- An SAR study of hydroxy-trifluoromethylpyrazolines as inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader assay
-
The proteins Orai1 and STIM1 control store-operated Ca2+ entry (SOCE) into cells. SOCE is important for migration, invasion and metastasis of MDA-MB-231 human triple negative breast cancer (TNBC) cells and has been proposed as a target for cancer drug discovery. Two hit compounds from a medium throughput screen, displayed encouraging inhibition of SOCE in MDA-MB-231 cells, as measured by a Fluorescence Imaging Plate Reader (FLIPR) Ca2+ assay. Following NMR spectroscopic analysis of these hits and reassignment of their structures as 5-hydroxy-5-trifluoromethylpyrazolines, a series of analogues was prepared via thermal condensation reactions between substituted acylhydrazones and trifluoromethyl 1,3-dicarbonyl arenes. Structure-activity relationship (SAR) studies showed that small lipophilic substituents at the 2- and 3-positions of the RHS and 2-, 3- and 4-postions of the LHS terminal benzene rings improved activity, resulting in a novel class of potent and selective inhibitors of SOCE.
- Stevenson, Ralph J.,Azimi, Iman,Flanagan, Jack U.,Inserra, Marco,Vetter, Irina,Monteith, Gregory R.,Denny, William A.
-
p. 3406 - 3413
(2018/05/24)
-
- One-pot synthesis of difluoromethyl ketones by a difluorination/fragmentation process
-
Difluoromethyl ketones are an under-studied class of ketones which have great potential as useful building blocks for materials and drug design. Here we report a simple and convenient synthesis of this class of compounds via a one-pot difluorination/fragm
- Leng, Daniel J.,Black, Conor M.,Pattison, Graham
-
supporting information
p. 1531 - 1535
(2016/02/10)
-
- Pyrazolo[1,5a]pyrimidines as a new class of FUSE binding protein 1 (FUBP1) inhibitors
-
The transcriptional regulator FUSE binding protein 1 (FUBP1) is aberrantly upregulated in various malignancies, fulfilling its oncogenic role by the deregulation of critical genes involved in cell cycle control and apoptosis regulation. Thus, the pharmaceutical inhibition of this protein would represent an encouraging novel targeted chemotherapy. Here, we demonstrate the identification and initial optimization of a pyrazolo[1,5a]pyrimidine-based FUBP1 inhibitor derived from medium throughput screening, which interferes with the binding of FUBP1 to its single stranded target DNA FUSE. We were able to generate a new class of FUBP1 interfering molecules with in vitro and biological activity. In biophysical assays, we could show that our best inhibitor, compound 6, potently inhibits the binding of FUBP1 to the FUSE sequence with an IC50value of 11.0 μM. Furthermore, hepatocellular carcinoma cells exhibited sensitivity towards the treatment with compound 6, resulting in reduced cell expansion and induction of cell death. Finally, we provide insights into the corresponding SAR landscape, leading to a prospective enhancement in potency and cellular efficacy.
- Hauck, Stefanie,Hiesinger, Kerstin,Khageh Hosseini, Sabrina,Achenbach, Janosch,Biondi, Ricardo M.,Proschak, Ewgenij,Z?rnig, Martin,Odadzic, Dalibor
-
p. 5717 - 5729
(2016/11/09)
-
- Substituted pyrazoles as novel sEH antagonist: Investigation of key binding interactions within the catalytic domain
-
A novel series of pyrazole sEH inhibitors is reported. Lead optimization efforts to replace the aniline core are also described. In particular, 2-pyridine, 3-pyridine and pyridazine analogs are potent sEH inhibitors with favorable CYP3A4 inhibitory and microsomal stability profiles.
