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Synthesis and biological activity of novel mitomycin C analogs derived from mitomycin A
Author(s) -
Kuroda Tokuyuki,
Hisamura Koji,
Matsukuma Ikuo,
Osawa Yutaka,
Sugaya Toru,
Nishikawa Hiroshi,
Morimoto Makoto,
Ashizawa Tadashi,
Nakamizo Nobuhiro,
Otsuji Yoshio
Publication year - 1994
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570310120
Subject(s) - chemistry , nucleophile , mitomycin c , stereochemistry , biological activity , hydroxylamine , alkylation , in vitro , intramolecular force , in vivo , medicinal chemistry , organic chemistry , biochemistry , catalysis , microbiology and biotechnology , biology , medicine , surgery
A variety of mitomycin C analogs were synthesized from mitomycin A and their biological activities were studied. Mitomycin A ( 1 ) underwent nucleophilic displacement reactions involving intramolecular hydrogen migrations upon treatment with nitrogen nucleophiles bearing mobile hydrogens, but the mode of hydrogen migration depended on the nature of the nucleophiles. The reaction with alkoxyamines gave compounds 6 and 7 which have the 5 H ‐6‐alkoxyimino‐4,7‐dione structure in ring A of 1 . However, the reaction with hydroxylamine and benzoylhydrazine afforded compounds 11 and 13 which have the 4‐hydroxy‐6‐hydroxyimino‐7‐one structure and the 4‐hydroxy‐6‐hydrazono‐7‐one structure, respectively, in ring A of 1 . These products were converted into various types of mitomycin C derivatives by methylation with methyl iodide or dimethyl sulfate. The mechanistic features of these reactions are discussed. The in vitro and in vivo biological activities were tested by using P388 leukemia and Sarcoma 180 tumor cells. Several of the synthesized compounds exhibited better activity than that of mitomycin C.