Rowlands M G, Budworth J, Jarman M, Hardcastle I R, McCague R, Gescher A
Cancer Research Campaign Centre for Cancer Therapeutics, Institute of Cancer Research, CRC Laboratory, Belmont, Sutton, Surrey, U.K.
Biochem Pharmacol. 1995 Aug 25;50(5):723-6. doi: 10.1016/0006-2952(95)00186-4.
A variety of analogues of tamoxifen were tested for inhibition of protein kinase C (PKC) activity in MCF-7 breast cancer cells. These results were compared with the calmodulin antagonism exhibited by the analogues as measured by inhibition of calmodulin-dependent cyclic AMP phosphodiesterase. The same structural features that enhanced PKC inhibition also led to an increase in calmodulin antagonism, namely 4-iodination and elongation of the basic side-chain. The most potent analogue has a 4-iodine substituent and eight carbon atoms in its basic side-chain with IC50 values of 38 microM for PKC inhibition and 0.3 microM for calmodulin antagonism, which compares with 92 and 6.8 microM, respectively, for tamoxifen. Some selectivity was achieved with a ring-fused analogue that retained the potency of tamoxifen as a PKC inhibitor, but lacked calmodulin antagonism.
测试了多种他莫昔芬类似物对MCF - 7乳腺癌细胞中蛋白激酶C（PKC）活性的抑制作用。将这些结果与通过抑制钙调蛋白依赖性环磷酸腺苷磷酸二酯酶测定的类似物所表现出的钙调蛋白拮抗作用进行比较。增强PKC抑制作用的相同结构特征也导致钙调蛋白拮抗作用增加，即4 - 碘化作用和碱性侧链的延长。最有效的类似物在其碱性侧链上有一个4 - 碘取代基和八个碳原子，PKC抑制的IC50值为38 microM，钙调蛋白拮抗的IC50值为0.3 microM，相比之下，他莫昔芬的这两个值分别为92 microM和6.8 microM。通过一种稠环类似物实现了一定的选择性，该类似物保留了他莫昔芬作为PKC抑制剂的效力，但缺乏钙调蛋白拮抗作用。
