Curcuminoids Block TGF-b Sibnaling in HBC

Effects of curcuminoids on breast cancer cell secretion of the bone-resorptive peptide parathyroid hormone-related protein (PTHrP) and on lytic breast cancer bone metastasis were evaluated.

 

 

In vitro, transforming growth factor (TGF)-β-stimulated PTHrP secretion was inhibited by curcuminoids (IC₅₀ = 24 μM) in MDA-MB-231 human breast cancer cells independent of effects on cell growth inhibition.


Effects on TGF-β signaling revealed decreases in phospho-Smad2/3 and Ets-1 protein levels with no effect on p-38 MAPK-mediated TGF-β signaling.


 In vivo, mice were inoculated with MDA-MB-231 cells into the left cardiac ventricle and treated ip every other day with curcuminoids (25 or 50 mg/kg) for 21 days.


Osteolytic bone lesion area was reduced up to 51% (p < 0.01).


Consistent with specific effects on bone osteolysis, osteoclast number at the bone–tumor interface was reduced up to 53% (p < 0.05), while tumor area within bone was unaltered.


 In a separate study, tumor mass in orthotopic mammary xenografts was also unaltered by treatment.


These data suggest that curcuminoids prevent TGF-β induction of PTHrP and reduce osteolytic bone destruction by blockade of Smad signaling in breast cancer cells.

 

 

Cancer Drug Clinical Candidate Tipifarnib for Anti-Chagas Disease Drug Discovery

We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14α-demethylase.


Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and display increased potency for killing parasites.


This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe.


Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14α-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4).


Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogues are ideal leads for the development of drugs to treat Chagas disease.


 

N-Heteroarylation of Chiral α-Aminoesters by Means of Palladium-Catalyzed Buchwald–Hartwig Reaction

N-Heteroaryl-α-amino acid derivatives are valuable pharmacological agents as peptidomimetics.

 

 

Classical S_NAr methods using acid catalysis and elevated temperatures could not be extended to various α-amino acids and fairly electrophilic heterocyclic partners.

 

 

Here, we report a mild and versatile method of N-heteroarylation of chiral α-aminoesters without racemization, involving Buchwald–Hartwig conditions.

 

 

It could be extended to various α-amino acids and azines.

 

This efficient N-heteroarylation leads to (i) a chemical library of putative peptidomimetics combining diverse azaheterocycles with the chiral α-aminoesters and their corresponding derivatives (amides, alcohols, etc.) and (ii) arginine derivatives designed as NPFF receptor ligands.

http://pubs.acs.org/doi/pdfplus/10.1021/jo4011427

Setileuton, a Potent and Selective 5-Lipoxygenase Inhibitor

Versatile One-Pot Route to 2-Quinoline-3-carboxamides

Novel Inhibitors of TGF Signaling

 

 

Annulated 1,4-Dihydropyridines Cardiomyogenic Compounds

as Novel Inhibitors of TGFβ Signaling

 

 

 

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 IC₅₀s 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.

 

 

 

 

http://pubs.acs.org/doi/abs/10.1021/jm301144g?prevSearch=TGF%25CE%25B2%2BInhibitor&searchHistoryKey=

 

 

 

 

 

Cyanine Dye N744 Inhibits Tau Fibrillization

Cyanine Dye N744 Inhibits Tau Fibrillization by Blocking Filament Extension:  Implications for the Treatment of Tauopathic Neurodegenerative Diseases