Isoxazolyl-urea derivative evokes apoptosis and paraptosis by abrogating the Wnt/ß-catenin axis in colon cancer cells.

Deregulated activation of the Wnt/ß-catenin pathway is observed in many types of human malignancies including colon cancer. Abrogation of the Wnt/ß-catenin pathway has been demonstrated as an effective way of inducing cancer cell death. Herein, a new isoxazolyl-urea (QR-5) was synthesized and examined its efficacy on the viability of colon cancer cell lines. QR-5 displayed selective cytotoxicity towards colon cancer cells over normal counterparts. QR-5 induced apoptosis as evidenced by elevation in sub-G1 cells, decrease in Bcl-2, MMP-9, COX-2, VEGF and cleavage of PARP and caspase-3. QR-5 reduced the mitochondrial membrane potential, decreased the expression of Alix and elevated the expression of ATF4 and CHOP indicating the induction of paraptosis. The inhibitor of apoptosis (Z-DEVD-FMK) and paraptosis (CHX) could not restore Alix expression and PARP cleavage in QR-5 treated cells, respectively suggesting the complementation between the two cell death pathways. QR-5 suppressed the expression of Wnt/ß-catenin pathway proteins which was also evidenced by the downregulation of nuclear and cytoplasmic ß-catenin. The dependency of QR-5 on ß-catenin for inducing apoptosis and paraptosis was demonstrated using knockdown experiments using ß-catenin specific siRNA. Overall, QR-5 induces apoptosis as well as paraptosis by mitigating the Wnt/ß-catenin axis in colon cancer cells.

Microwave assisted one-pot access to pyrazolo quinolinone and tetrahydroisoxazolo quinolinone derivatives via T3P®-DMSO catalysed tandem oxidative-condensation reaction.

A new approach for the synthesis of two important annulated pyrazolo quinolinone and tetrahydroisoxazolo quinolinone derivatives from multicomponent reactions was achieved by using T3P®-DMSO-catalysed reactions of stable alcohols, cyclic 1,3-dicarbonyl compounds and amino derivatives of phenyl pyrazoles and isoxazole and has been reported for the first time. This reaction occurred via a tandem oxidative-condensation reaction under microwave irradiation and notable characteristics of this protocol are MCR reactions, shorter reaction time, less waste creation, ease of workup, stable precursors, broad substrate scope and functional group tolerance.

A new triazolyl-indolo-quinoxaline induces apoptosis in gastric cancer cells by abrogating the STAT3/5 pathway through upregulation of PTPεC.

Signal transducer and activator of transcription 3 (STAT3) and STAT5 are the transcription factors that have been studied extensively in relevance to the development of cancers in humans. Suppression of either STAT3 or STAT5-mediated signaling events has been demonstrated to be effective in inducing cytotoxicity in cancer cells. Herein, new hybrids of triazolyl-indolo-quinoxaline are synthesized and examined for their effect on the activation of STAT3 and STAT5 pathways in gastric cancer (GC) cells. Among the newly synthesized compounds, 2,3-difluoro-6-((1-(3-fluorophenyl)-1H-1,2,3-triazol-5-yl)methyl)-6H-indolo[2,3-b]quinoxaline (DTI) displayed selective cytotoxicity against GC cells over their normal counterpart. Flow cytometric analysis, annexin-V-fluorescein isothiocyanate staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, live and dead assay, and caspase activation experiments suggested DTI as a potent inducer of apoptosis. The mechanistic approach revealed that DTI imparts cytotoxicity via downregulating the phosphorylation of STAT3Y705 and STAT5Y694/699 . DTI significantly reduced the nuclear pool of STAT3/STAT5 and reduced the DNA interaction ability of STAT3/STAT5 as evidenced by immunofluorescence and electrophoretic mobility shift assay. Further investigation revealed that inhibitory effects towards STAT proteins were mediated through the suppression of upstream kinases such as JAK1, JAK2, and Src. Treatment of GC cells with pervanadate counteracted the DTI-driven STAT3/STAT5 inhibition suggesting the involvement of tyrosine phosphatase. Upon DTI exposure, there was a significant upregulation in the mRNA and protein expression of PTPεC, which is a negative regulator of the JAK-STAT pathway. Knockdown of PTPεC suppressed the DTI-induced STATs inhibition in GC cells. Taken together, triazolyl-indolo-quinoxaline is presented as a new inhibitor of the STAT3/STAT5 pathway in GC cells.

