Biphenyl Urea Research Articles

Exploring Structural Determinants of Bias among D4 Subtype-Selective Dopamine Receptor Agonists.

The high affinity dopamine D4 receptor ligand APH199 and derivatives thereof exhibit bias toward the Gi signaling pathway over β-arrestin recruitment compared to quinpirole. Based on APH199, two novel groups of D4 subtype selective ligands were designed and evaluated, in which the original benzyl phenylsemicarbazide substructure was replaced by either a biphenylmethyl urea or a biphenyl urea moiety. Functional assays revealed a range of different bias profiles among the newly synthesized compounds, namely, with regard to efficacy, potency, and GRK2 dependency, in which bias factors range from 1 to over 300 and activation from 15% to over 98% compared to quinpirole. These observations demonstrate that within bias, an even more precise tuning toward a particular profile is possible, which─in a general sense─could become an important aspect in future drug development. Docking studies enabled further insight into the role of the ECL2 and the EPB in the emergence of bias, thereby taking advantage of the diversity of functionally selective D4 agonists now available.

Induction of estrogen receptor β-mediated autophagy sensitizes breast cancer cells to TAD1822-7, a novel biphenyl urea taspine derivative.

Female breast cancer has become the most commonly diagnosed cancer worldwide. As a tumor suppressor, estrogen receptor β (ERβ) can be potentially targeted for breast cancer therapy. TAD1822-7 was evaluated for ERβ-mediated autophagy and cell death using cell proliferation assay, Annexin V/PI staining, immunofluorescence, western blotting, ERβ siRNA, ERβ plasmid transfection and hypoxia cell models. TAD1822-7 upregulated ERβ causing cell death and induced mitochondrial dysfunction and autophagy companied with mitochondrial located ERβ. Enhanced levels of microtubule associated protein1 light chain 3 (LC3)-II and p62/SQSTM1 (p62) indicated that TAD1822-7 blocked the late-stage autolysosome formation, leading to cell death. Mechanistically, TAD1822-7-induced cell death was mediated by phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathways. Moreover, TAD1822-7 modulated hypoxia inducible factor (HIF) functions and autophagy via the inhibition of HIF-1β in the context of hypoxia-induced autophagy. ERβ overexpression and ERβ agonist showed similar effects, whereas ERβ siRNA abrogated TAD1822-7-induced cell death, the inhibition of PI3K/AKT pathway and autophagy. The involvement of PI3K/AKT pathway and autophagy was also demonstrated in TAD1822-7-treated hypoxic breast cancer cells. These findings provide new insight into the mechanism underlying the inhibitory effects of TAD1822-7 via ERβ-mediated pathways in breast cancer cells.

TAD1822-7 induces ROS-mediated apoptosis of HER2 positive breast cancer by decreasing E-cadherin in an EphB4 dependent manner

HER2-positive breast cancer (HER2-BC) shows the over-expression of tyrosine kinase receptor EphB4 associated with poor disease prognosis. E-cadherin is found as a survival factor in multiple models of breast cancer by suppressing reactive oxygen-mediated apoptosis. This study confirmed that both HER2 and EphB4 are positively correlated with E-cadherin in HER2-BC. Inhibition of HER2 or EphB4 is discovered to induce ROS-dependent apoptosis by decreasing E-cadherin expression in SKBR3 and MDA-MB-453 cells. TAD1822-7 (TAD), a novel biphenyl urea taspine derivative, exhibits good growth inhibition, apoptosis induction and ROS accumulation effects on SKBR3 and MDA-MB-453 cells. Mechanistic investigation revealed that TAD blockades both EphB4 positive signal transduction and activation of HER2 signal transduction, thereby suppressing E-cadherin/TGF-β/p-Smad2/3 signaling axis to elicit ROS-dependent endogenous mitochondrial apoptosis. Together, these findings not only provide a new approach for HER2-BC therapy but also increase our understanding of the regulating effect of E-cadherin by HER2 and EphB4 in ROS-mediated apoptosis.