- Lo, Ho Yin,Man, Chuk C.,Fleck, Roman W.,Farrow, Neil A.,Ingraham, Richard H.,Kukulka, Alison,Proudfoot, John R.,Betageri, Raj,Kirrane, Tom,Patel, Usha,Sharma, Rajiv,Hoermann, Mary Ann,Kabcenell, Alisa,Lombaert, Stéphane De
-
scheme or table
p. 6379 - 6383
(2010/12/19)
-
- Interactions of aroyl- and heteroaroyltrifluoroacetones with thiobenzoylhydrazine
-
The interaction of aroyl(heteroaroyl)trifluoroacetones with thiobenzoylhydrazine may occur at both carbonyl groups. Reaction at the trifluoroacetyl group is facilitated by terminal substituents in the 1,3-dicarbonyl part, which leads can effectively conjugate with the adjacent carbonyl group. The products of condensation at the trifluoroacetyl group are 2-[2-aryl(heteroaroyl)-2-oxoethyl]-5-phenyl-2-trifluoromethyl-2,3-dihydro-1,3, 4-thiadiazoles, while condensation at the aroyl(heteroaroyl)group gave 3-aryl(heteroaryl)-5-hydroxy-1-thiobenzoyl-5-trifluoromethyl-4, 5-dihydro-1H-pyrazoles, which are not prone to tautomeric transformations in solution. 2008 Springer Science+Business Media, Inc.
- Pakalnis,Zerova,Yakimovitch,Alekseyev
-
p. 606 - 614
(2013/07/25)
-
- SUBSTITUTED PYRAZOLE COMPOUNDS USEFUL AS SOLUBLE EPOXIDE HYDROLASE INHIBITORS
-
Disclosed are compounds active against soluble epoxide hydrolase (sEH), compositions thereof and methods of using and making same.
- -
-
Page/Page column 81-82
(2008/06/13)
-
- Reaction of aroyl- and hetaroyltrifluoroacetones with acylhydrazines: Regioselectivity and tautomerism of the condensation products
-
Acylhydrazines react with 1,3-diketones of the general formula CF 3COCH2COR (where R is an aryl or hetaryl group) at both carbonyl groups. The reaction at the trifluoroacetyl group is favored by donor substituents in the aromatic ring of the 1,3-diketone or by the 2-furyl and, especially, 2-thienyl group as a hetaryl substituent, as well as by elevated temperature. The condensation products at the carbonyl group contiguous to the aryl or hetaryl ring have the structure of 5-hydroxy-4,5-dihydropyrazoles and do not undergo tautomeric transformations in solution. The condensation products at the trifluoroacetyl group have either 5-hydroxy-4,5-dihydropyrazole or hydrazone structure and give rise to ring-chain tautomeric equilibrium in solution. Electron-withdrawing substituents in the aromatic ring of the 1,3-dicarbonyl fragment and CDCl3 as solvent favor formation of the cyclic tautomer. The state of the tautomeric equilibrium is weakly sensitive to structural variations in the hydrazine component.
- Pakal'nis,Zerova,Yakimovich
-
p. 1732 - 1741
(2008/04/05)
-
- PYRAZOLO AND IMIDAZO-PYRIMIDINE DERIVATIVES
-
The present invention relates to novel pyrazolo- and imidazo-pyrimidine derivatives of formula (I) wherein A, D, E, L, M, Q, R1, R2 and R3 are as defined in the description and claims and to processes for their preparation, pharmaceutical compositions containing said derivatives and their use in the prevention and treatment of diseases.
- -
-
Page/Page column 20
(2008/06/13)
-
- Synthesis and SAR/3D-QSAR studies on the COX-2 inhibitory activity of 1,5-diarylpyrazoles to validate the modified pharmacophore
-
Diverse analogs of 1,5-diarylpyrazoles having 3-hydroxymethyl-4-sulfamoyl (SO2NH2)/methyl sulfonyl (SO2Me)-pheny group at N1 were synthesized and evaluated for their in vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The SAR study mainly involved the variations at positions C-3, C-5 and N1 of the pyrazole ring. Several small hydrophobic groups at/around position-4 of C-5 phenyl, viz. 3,4-dimethylphenyl analog 9, 3-methyl-4-methylsulfanylphenyl analog 14 and 2,3-dihydrobenzo[b] thiophenyl analog 17, exhibited impressive COX-2 inhibitory potency. In general, the sulfonamide analogues with a CHF2 at C-3 were found to be more potent than those having a CF3 group. The three dimensional quantitative structure activity relationship comprising comparative molecular field analysis (3D-QSAR-CoMFA) afforded the models with high predictivity which further validated the acceptance of hydroxymethyl (CH2OH) group in the hydrophilic pocket of the COX-2 enzyme.
- Singh, Sunil K.,Saibaba,Rao, K. Srinivasa,Reddy, P. Ganapati,Daga, Pankaj R.,Rajjak, S. Abdul,Misra, Parimal,Rao, Y. Koteswar
-
p. 977 - 990
(2007/10/03)
-