Document Detail

Efficient synthesis of RITA and its analogues: derivation of analogues with improved antiproliferative activity via modulation of p53/miR-34a pathway.
MedLine Citation:
PMID:  23151607     Owner:  NLM     Status:  Publisher    
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 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 markedly activated p53 in HCT116 cells at 100 nM, triggering apoptosis. Importantly, we found that both RITA and compound 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.
Jinshun Lin; Xiuli Jin; Yiwen Bu; Deliang Cao; Nannan Zhang; Shangfu Li; Qinsheng Sun; Chunyan Tan; Chunmei Gao; Yuyang Jiang
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-15
Journal Detail:
Title:  Organic & biomolecular chemistry     Volume:  -     ISSN:  1477-0539     ISO Abbreviation:  Org. Biomol. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101154995     Medline TA:  Org Biomol Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Chemistry, Tsinghua University, Beijing 100084, China.
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