Synthesis and SAR of b-Annulated 1,4-Dihydropyridines Define Cardiomyogenic Compounds as Novel Inhibitors of TGFβ Signaling.
ABSTRACT A medium-throughput murine embryonic stem cell (mESC)-based high-content screening of 17000 small molecules for cardiogenesis led to the identification of a b-annulated 1,4-dihydropyridine (1,4-DHP) that inhibited transforming growth factor β (TGFβ)/Smad signaling by clearing the type II TGFβ receptor from the cell surface. Because this is an unprecedented mechanism of action, we explored the series' structure-activity relationship (SAR) based on TGFβ inhibition, and evaluated SAR aspects for cell-surface clearance of TGFβ receptor II (TGFBR2) and for biological activity in mESCs. We determined a pharmacophore and generated 1,4-DHPs with IC(50)s for TGFβ inhibition in the nanomolar range (e.g., compound 28, 170 nM). Stereochemical consequences of a chiral center at the 4-position was evaluated, revealing 10- to 15-fold more potent TGFβ inhibition for the (+)- than the (-) enantiomer. This stereopreference was not observed for the low level inhibition against Activin A signaling and was reversed for effects on calcium handling in HL-1 cells.
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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. Copyright © 2015 Elsevier Masson SAS. All rights reserved.European Journal of Medicinal Chemistry 03/2015; 95:249-266. DOI:10.1016/j.ejmech.2015.03.027 · 3.43 Impact Factor
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ABSTRACT: We report the first oxidative condensation between N,N-dimethylenaminones with amines to form 1,4-dihydropyridines in moderate to good yields, promoted by oxone and trifluoroacetic acid in PEG-400. This reaction features an unusual oxidation of in situ formed dimethylamine to efficiently provide the 4-methylene of 1,4-dihydropyridines, and a highly environment-friendly reaction condition.Tetrahedron Letters 02/2015; 56(6). DOI:10.1016/j.tetlet.2014.12.118 · 2.39 Impact Factor
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ABSTRACT: Different types of multicomponent reactions (MCRs) are reported using Bi2O3, BiVO4, and Bi2WO6 (nanoparticle) as heterogeneous catalysts. Among these, Bi2WO6 nano particles showed excellent reactivity for the synthesis of functionalized dihydropyridine, polyhydroquinoline, 4H-chromene and 2-amino-4H-benzo[b]pyran derivatives at ambient temperature in aqueous medium. All the reactions gave good to excellent yields in 10-45 minutes in the presence of 5 mol% (optimized) of the catalyst. The catalyst was regenerated and reused up to 5 cycles without losing catalytic activity. The gram scale synthesis of dihydropyridine gave the desired product in 82 % yield in 2 h.RSC Advances 10/2014; 4(97). DOI:10.1039/C4RA07708C · 3.71 Impact Factor