Finch R A, Revankar G R, Chan P K
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
Anticancer Drug Des. 1997 Apr;12(3):205-15.
Toyocamycin is an antitumor antibiotic which has a pyrrolo[2,3-D]pyrimidine aglycone with a -CN substituent on the 5-carbon. Treatment of HeLa cells with toyocamycin induces redistribution of the nuclear phosphoprotein nucleophosmin/B23 (NPM) from nucleoli to nucleoplasm (NPM-translocation) which can be detected by immunofluorescence. NPM-translocation is useful in showing drug effects and in detecting drug-resistant cancer cells. To study which structural features of toyocamycin are important for NPM-translocation, we used toyocamycin analogs in which the 5-position -CN was either deleted (tubercidin) or replaced with a -CONH2 (sangivamycin) or -C(NOH)NH2. HeLa cells were incubated with these analogs for 4 h and assayed for NPM-translocation by immunofluorescence. We found that the analog with the deletion of the -CN group (tubercidin) did not induce translocation while those with replacement of the -CN group with -CONH2 or -C(NOH)NH2 retained the NPM-translocation activity. When these or similar modifications were applied to 7-deazaguanosine, none of the guanosine analogs were effective. These results indicate that modifications at the 5-position of the pyrrolo[2,3-D]pyrimidine ring and a structure similar to adenine rather than guanine are essential for NPM-translocation. Since inhibition of RNA synthesis did not induce NPM-translocation, our results suggest that interference with NPM's binding in nucleoli by these analogs causes NPM-translocation.
丰加霉素是一种抗肿瘤抗生素，其吡咯并[2,3-D]嘧啶苷元在5位碳上带有一个-CN取代基。用丰加霉素处理HeLa细胞会诱导核磷蛋白核仁素/B23（NPM）从核仁重新分布到核质（NPM易位），这可以通过免疫荧光检测到。NPM易位可用于显示药物作用和检测耐药癌细胞。为了研究丰加霉素的哪些结构特征对NPM易位很重要，我们使用了丰加霉素类似物，其中5位的-CN要么被删除（杀结核菌素），要么被-CONH2（桑吉瓦霉素）或-C(NOH)NH2取代。将HeLa细胞与这些类似物孵育4小时，并通过免疫荧光检测NPM易位。我们发现，删除-CN基团的类似物（杀结核菌素）不会诱导易位，而用-CONH2或-C(NOH)NH2取代-CN基团的类似物保留了NPM易位活性。当将这些或类似的修饰应用于7-脱氮鸟苷时，没有一种鸟苷类似物有效。这些结果表明，吡咯并[2,3-D]嘧啶环5位的修饰以及类似于腺嘌呤而非鸟嘌呤的结构对NPM易位至关重要。由于抑制RNA合成不会诱导NPM易位，我们的结果表明，这些类似物对NPM在核仁中结合的干扰导致了NPM易位。
