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Neocarzinostatin Chromophore: Structure and Mechanism of DNA Cleavage

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Neocarzinostatin

Summary

Neocarzinostatin (NCS) is a member of a family of chromoprotein antitumor antibiotics. It consists of two noncovalently bound components, a labile chromophore component (NCS-chrom) with biological activities such as DNA cleavage and a protein component that stabilizes NCS-chrom. NCSchrom was the first of the enediyne antibiotics to be isolated and characterized. The chemical structure has been elucidated: a novel epoxybicyclo [7,3,01 dodecadienediyne system, an interconnecting highly unsaturated 12-member carbon ring subunit, bearing subunits 2-hydroxy-5-methyl-7-methoxyl1-naphthoate, 2,6-dideoxy-2-methylamino-galactose, and ethylene carbonate. The mechanism for the activation of NCS-chrom highlights one of the crucial roles of the thiol in the mechanism of action of NCS. Nucleophilic attack by a thiol results in a Bergman-type electronic rearrangement to form a biradical species that cleaves DNA by abstracting hydrogen atoms from the deoxyribose sugar. Moreover, another pathway for the thiol-independent mechanism of action of NCS-chrom has been proposed. In this mechanism, the spirolactone cumulene is stereoselectively generated via an intramolecular Michael addition at C-12 by the enolate anion of naphthoate of NCS-chrom, resulting in the formation of the biradical.

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Authors and Affiliations

  1. Pharmacy, Fukushima Medical College Hospital, 1 Hikarigaoka, Fukushima, 960-12, Japan

    Kiyoto Edo

  2. Tohoku College of Medical Technology and Welfare, Kunimi, Sendai, Miyagi, 981, Japan

    Yoshio Koide

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  1. Kiyoto Edo
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  2. Yoshio Koide
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Editors and Affiliations

  1. Department of Microbiology, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto, 860, Japan

    Hiroshi Maeda Ph.D., M.D. (Professor and Chairman) (Professor and Chairman)

  2. Pharmacy, Fukushima Medical College Hospital, 1 Hikariga-oka, 960-12, Fukushima, Japan

    Kiyoto Edo Ph.D. (Associate Professor and Director) (Associate Professor and Director)

  3. Tohoku University, 2-1 Seiryo-cho, Aoba-ku, 980-77, Sendai, Miyagi, Japan

    Nakao Ishida M.D., Ph.D. (Professor Emeritus and Former President, President) (Professor Emeritus and Former President, President)

  4. Sendai Institute of Microbiology, 2-5-22 Ichiban, Aoba-ku, Sendai, Miyagi, 980, Japan

    Nakao Ishida M.D., Ph.D. (Professor Emeritus and Former President, President) (Professor Emeritus and Former President, President)

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© 1997 Springer Japan

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Edo, K., Koide, Y. (1997). Neocarzinostatin Chromophore: Structure and Mechanism of DNA Cleavage. In: Maeda, H., Edo, K., Ishida, N. (eds) Neocarzinostatin. Springer, Tokyo. https://doi.org/10.1007/978-4-431-66914-2_3

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  • DOI: https://doi.org/10.1007/978-4-431-66914-2_3

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-66916-6

  • Online ISBN: 978-4-431-66914-2

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