Synthesis, characterization and cytotoxicity studies of 1,2,3-triazoles and 1,2,4-triazolo [1,5-a] pyrimidines in human breast cancer cells.

Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is essential for physiological functions of tissues and neovasculature. VEGFR signaling is associated with the progression of pathological angiogenesis in various types of malignancies, making it an attractive therapeutic target in cancer treatment. In the present work, we report the synthesis of 1,4-disubstituted 1,2,3-triazoles and 1,2,4-triazolo[1, 5-a]pyrimidine derivatives via copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and screened for their anticancer activity against MCF7 cells. We identified 1-(2'-ethoxy-4'-fluoro-[1,1'-biphenyl]-4-yl)-4-phenyl-1H-1,2,3-triazole (EFT) as lead cytotoxic agent against MCF7 cell lines with an IC50 value of 1.69 µM. Further evaluation revealed that EFT induces cytotoxicity on Ishikawa, MDA-MB-231 and BT474 cells with IC50 values of 1.97, 4.81 and 4.08 µM respectively. However, EFT did not induce cytotoxicity in normal lung epithelial (BEAS-2B) cells. Previous reports suggested that 1,2,3-triazoles are the inhibitors of VEGFR1 and therefore, we evaluated the effect of EFT on the expression of VEGFR1. The results demonstrated that EFT downregulates the expression of VEGFR1 in MCF7 cells. In summary, we identified a potent cytotoxic agent that imparts its antiproliferative activity by targeting VEGFR1 in breast cancer cells. The novel compound could serve as a lead structure in developing VEGFR1 inhibitors.

Three closely related 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridines: synthesis, molecular conformations and hydrogen bonding in zero, one and two dimensions.

In each of 1-(4-fluorophenyl)-5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, C21H19F4N3O2S, (I), 1-(4-chlorophenyl)-5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, C21H19ClF3N3O2S, (II), and 1-(3-methylphenyl)-5-methylsulfonyl-3-[4-(trifluoromethyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine, C22H22F3N3O2S, (III), the reduced pyridine ring adopts a half-chair conformation with the methylsulfonyl substituent occupying an equatorial site. Although compounds (I) and (II) are not isostructural, having the space groups Pbca and P212121, respectively, their molecular conformations are very similar, but the conformation of compound (III) differs from those of (I) and (II) in the relative orientation of the N-benzyl and methylsulfonyl substituents. In compounds (II) and (III), but not in (I), the trifluoromethyl groups are disordered over two sets of atomic sites. Molecules of (I) are linked into centrosymmetric dimers by C-H...π(arene) hydrogen bonds, molecules of (II) are linked by two C-H...O hydrogen bonds to form ribbons of R33(18) rings, which are themselves further linked by a C-Cl...π(arene) interaction, and a combination of C-H...O and C-H...π(arene) hydrogen bonds links the molecules of (III) into sheets. Comparisons are made with the structures of some related compounds.

Anti-Cancer Activity of 2,4-Disubstituted Thiophene Derivatives: Dual Inhibitors of Lipoxygenase and Cyclooxygenase.

2,4-Disubstituted thiophene derivatives were synthesized and assessed for antiinflammatory and anti-cancer activities by targeting two important enzymes of the arachidonic acid metabolism. Both lipoxygenase and cyclooxygenase enzymes play vital role in chronic inflammation and carcinogenesis. Previous studies have proved that COX-2 and 5-LOX are highly activated in various types of cancers; hence inhibition of these clinically important enzymes constitutes the essential criterion for the suppression of tumor progression and metastasis. Among the tested derivatives, 2d and 2g compounds emerged as potent inhibitors of lipoxygenase and cyclooxygenase enzymes. The potent inhibitor of cyclooxygenase was further tested for in vitro cytotoxicity on cervical cancer (HeLa) cells and in vivo tumor model studies using EAT bearing mice where 2-(3,4,5- trimethoxyphenyl)-4-(N-methylindol-3-yl) thiophene (2g) showed eloquent activity. Further, in silico modeling results confirmed the active catalytic ligand binding pockets, which is evident from higher atomic contact energy values of 2d and 2g than compared to standard drug. Thus, 2g may find better application in management of inflammation and in proapoptotic therapeutic engineering.