| Design and synthesis of novel derivatives of all-trans retinoic acid demonstrate the combined importance of acid moiety and conjugated double bonds in its binding to PML-RAR-alpha oncogene in acute promyelocytic leukemia. | |
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MedLine Citation:
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PMID: 20536349 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The binding of all-trans retinoic acid (ATRA) to retinoid receptor-alpha (RAR-alpha) relieves transcriptional repression induced by the promyelocytic leukemia-retinoic acid receptor (PML-RAR) oncoprotein. The ATRA molecule contains a cyclohexenyl ring, a polyene chain containing conjugated double alkene bonds, and a terminal carboxyl group. To determine the contributions of these structural components of ATRA to its clinical efficacy, we synthesized three novel retinoids. These consisted of either a modified conjugated alkene backbone with an intact acid moiety (13a) or a modified conjugated alkene backbone and conversion of the acid group to either an ester (13b) or an aromatic amide (13c). Reporter assays demonstrated that compound 13a successfully relieved transcriptional repression by RAR-alpha, while 13b and 13c could not, demonstrating the critical role of the acid moiety in this binding. However, only ATRA was able to significantly inhibit the proliferation of APL cells while 13a, 13b, or 13c was not. Furthermore, only 13a led to partial non-significant differentiation of NB4 cells, demonstrating the importance of C9-C10 double bonds in differentiation induced CD11 expression. Our results demonstrate that both the acid moiety and conjugated double bonds present in the ATRA molecule are important for its biological activity in APL and have important implications for the design of future novel retinoids. |
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Authors:
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Carolina Schinke; Swati Goel; Tushar D Bhagat; Li Zhou; Yongkai Mo; Robert Gallagher; George W Kabalka; Leonidas C Platanias; Amit Verma; Bhaskar Das |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Leukemia & lymphoma Volume: 51 ISSN: 1029-2403 ISO Abbreviation: Leuk. Lymphoma Publication Date: 2010 Jun |
Date Detail:
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Created Date: 2010-06-11 Completed Date: 2010-09-27 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 9007422 Medline TA: Leuk Lymphoma Country: England |
Other Details:
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Languages: eng Pagination: 1108-14 Citation Subset: IM |
Affiliation:
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Albert Einstein College of Medicine, Bronx, NY, USA. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Antigens, CD11
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analysis Apoptosis / drug effects Cell Differentiation / drug effects Cell Line, Tumor Cell Proliferation / drug effects* Drug Design Flow Cytometry Gene Expression Regulation / drug effects Humans Infant Leukemia, Promyelocytic, Acute / genetics, metabolism, pathology Luciferases / genetics, metabolism Molecular Structure Oncogene Proteins, Fusion / genetics, metabolism* Recombinant Fusion Proteins / genetics, metabolism Response Elements / genetics Transfection Tretinoin / chemical synthesis, metabolism, pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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1R01HL082946-01/HL/NHLBI NIH HHS; CA121192/CA/NCI NIH HHS; R01 CA121192-03/CA/NCI NIH HHS; R01 CA121192-04/CA/NCI NIH HHS; R01 HL082946-04/HL/NHLBI NIH HHS; T32 CA009173/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antigens, CD11; 0/Oncogene Proteins, Fusion; 0/Recombinant Fusion Proteins; 0/promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; 302-79-4/Tretinoin; EC 1.13.12.-/Luciferases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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