Sami S M, Dorr R T, Alberts D S, Remers W A
Department of Pharmaceutical Sciences and Cancer Center, University of Arizona, Tucson 85721.
J Med Chem. 1993 Mar 19;36(6):765-70. doi: 10.1021/jm00058a014.
A new class of antitumor agents, having structural analogy to amonafide, but differing by the addition of a fourth ring in the nucleus, was synthesized conveniently from anthracene. Compounds with a variety of substituents, containing a basic nitrogen atom and located on the imide nitrogen, were prepared. Thirteen of 19 new compounds had greater growth inhibitory potency than amonafide in a panel of cultured murine and human tumor cells using the sulforhodamine B and MTT dye assays. The most active agents were similarly more toxic than amonafide to normal neonatal rat myocytes in vitro, but they had better chemotherapeutic indexes. From these compounds, the one with a 2-(dimethylamino)ethyl side chain (named azonafide) was chosen for further study. It showed high potency against a panel of cultured human colon cancer cells and it was active against ip P388 leukemia and subcutaneous B16 melanoma in mice. Preliminary structure-activity correlations suggest that the basicity of the side-chain nitrogen and the length of side chain are important determinants of antitumor potency in vitro. Steric hindrance and rigidity of the side chains might be other determinants.
合成了一类新型抗肿瘤药物，它们与氨苯吖啶结构类似，但核中多了一个环，可由蒽方便地合成。制备了一系列具有不同取代基的化合物，这些取代基含有碱性氮原子且位于酰亚胺氮上。在一组培养的小鼠和人肿瘤细胞中，使用磺酰罗丹明B和MTT染料测定法，19种新化合物中有13种比氨苯吖啶具有更强的生长抑制效力。活性最强的药物在体外对正常新生大鼠心肌细胞的毒性同样比氨苯吖啶大，但它们具有更好的化疗指数。从这些化合物中，选择了具有2-(二甲氨基)乙基侧链的化合物（命名为偶氮吖啶）进行进一步研究。它对一组培养的人结肠癌细胞显示出高效力，并且对小鼠体内的腹腔注射P388白血病和皮下B16黑色素瘤具有活性。初步的构效关系表明，侧链氮的碱性和侧链长度是体外抗肿瘤效力的重要决定因素。侧链的空间位阻和刚性可能是其他决定因素。
