Man-designed bleomycins. synthesis of dioxygen activating molecules and a DNA cleaving molecule based on bleomycin-Fe(II)-02 complex

✍ Scribed by Atsushi Kittaka; Yuichi Sugano; Masami Otsuka; Masaji Ohno

• Publisher: Elsevier Science
• Year: 1988
• Tongue: French
• Weight: 916 KB
• Volume: 44
• Category: Article
• ISSN: 0040-4020
• DOI: 10.1016/s0040-4020(88)90018-x

✦ Synopsis

A synthetic model for the metal binding site of bleomycin with a 4-methoxypyridine nucleus and a tert-butyl group is shown to be comparable to bleomycin interms of dioxygen activation.

This model ligand is coupled with a DNA affinity moiety, tetrapeptide S, to afford a mandesigned bleomycin which exhibits potent DNA cleaving activity in vitro.

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Bleomycins

(BLMs) are a family of antitumor antibiotics used in the clinical treatment of Hodgkin's lymphoma, carcinomas of the skin, head and neck, and tumors of testis. 2-5 BLM comprises a linear hexapeptide and a disaccharide and each part of the molecule appears to play its specified role co-operatively to exert the antitumor activity. While the $-aminoalanine-pyrimidine-B-hydroxyhistidine region contributes to the iron chelation and subsequent dioxygen activation, the bithiazole-terminal amine moiety recognizes and binds to DNA, inducing the base sequence specific cleavage of DNA (Figure 1).6 The