptides see W. Glunz, S. Hintermann, J.B. Schwarz, S. D. Kuduk, X.-T. Chen, L. J. Williams, D. Sames, S. J. Danishefsky, V. Kudryashov, K. O. Lloyd, J. Am. Chem. Soc. 1999, 121, 10 636, and references therein. [14] R. D. Cummings in Glycoconjugates (Eds.: H. J. Allen, E. C. Kisailus), Marcel Dekker, New York, 1992, chap. 10, p. 333. [15] For the general strategy we employ in reaching the ªhigh mannoseº core system, see P. H. Seeberger, P. F. Cirillo, S. Hu, X. Beebe, M. T. Bilodeau, S. J. Danishefsky, Enantiomer J. Stereochem. 1996, 1, 311. [16] S. J. Danishefsky, M. T. Bilodeau, Angew. Chem. 1996, 108, 1482; Angew. Chem. Int. Ed. Engl. 1996, 35, 1380. [17] S. J. Danishefsky, S. Hu, P. F. Cirillo, M. Eckhardt, P. H. Seeberger, Chem. Eur. J. 1997 , 3, 1617. [18] see: D. A. Griffith, S. J. Danishefsky, J. Am. Chem. Soc. 1990, 112, 5811. [19] E. N. Cain, L. L. Welling, Tetrahedron Lett. 1975, 16, 1353. [20] L. M. Likhosherstov, O. S. Novikova, V. A. Derevitskaja, N. K. Kochetkov, Carb. Res. 1986, 146, C1; S. T. Cohen-Anisfeld, P. T. Lansbury, Jr., J. Org. Chem. 1990, 55, 5560. [21] S. T.Cohen-Anisfeld, P. T. Lansbury, Jr., J. Am. Chem. Soc. 1993, 115, 10 531. [22] Since our yield is far from quantitative, we cannot rule out the possibility of aspartimide formation, or even products arising from N-acylation by the a-carboxy group of the Asn residue via such an intermediate. This same issue, which can be raised with respect to the previous cases, [21] requires further detailed study. [23] A. I. Meyers, D. L. Comins, D. M. Roland, R. Henning,K. Shimizu, J. Am. Chem. Soc. 1979, 101, 7104. [24] Prepared by San San Yi, Microchemistry Laboratory, Sloan-Kettering Institute for Cancer Research. [25] PE Sciex API-100. [*] Prof. Dr. K. Toshima, S. Takai, Y. Maeda, R. Takano, Prof. Dr. S. Matsumura Department of Applied Chemistry Faculty of Science and Technology Keio University 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522 (Japan) Fax: ( 81) 45-566-1576 E-mail: [email protected] [**] This research was partially supported by a Grant-in-Aid for Encour- agement of Young Scientists from the Ministry of Education, Science, Sports, and Culture, Japan, and a research grant of Keio University Special Grant-in-Aid for Innovative Collaborative Research Projects.

Chemical Synthesis and DNA Photocleavage of the Intercalator–Carbohydrate Hybrid Moiety of the Neocarzinostatin Chromophore

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Page 1: Chemical Synthesis and DNA Photocleavage of the Intercalator–Carbohydrate Hybrid Moiety of the Neocarzinostatin Chromophore

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