Kim J Y, Su T L, Chou T C, Koehler B, Scarborough A, Ouerfelli O, Watanabe K A
Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division of Graduate School of Medical Sciences, Cornell University, New York, New York 10021, USA.
J Med Chem. 1996 Jul 5;39(14):2812-8. doi: 10.1021/jm950881y.
A series of mitomycin C (MMC) analogues, namely cyclopentanthraquinone derivatives, were synthesized via Diels-Alder cyclization of naphthoquinone with 1-vinylcyclopent-1-enes. These new compounds are planar structures, like MMC, and bear an aziridine ring and a methyl carbamate side chain. After bioreduction, they are anticipated to be capable of intercalating into double-stranded DNA and bind covalently. Structure-activity relationships were studied. Of these compounds, 2,3-aziridino-4-[[(methylamino)carbonyl]methyl] cyclopent[alpha]anthracene-6,11-dione (4) was shown to have inhibitory activity against several leukemic and solid tumor cell lines. Mice (BDF1) bearing Lewis lung adenocarcinoma were treated with 4 and MMC (i.p., QD x 5). At a dose of 30.0 mg/kg, compound 4 was as effective as MMC (0.8 mg/kg). Compound 4 appears to be less toxic than MMC. DNA unwinding assay indicated that 4 is able to intercalate into DNA double strands and is also a topoisomerase II inhibitor.
通过萘醌与1-乙烯基环戊-1-烯的狄尔斯-阿尔德环化反应合成了一系列丝裂霉素C（MMC）类似物，即环戊蒽醌衍生物。这些新化合物与MMC一样是平面结构，带有氮丙啶环和甲基氨基甲酸酯侧链。经生物还原后，预计它们能够嵌入双链DNA并共价结合。对其构效关系进行了研究。在这些化合物中，2,3-氮丙啶基-4-[[(甲氨基)羰基]甲基]环戊[α]蒽-6,11-二酮（4）对几种白血病和实体瘤细胞系具有抑制活性。用4和MMC（腹腔注射，每日1次，共5次）处理携带Lewis肺癌的小鼠（BDF1）。在30.0 mg/kg的剂量下，化合物4与MMC（0.8 mg/kg）的效果相同。化合物4的毒性似乎比MMC小。DNA解旋试验表明，4能够嵌入DNA双链，并且还是一种拓扑异构酶II抑制剂。
