title: Design, synthesis and 3D-QSAR studies of novel 1,4-dihydropyridines as TGFβ/Smad inhibitors.
abstract: 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 (r(2) = 0.93) with a good predictive power (r(2)pred = 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.
authors.affiliation: TU Dortmund University, Department of Chemistry & Chemical Biology, Otto-Hahn-Str. 6, 44227 Dortmund, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Längle
authors.affiliation: TU Dortmund University, Department of Chemistry & Chemical Biology, Otto-Hahn-Str. 6, 44227 Dortmund, Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Marquardt
authors.affiliation: TU Dortmund University, Department of Chemistry & Chemical Biology, Otto-Hahn-Str. 6, 44227 Dortmund, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Heider
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Brigita
authors.initials: B
authors.lastname: Vigante
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Gunars
authors.initials: G
authors.lastname: Duburs
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia.
authors.forename: Iveta
authors.initials: I
authors.lastname: Luntena
authors.affiliation: TU Dortmund University, Department of Chemistry & Chemical Biology, Otto-Hahn-Str. 6, 44227 Dortmund, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Flötgen
authors.affiliation: TU Dortmund University, Department of Chemistry & Chemical Biology, Otto-Hahn-Str. 6, 44227 Dortmund, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Golz
authors.affiliation: TU Dortmund University, Department of Chemistry & Chemical Biology, Otto-Hahn-Str. 6, 44227 Dortmund, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Strohmann
authors.affiliation: TU Dortmund University, Department of Chemistry & Chemical Biology, Otto-Hahn-Str. 6, 44227 Dortmund, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Koch
authors.affiliation: TU Dortmund University, Department of Chemistry & Chemical Biology, Otto-Hahn-Str. 6, 44227 Dortmund, Germany. Electronic address: dennis.schade@tu-dortmund.de.
authors.forename: Dennis
authors.initials: D
authors.lastname: Schade
mesh_terms: D060326:Chemistry Techniques, Synthetic; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D051785:Smad Proteins / Q000037:antagonists & inhibitors*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004095:Dihydropyridines; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C038806:1,4-dihydropyridine
keywords: 3D-QSAR model; Absolute configuration; Crystal structure; Molecular electrostatic potential (MEP); Structure–activity relationships (SARs); Transforming growth factor β (TGFβ); b-Anellated 1,4-dihydropyridines (1,4-DHPs)