title: Search for novel anti-tumor agents from ridaifens using JFCR39, a panel of human cancer cell lines.
abstract: To overcome the heterogeneous nature of cancer, the search for potent anti-cancer drug candidates with new modes of action is essential. For that purpose, we prepared forty-eight Ridaifens (RIDs), a novel series of tamoxifen-derivatives. Then, we screened them, searching for novel candidates for a new class of anti-cancer drug using a panel of human cancer cell lines (JFCR39) and by a binding assay to estrogen receptor α (ERα). First, the growth inhibition of the forty-eight RIDs against JFCR39 was evaluated. Forty RIDs showed higher growth-inhibitory activity than that of tamoxifen. The structure-activity relationship (SAR) study revealed that the aminoalkoxyphenyl groups at the C-1 position and the common central ethylenic bond were important in retaining a high level of growth-inhibitory activity. Subsequently, the ERα binding activity of all the RIDs was measured by a competitive binding assay. The SAR study for ERα binding activity indicated that both the phenyl group and the ethyl group at the C-2 position in the ethylenic bond were essential. Based on the screenings, we identified RID-SB1 and RID-SB8, which demonstrated potent tumor growth inhibition but had completely lost ERα binding activity. Furthermore, the COMPARE analysis using JFCR39 suggested that RID-SB1 and RID-SB8 had different molecular modes of action compared to those of the current anti-cancer drugs including tamoxifen. These results indicate that RID-SB1 and RID-SB8 are interesting candidates for novel anti-cancer agents with unique modes of action.
authors.affiliation: Division of Molecular pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Wen-zhi
authors.initials: WZ
authors.lastname: Guo
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Wang
authors.forename: Eri
authors.initials: E
authors.lastname: Umeda
authors.forename: Isamu
authors.initials: I
authors.lastname: Shiina
authors.forename: Shingo
authors.initials: S
authors.lastname: Dan
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000378:metabolism; D006801:Humans; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D013629:Tamoxifen