| Design and Stereoselective Synthesis of Retinoids with Ferrocene or N-Butylcarbazole Pharmacophores that Induce Post-Differentiation Apoptosis in Acute Promyelocytic Leukemia Cells. | |
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MedLine Citation:
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PMID: 21506276 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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New ferrocene and N-alkylcarbazole retinoids were designed and synthesized stereoselectively in good yields. A number of these synthesized ligands, in particular 2, 3, and 11, were found to exhibit a high RARα activation potential and to effectively induce post-differentiation apoptosis in NB4 acute promyelocytic leukemia (APL) cells. Increasing the length of the side chain attached to the heterocycle of the carbazole arotinoids creates new opportunities for altered compound catabolism and for fine-tuning of the apoptosis-inducing potential of the ligand. In the carbazole series of new retinoids, maximal activity was established for N-butylcarbazole analogue 11 in all assays (i.e., RARα activation, differentiation induction, and apoptosis induction). Study of the mechanism of apoptosis revealed an activation of initiator caspases-8 and -9, followed by efficient cleavage of effector caspase-3 on day 6 of treatment. Subsequent induction of a caspase cascade in NB4 cells triggered ultimate leukemic cell death. The selected ligands 2, 3, and 11 may provide alternate options for the treatment of APL in cases of life-threatening ATRA syndrome, resistance, and high toxicity to conventionally used retinoids. |
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Authors:
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Diana Ivanova; Hinrich Gronemeyer |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-19 |
Journal Detail:
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Title: ChemMedChem Volume: - ISSN: 1860-7187 ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-4-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101259013 Medline TA: ChemMedChem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
Affiliation:
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ChimOrbel Ltd., 83 blvd. Nicola Petkov, 1614 Sofia (Bulgaria), Fax: (+359) 2 957 86 58. dianadoc@abv.bg. |
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