Synthesis and antitumor activity of novel 6-alkyl-6-demethylmitomycins.
A series of 6-alkyl-6-demethylmitomycins (1-5) was synthesized and evaluated for anticellular and antitumor activities. These novel compounds were prepared by Michael addition of various carbanion species to 6-demethyl-7, 7-(ethylenedioxy)-6, 7-dihydro-6-methylidenemitosane (6 and 9) followed by treatment with NH3 or MeOH/K2CO3. Alkylation at the C-6 position of 6-demethyl-6-selenide (7) was also useful for the alternative synthesis of 6-alkyl-6-demethylmitomycins. The antitumor activity of these derivatives was evaluated, and 6-demethyl-6-ethylmitomycin A (2a) was found to exhibit excellent activity against S-180 solid tumor in mice. The structure-activity relationship is also discussed.
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; D051379:Mice; D008937:Mitomycins / Q000138:chemical synthesis* / Q000494:pharmacology*; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D008937:Mitomycins