Orlemans E O, Verboom W, Scheltinga M W, Reinhoudt D N, Lelieveld P, Fiebig H H, Winterhalter B R, Double J A, Bibby M C
Laboratory of Organic Chemistry, University of Twente, Enschede, The Netherlands.
J Med Chem. 1989 Jul;32(7):1612-20. doi: 10.1021/jm00127a035.
Mitosenes of both the pyrrolo- and pyrido[1,2-a]indole type have been prepared via modification of these heterotricyclic compounds. Several mitosenes have been studied for their reactions with nucleophiles under reductive conditions. The results of these experiments show that the biological activity of mitosenes is based on the mechanism of bioreductive activation. When both leaving groups at C-1 and C-10 in the mitosene are the same, the nucleophile preferably adds to C-10 under reductive conditions. All mitosenes were studied for their biological activities in vitro against L1210, WiDr, and A204. On the basis of these results a selection of three mitosenes was made for a more detailed biological evaluation. Several tumor model systems were used, viz. P388, human tumor xenografts, MAC 13, and MAC 16. The results of these studies show that mitosenes have a more limited range of activities than mitomycin C. Surprisingly, the in vivo activities of mitosene diol 8b and mitosene diacetate 10b against the gastric human tumor xenograft GXF 97 were very high and comparable with that of mitomycin C.
通过对这些杂三环化合物进行修饰，已制备出吡咯并[1,2-a]吲哚型和吡啶并[1,2-a]吲哚型的米托蒽醌。已对几种米托蒽醌在还原条件下与亲核试剂的反应进行了研究。这些实验结果表明，米托蒽醌的生物活性基于生物还原激活机制。当米托蒽醌中C-1和C-10处的两个离去基团相同时，亲核试剂在还原条件下优先加成到C-10上。对所有米托蒽醌进行了体外抗L1210、WiDr和A204的生物活性研究。基于这些结果，选择了三种米托蒽醌进行更详细的生物学评价。使用了几种肿瘤模型系统，即P388、人肿瘤异种移植物、MAC 13和MAC 16。这些研究结果表明，米托蒽醌的活性范围比丝裂霉素C更有限。令人惊讶的是，米托蒽醌二醇8b和米托蒽醌二乙酸酯10b对人胃肿瘤异种移植物GXF 97的体内活性非常高，与丝裂霉素C相当。
