Arai H, Kanda Y, Ashizawa T, Morimoto M, Gomi K, Kono M, Kasai M
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Company, Ltd. Shizuoka, Japan.
J Med Chem. 1994 Jun 10;37(12):1805-9. doi: 10.1021/jm00038a009.
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.
合成了一系列6-烷基-6-去甲基丝裂霉素（1-5），并对其细胞毒性和抗肿瘤活性进行了评估。这些新型化合物是通过将各种碳负离子物种与6-去甲基-7,7-（乙二氧基）-6,7-二氢-6-亚甲基丝裂霉素烷（6和9）进行迈克尔加成反应，然后用NH₃或MeOH/K₂CO₃处理而制备的。在6-去甲基-6-硒化物（7）的C-6位进行烷基化反应对于6-烷基-6-去甲基丝裂霉素的另一种合成也很有用。评估了这些衍生物的抗肿瘤活性，发现6-去甲基-6-乙基丝裂霉素A（2a）对小鼠S-180实体瘤具有优异的活性。还讨论了构效关系。
