Design, synthesis and 3D-QSAR studies of novel 1,4-dihydropyridines as TGFβ/Smad inhibitors
| Autor: | Viktoria Marquardt, Gunars Duburs, Christopher Golz, Dirk Flötgen, Daniel Längle, Oliver Koch, Carsten Strohmann, Iveta Luntena, Elena Heider, Brigita Vigante, Dennis Schade |
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| Rok vydání: | 2015 |
| Předmět: |
Pharmacology
Models Molecular Quantitative structure–activity relationship Dihydropyridines Ligand Chemistry Protein Conformation Organic Chemistry Absolute configuration Quantitative Structure-Activity Relationship DHPS Smad Proteins General Medicine Computational biology SMAD Chemistry Techniques Synthetic HEK293 Cells Biochemistry Design synthesis Transforming Growth Factor beta Drug Design Drug Discovery Lipophilicity Humans Mode of action |
| Zdroj: | European journal of medicinal chemistry. 95 |
| ISSN: | 1768-3254 |
| Popis: | Targeting TGFβ/Smad signaling is an attractive strategy for several therapeutic applications given its role as a key player in many pathologies, including cancer, autoimmune diseases and fibrosis. The class of b-annelated 1,4-dihydropyridines (DHPs) represents promising novel pharmacological tools as they interfere with this pathway in a novel fashion, i.e. through induction of TGFβ receptor type II degradation. In the present work, >40 rationally designed, novel DHPs were synthesized and evaluated for TGFβ inhibition, substantially expanding the current understanding of the SAR profile. Key findings include that the 2-position tolerates a wide variety of polar functionalities, suggesting that this region could possibly be solvent-exposed within the (thus far) unknown cellular target. A structural explanation for pathway selectivity is provided based on a diverse series of 4″-substituted DHPs, including molecular electrostatic potential (MEP) calculations. Moreover, the absolute configuration for the chiral 4-position was determined by X-ray crystal analysis and revealed that the bioactive (+)-enantiomers are (R)-configured. Another key objective was to establish a 3D-QSAR model which turned out to be robust (r2 = 0.93) with a good predictive power (r2pred = 0.69). This data further reinforces the hypothesis that this type of DHPs exerts its novel TGFβ inhibitory mode of action through binding a distinct target and that unspecific activities that would derive from intrinsic properties of the ligands (e.g., lipophilicity) play a negligible role. Therefore, the present study provides a solid basis for further ligand-based design of additional analogs or DHP scaffold-derived compounds for hit-to-lead optimization, required for more comprehensive pharmacological studies in vivo. |
| Databáze: | OpenAIRE |
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