title: Structural and functional relationships of toyocamycin on NPM-translocation.
abstract: 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.
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Finch
authors.forename: G R
authors.initials: GR
authors.lastname: Revankar
authors.forename: P K
authors.initials: PK
authors.lastname: Chan
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001692:Biological Transport; D006367:HeLa Cells; D006801:Humans; D013329:Structure-Activity Relationship; D014127:Toyocamycin / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D014127:Toyocamycin