Catalytic microwave synthesis of biphenyl urea over mesoporous ZrO2-Al2O3

Solid acids such as ZrO2, Al2O3 and ZrO2-Al2O3 were prepared and analyzed for their physico-chemical properties like surface acidity and acid site distribution by NH3-TPD, crystalline nature by powder XRD, functionality by FT-IR, morphology by TEM and elemental analysis by ICP-OES methods. These solid acids were used as catalysts in the solvent free synthesis of biphenyl urea using microwave irradiation technique starting from aniline and dimethyl carbonate. Surface acidity and the phase of the solid acid were found to have a significant role in the synthesis of biphenyl urea. Up to (98%) yield of biphenyl urea with 100% selectivity was obtained in just 12 min. The activity of ZrO2-Al2O3 was compared with Mo(VI)/ZrO2 which is a solid super acid. For comparison, the reactions were also carried out by using conventional heating method. Kinetic studies were carried out to determine energy of activation of the solid acids. These solid acid catalysts were found to be reactivable and reusable when used for up to six reaction cycles.

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL‐2R signalling pathway

IL‐2R pathway is a key regulator in the development of immune cells and has emerged as a promising drug target in cancer treatment, but there is a scarcity of related inhibitors. TPD7 is a novel biphenyl urea taspine derivate, which has been shown anti‐cancer effect. Here, we demonstrated the anti‐cancer activity of TPD7 in cutaneous T cell lymphoma and investigated the underlying mechanism of TPD7 through IL‐2R signalling. The inhibitory effect of TPD7 on cell viability exhibited a strong correlation with the expression level of IL‐2R, and cutaneous T cell lymphoma H9 and HUT78 cells were most sensitive to TPD7. TPD7 was nicely bound to IL‐2R and down‐regulated the mRNA and protein levels of IL‐2R. Furthermore, TPD7 suppressed the downstream cascades of IL‐2R including JAK/STAT, PI3K/AKT/mTOR and PLCγ/Raf/MAPK signalling, resulting in Bcl‐2 mitochondrial apoptosis pathway and cell cycle proteins CDK/Cyclins regulation. And, these were verified by flow cytometry analysis that TPD7 facilitated cell apoptosis in H9 cells via mitochondrial pathway and impeded cell cycle progression at G2/M phase. TPD7 is a novel anti‐cancer agent and may be a potential candidate for cutaneous T cell lymphoma treatment by regulating IL‐2R signalling pathway.

A novel biphenyl urea compound, TPD7, stimulates apoptosis through modulating Fas signaling and Bcl-2 family proteins in cervical cancer.

We recently reported that TPD7 suppressed tumor cell proliferation, and inhibited invasion, through the suppression of C-X-C chemokine receptor type4 (CXCR4). In the present study, we investigated the anticancer effect of TPD7 on apoptosis and invasion of cervical cancer HeLa cells. Cell cycle analysis revealed that TPD7 decreased cyclin-dependent kinase (CDK)1 and cyclinD1 expression, and increased cyclin A expression, following Sphase blockade. TPD7 induced chromatin condensation and significantly elevated the number of apoptotic cells, suggesting that its inhibitory effect on HeLa cells was due to the induction of cell cycle blockade and apoptosis. Mechanistically, TPD7 altered the extrinsic apoptosis pathway by upregulating Fas expression, and the intrinsic pathway by modulating Bcl-2 family proteins, p53, and NF-κB p65, leading to enhanced apoptosis. TPD7 inhibited HeLa cell invasion by downregulating the expression of matrix metalloproteinase (MMP)-9 and CXCR4 proteins. Invivo experiments revealed that TPD7 inhibited tumor growth in HeLa cell xenografted mice. These findings indicated that TPD7 may be a potential chemoprevention agent for the management of cervical carcinoma.

Synergistic Effect of TPD7 and Berberine against Leukemia Jurkat Cell Growth through Regulating Ephrin-B2 Signaling.

TPD7, a novel biphenyl urea taspine derivative, and berberine have presented inhibition on VEGFR2 that can be regulated by ephrin-B2 reverse signaling through interactions with the PDZ domain. The purpose of this study is to investigate the inhibitory effect of the combination of TPD7 and berberine (TAB) on T-cell acute lymphoblastic leukemia cell growth. TPD7 and berberine together synergistically inhibited the proliferation of Jurkat cells. Also, the combination of TAB induced G1 -phase cell-cycle arrest by downregulating the level of cyclin D1, cyclin E, and CDC2. Furthermore, the combination of TAB significantly enhanced apoptosis in Jurkat cells, and the apoptosis most likely resulted from the modulation of the level of Bcl-2 family members. Most importantly, the concomitant treatment simultaneously regulated the ephrin-B2 and VEGFR2 signaling, as well as modulated the MEK/ERK and PTEN/PI3K/AKT/mTOR signaling. Therefore, the combination treatment of TAB may be a promising therapeutic method in treating T-cell acute lymphoblastic leukemia. Copyright © 2017 John Wiley & Sons, Ltd.

