title: Efficient synthesis of RITA and its analogues: derivation of analogues with improved antiproliferative activity via modulation of p53/miR-34a pathway.
abstract: A novel approach to synthesize RITA by practical palladium-catalyzed C-C bond-forming Suzuki reactions at room temperature was developed, which was used for deriving a series of substituted tricyclic α-heteroaryl (furan/thiophene) analogues of RITA under mild conditions. These novel analogues showed notable antiproliferative activity against cancer cell lines with wild-type p53 (i.e., HCT116, A549, MCF-7 and K562), but much less activity in HCT116/p53(-/-) cells. In particular, compound 1f demonstrated promising antiproliferative activity compared to RITA, with IC(50) = 28 nM in MCF-7 vs. 54 nM for RITA, and cancer cell selectivity. Compound 1f markedly activated p53 in HCT116 cells at 100 nM, triggering apoptosis. Importantly, we found that both RITA and compound 1f induced G(0)/G(1) cell cycle arrest by up-regulating miR-34a, which in turn down-regulated the expression of cell cycle-related proteins CDK4 and E2F1. In summary, this study reports an effective synthetic approach for RITA and its analogues, and elucidates a novel antiproliferative mechanism of these compounds.
authors.affiliation: Department of Chemistry, Tsinghua University, Beijing 100084, China.
authors.forename: Jinshun
authors.initials: J
authors.lastname: Lin
authors.forename: Xiuli
authors.initials: X
authors.lastname: Jin
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Bu
authors.forename: Deliang
authors.initials: D
authors.lastname: Cao
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhang
authors.forename: Shangfu
authors.initials: S
authors.lastname: Li
authors.forename: Qinsheng
authors.initials: Q
authors.lastname: Sun
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tan
authors.forename: Chunmei
authors.initials: C
authors.lastname: Gao
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis*; D015394:Molecular Structure; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C118989:NSC 652287; D016159:Tumor Suppressor Protein p53