Semi-synthetic ecdysteroids as gene-switch actuators: synthesis, structure-activity relationships, and prospective ADME properties
| Autor: | Jianzhong Liu, Silvia Lapenna, Anton J. Hopfinger, Laurence Dinan, Jennifer L. Friz, Robert E. Hormann |
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| Rok vydání: | 2008 |
| Předmět: |
Receptors
Steroid animal structures Stereochemistry Gene Expression Biology Biochemistry chemistry.chemical_compound Mice Structure-Activity Relationship In vivo Drug Discovery Gene expression Structure–activity relationship Animals Humans General Pharmacology Toxicology and Pharmaceutics Receptor Cells Cultured ADME Pharmacology Ecdysteroid fungi Organic Chemistry Ecdysteroids Metabolism 3T3 Cells biology.organism_classification Drosophila melanogaster chemistry Drug Design Molecular Medicine Caco-2 Cells hormones hormone substitutes and hormone antagonists |
| Zdroj: | ChemMedChem. 4(1) |
| ISSN: | 1860-7187 |
| Popis: | The ligand-inducible, ecdysteroid receptor (EcR) gene-expression system can add critical control features to protein expression in cell and gene therapy. However, potent natural ecdysteroids possess absorption, distribution, metabolism and excretion (ADME) properties that have not been optimised for use as gene-switch actuators in vivo. Herein we report the first systematic synthetic exploration of ecdysteroids toward modulation of gene-switch potency. Twenty-three semi-synthetic O-alkyl ecdysteroids were assayed in both a natural insect system (Drosophila B(II) cells) and engineered gene-switch systems in mammalian cells using Drosophila melanogaster, Choristoneura fumiferana, and Aedes aegypti EcRs. Gene-switch potency is maintained, or even enhanced, for ecdysteroids methylated at the 22-position in favourable cases. Furthermore, trends toward lower solubility, higher permeability, and higher blood-brain barrier penetration are supported by predicted ADME properties, calculated using the membrane-interaction (MI)-QSAR methodology. The structure-activity relationship (SAR) of alkylated ecdysteroids indicates that 22-OH is an H-bond acceptor, 25-OH is most likely an H-bond donor, and 2-OH and 3-OH are donors and/or acceptors in network with each other, and with the EcR. The strategy of alkylation points the way to improved ecdysteroidal actuators for switch-activated gene therapy. |
| Databáze: | OpenAIRE |
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