Synthesis, characterization and photophysical studies of self-assembled azo biphenyl urea derivatives.

We reported the synthesis of a new series of azobiphenyl based urea derivatives 7 and their stimulus-responsive supramolecular structures in the form of sheet like self-assembled formations. The self-assembled nanostructural formations of azo derivatives 7 are strongly dependent on the nature of the solvent present in the systems. Further, we found that the amide hydrogen played a crucial role in hydrogen bonding interactions to form a sheet like morphology upon stimulus responsive self-assembly. This was confirmed by transmission electron microscopy and atomic force microscopy.

Biphenyl urea derivatives as selective CYP1B1 inhibitors.

Highly selective CYP1B1 inhibitors have potential in the treatment of hormone-induced breast and prostate cancers. Mimicry of potent and selective CYP1B1 inhibitors, α-naphthoflavone and stilbenes, revealed that two sets of hydrophobic clusters suitably linked via a polar linker could be implanted into a new scaffold 'biphenyl ureas' to create potentially a new class of CYP1B1 inhibitors. A series of sixteen biphenyl ureas were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™, yeast-derived recombinant microsomal enzymes. The most active human CYP1B1 inhibitors were further studied for their selectivity against human CYP1A1, CYP1A2, CYP3A4 and CYP2D6 enzymes. The meta-chloro-substituted biphenyl urea 5h was the most potent inhibitor of CYP1B1 with IC50 value of 5 nM. It displayed excellent selectivity over CYP1A1, CYP1A2, CYP3A4 and CYP2D6 (IC50 >10 μM in the four CYP assays, indicating >2000-fold selectivity). Similarly, two methoxy-substituted biphenyl ureas 5d and 5e also displayed potent and selective inhibition of CYP1B1 with IC50 values of 69 and 58 nM, respectively, showing >62 and >98-fold selectivity over CYP1A1, CYP1A2, CYP3A4 and CYP2D6 enzymes. In order to probe if the relatively insoluble biphenyl ureas were cell permeable and if they could at all be used for future cellular studies, their CYP1B1 inhibition was investigated in live recombinant human and yeast cells. Compound 5d displayed the most potent inhibition with IC50s of 20 nM and 235 nM, respectively, in the two cell-based assays. The most potent and selective CYP1B1 inhibitor (compound 5h) from Sacchrosomes, also displayed potent inhibition in live cell assays. Molecular modeling was performed to understand the trends in potency and selectivity observed in the panel of five CYP isoenzymes used for the in vitro studies.

A novel biphenyl urea derivate inhibits the invasion of breast cancer through the modulation of CXCR4.

The increased migration and invasion of breast carcinoma cells are key events in the development of metastasis to the lymph nodes and distant organs. CXCR4, the receptor for stromal-derived factor-1, is reportedly involved in breast carcinogenesis and invasion. In this study, we investigated a novel biphenyl urea derivate, TPD7 for its ability to affect CXCR4 expression as well as function in breast cancer cells. We demonstrated that TPD7 inhibited the breast cancer proliferation and down-regulated the CXCR4 expression on breast cancer cells both over-expressing and low-expressing HER2, an oncogene known to induce the chemokine receptor. Treatments with pharmacological proteasome inhibitors partial suppressed TPD7-induced decrease in CXCR4 expression. Real-time PCR analysis revealed that down-regulation of CXCR4 by TPD7 also occurred at the translational level. Inhibition of CXCR4 expression by TPD7 further correlated with the suppression of SDF-1α-induced migration and invasion in breast tumour cells, knockdown of CXCR4 attenuated TPD7-inhibitory effects. In addition, TPD7 treatment significantly suppressed matrix metalloproteinase (MMP)-2 and MMP-9 expression, the downstream targets of CXCR4, perhaps via inactivation of the ERK signaling pathway. Overall, our results showed that TPD7 exerted its anti-invasive effect through the down-regulation of CXCR4 expression and thus had the potential for the treatment of breast cancer.

