Design and stereoselective synthesis of retinoids with ferrocene or N-butylcarbazole pharmacophores that induce post-differentiation apoptosis in acute promyelocytic leukemia cells.

Abstract

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.

• Authors: Diana Ivanova, Hinrich Gronemeyer, Angel R de Lera
• Journal: ChemMedChem (ChemMedChem) Vol. 6 Issue 8 Pg. 1518-29 (Aug 01 2011) ISSN: 1860-7187 [Electronic] Germany
• PMID: 21506276 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• 3,7-dimethyl-9-ferrocenylnona-2,4,6,8-tetraenoic acid
• Antineoplastic Agents
• Benzoates
• Carbazoles
• Fatty Acids, Unsaturated
• Ferrous Compounds
• Metallocenes
• RARA protein, human
• Receptors, Retinoic Acid
• Retinoic Acid Receptor alpha
• Retinoids
• p-(2-(N-butylcarbazol-3'-yl)ethen-1-yl)benzoic acid
• p-(4-ferrocenylbuta-1,3-dien-1-yl)benzoic acid
• carbazole
• Caspase 3
• Caspase 8
• Caspase 9
• ferrocene

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Benzoates (chemical synthesis, pharmacology, therapeutic use)
• Carbazoles (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Caspase 9 (metabolism)
• Cell Differentiation
• Cell Line, Tumor
• Drug Design
• Fatty Acids, Unsaturated (chemical synthesis, pharmacology, therapeutic use)
• Ferrous Compounds (chemical synthesis, chemistry, pharmacology, therapeutic use)
• Humans
• Leukemia, Promyelocytic, Acute (drug therapy)
• Metallocenes
• Receptors, Retinoic Acid (agonists, metabolism)
• Retinoic Acid Receptor alpha
• Retinoids (chemistry, pharmacology, therapeutic use)
• Stereoisomerism
• Structure-Activity Relationship