Synthesis and antitumor activity of novel mitomycin derivatives containing functional groups at the C-6-methyl position.
A series of C-6-substituted methyl mitomycins was synthesized and evaluated for anticellular and antitumor activities. These novel compounds were prepared by Michael addition of various alcohols or thiols to 6-demethyl-7,7-(ethylenedioxy)-6,7-dihydro-6-methylidenemitosanes followed by treatment with NH3 or MeOH/K2CO3. Most compounds were potent against HeLa S3, and some of them showed superior activity to that of mitomycin C (MMC) against P388 leukemia and sarcoma 180 in mice. In addition, some compounds exhibited remarkable activity against MMC-resistant P388 in mice. FAB-MS spectra of these mitomycin derivatives showed the elimination of the C-6-methyl substituents from the mitomycin skeletons to form quinonemethides. Interestingly, treatment of 6-demethyl-6-[[(2-pyrimidinyl)thio]methyl ]mitomycin C (12v) with diethylamine afforded 6-demethyl-6-[(diethylamino)methyl]mitomycin C (31) in good yield. These results suggested that the C-6-substituted methyl mitomycins would have different biological character from that of MMC.
Arai
H
H
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company, Ltd. Shizuoka, Japan.
Kanda
Y
Y
Ashizawa
T
T
Morimoto
M
M
Gomi
K
K
Kono
M
M
Kasai
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D008937:Mitomycins / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000473:pathology; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008937:Mitomycins