Design and Synthesis of Potent Retinoid X Receptor Selective Ligands That Induce Apoptosis in Leukemia Cells
| Autor: | Marcus F. Boehm, Lin Zhang, Lin Zhi, Michael R. McClurg, Elain Berger, Murriel Wagoner, Dale E. Mais, Carla M. Suto, Peter J. A. Davies, Richard A. Heyman, Alex M. Nadzan |
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| Rok vydání: | 1995 |
| Předmět: |
Programmed cell death
Tetrahydronaphthalenes Receptors Retinoic Acid Apoptosis Retinoid X receptor Ligands Binding Competitive Niacin Cell Line Biological pathway Retinoids Structure-Activity Relationship Leukemia Promyelocytic Acute Drug Discovery Tumor Cells Cultured medicine Humans Structure–activity relationship Receptor Bexarotene Transglutaminases Chemistry Nicotinic Acids In vitro Retinoid X Receptors Biochemistry Cell culture Drug Design Molecular Medicine Transcription Factors medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 38:3146-3155 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00016a018 |
| Popis: | Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways. |
| Databáze: | OpenAIRE |
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