Synthesis and SAR of b -Annulated 1,4-Dihydropyridines Define Cardiomyogenic Compounds as Novel Inhibitors of TGFβ Signaling
Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121-2804, United States. Journal of Medicinal Chemistry
(Impact Factor: 5.45).
11/2012; 55(22). DOI: 10.1021/jm301144g
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.
Available from: Gunars Duburs
- "Starting off with esters of specific size and branching we could support the hypothesis that particularly C 3 eC 4 containing esters were most potent (i.e., IC 50 ¼ 0.5e0.7 mM), while groups larger than C 4 were detrimental to biological activity. Similar hints were already obtained in our previous study . To address the question whether a simple increase in lipophilicity and/or enrichment in lipid membranes could contribute to potent TGFb inhibition in a cellular assay setup, long chain ethylene glycol (18) and fatty (lauryl) alcohol (13) linker moieties were evaluated but turned out inactive. "
[Show abstract] [Hide abstract]
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 · 3.45 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Heteroaromatic structures are abundant in bioactive natural products, medicines, and other functional materials. Oxidative aromatization is a common method for preparing heteroaromatic species from simple building blocks. A bioinspired method was developed using robust flavin mimics as organocatalysts that perform O2-fueled oxidations of 1,4-dihydropyridines to pyridines and benzothiazolines to benzothiazoles in high yields (>95%) and purity at ambient temperature in methanol. The efficient oxidative aromatizations facilitated one-pot multicomponent syntheses of pyridines (from various aldehydes, dicarbonyl compounds, and ammonium acetate, in yields ranging from 35 to 95%) and benzothiazoles (from 2-aminothiophenol and various aldehydes, in 78–95% yield) without metals or reactive stoichiometric oxidants. For most substrates, neutral conditions were effective. Hindered 4-substituted dihydropyridines that oxidized slowly were accelerated by selection of more electrophilic flavin catalysts and the addition of various acids in a manner inversely proportional to pKa.
ACS Sustainable Chemistry & Engineering 05/2013; 1(8):1045-1051. DOI:10.1021/sc4001109 · 4.64 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Highly functionalized multi-substituted symmetric and asymmetric 1,4-dihydropyridines were concisely synthesized in moderate to good yields via one-pot multicomponent reactions (MCRs) of β-dicarbonyl compounds, aldehydes and amines at room temperature on montmorillonite. The merits of this method include the environmentally friendly reaction conditions, simple operation, broad substrate, satisfied yields and the reuse of the montmorillonite.
ChemInform 06/2013; 69(25):5242–5247. DOI:10.1016/j.tet.2013.04.006
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.