ANTICANCER SPECIFICITY OF SOME ELLIPTICINIUM SALTS AGAINST HUMAN BRAIN-TUMORS IN-VITRO
ANTICANCER SPECIFICITY OF SOME ELLIPTICINIUM SALTS AGAINST HUMAN BRAIN-TUMORS IN-VITRO
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DOI：
10.1021/jm00040a010
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发表时间：
1994-07-08
影响因子：
7.3
通讯作者：
BOYD, MR
中科院分区：
文献类型：
--
作者：
ACTON, EM;NARAYANAN, VL;BOYD, MR
新的结构活性关系（SAR）不同的已知SAR椭圆形的椭圆形已被揭示某些椭圆形盐。特别地，发现椭圆藻鎓如原型9-甲氧基-2-甲基椭圆藻鎓（I-或0Ac-）优先对NCI 60细胞系筛选组的脑肿瘤细胞系亚组具有细胞毒性。对于9-未取代的椭圆形鎓或带有9-甲基或9-氯取代基的其它椭圆形鎓，类似的特异性也是明显的。相比之下，9-羟基取代的椭圆树碱以及所有测试的非季铵化椭圆树碱缺乏脑肿瘤特异性。因此，似乎没有这种不寻常的偏好与氧化还原循环机制的相对可用性相关，因为氧化还原循环可能在9-甲基-和9-chloroellipticinium中被阻断。事实上，相关的研究表明，脑肿瘤的特异性介导的优先摄取和细胞内积累的特定的椭圆。本研究进一步支持NCI体外“疾病导向”的初步筛选可以促进发现新的，选择性细胞毒性的体内和机制研究的线索。
Novel structure-activity relationships (SAR) distinct from known SAR for ellipticines have been revealed for certain ellipticinium salts. In particular, ellipticiniums such as the prototypical 9-methoxy-2-methylellipticinium (I- or OAc-) were found to be preferentially cytotoxic to the brain tumor cell line subpanel of the NCI 60 cell-line screening panel. Similar specificity also was apparent with 9-unsubstituted ellipticiniums, or others bearing 9-methyl or 9-chloro substituents. In contrast, 9-hydroxy-substituted ellipticiniums, as well as all nonquaternized ellipticines tested, were devoid of brain tumor specificity. Therefore, it did not appear that this unusual preference was correlated with the relative availability of redox cycling mechanisms, since redox cycling presumably is blocked in 9-methyl- and 9-chloroellipticiniums. Indeed, related investigations have indicated that the brain tumor specificity is mediated by preferential uptake and intracellular accumulation of the specific ellipticiniums. The present study further supports that the NCI in vitro ''disease-oriented'' primary screen can facilitate the discovery of novel, selectively cytotoxic leads for in vivo and mechanistic investigations.