Discovery of novel VEGFR-2 inhibitors. Part II: biphenyl urea incorporated with salicylaldoxime.

A series of novel VEGFR-2 inhibitors containing oxime as hinge binding fragment were described. A strategy of pseudo six-membered ring formed through intramolecular hydrogen bond was employed to mimic the planar quinazoline. The oxime group was firstly introduced to interact with hinge region of VEGFR-2. Most of compounds tested showed moderate to high VEGFR-2 inhibitory activity. In particular, 12l, 12p and 12y exhibited significant enzymatic inhibitory activity as well as potent antiproliferative activity against cancer cells. Molecular docking suggested that the salicylaldoxime formed two hydrogen bonds with hinge region. These biphenylureas could serve as promising lead compounds for developing novel anticancer agents.

Biphenyl derivatives incorporating urea unit as novel VEGFR-2 inhibitors: Design, synthesis and biological evaluation

A series of novel biphenyl urea derivates were synthesized and investigated for their potential to inhibit vascular endothelial growth factor receptor-2 (VEGFR-2). In particular, A7, B3 and B4 displayed significant enzymatic inhibitory activities, with IC50 values of 4.06, 4.55 and 5.26nM. Compound A7 exhibited potent antiproliferative activity on several cell lines. SAR study suggested that the introduction of methyl at ortho-position of the biphenyl urea and tertiary amine moiety could improve VEGFR-2 inhibitory activity and antitumor effects. Molecular docking indicated that the urea moiety formed four hydrogen bonds with DFG residue. These biphenyl ureas could serve as promising lead compounds for further optimization.

Design, synthesis and biological evaluation of biphenyl urea derivatives as novel VEGFR-2 inhibitors

VEGFR-2 plays a critical role in vasculogenesis and VEGFR-2 inhibitors have been widely used in the treatment of cancer. In our continued efforts to search for potent and novel VEGFR-2 inhibitors as antitumor agents, we have identified a potent lead compound (HMQ-16) bearing a biphenyl scaffold. Rearrangement and replacement of arylcarbamoyl in HMQ-16 with a urea moiety generated a series of novel VEGFR-2 inhibitors. In order to enhance the affinity with VEGFR-2, the 4′-acetyl group was converted to an oxime group. Fourteen biphenyl urea derivatives were designed and synthesized as potent VEGFR-2 inhibitors. Six of them (T2, T5, T7, T9, T11, T14) exhibited potent VEGFR-2 inhibitory activity comparable to that of sorafenib. Compound T7 was the most potent with an IC50 value of 1.08 nM. The enzymatic and cellular assays suggested that T7 has potential as a valuable lead compound for further optimization.

Exploration of pyridine containing heteroaryl analogs of biaryl ureas as DGAT1 inhibitors

The diacylglycerol acyltransferase enzyme, DGAT1, presents itself as a potential target for obesity as this enzyme is dedicated to the final committed step in triglyceride biosynthesis. Biphenyl ureas, exemplified by compound 4, have been reported to be potent hDGAT1 inhibitors. We have synthesized and evaluated 2-pyridyl and 3-pyridyl containing biaryl ureas as hDGAT1 inhibitors. Our aim was to incorporate a heteroaryl scaffold within these molecules thereby improving the cLogP profile and making these compounds more drug-like. Compounds within this series exhibited potent hDGAT1 inhibition when evaluated using an in vitro enzymatic assay. Selected compounds were also subjected to an oral fat tolerance test in mice where the percent triglyceride reduction versus a vehicle control was evaluated. Of the studied heteroaryl analogs compound 44 exhibited an in vitro IC(50) of 17nM and a plasma triglyceride reduction of 79% along with a 12-fold improvement in solubility over the biphenyl urea compound 4.

An efficient and greener protocol towards synthesis of unsymmetrical N,N′-biphenyl urea

A simple and efficient route for the synthesis of Unsymmetrical N,N′-diphenyl urea have been developed in aqueous medium under base and catalyst free condition from corresponding substituted isocyanate and amines. The remarkable key feature of the reaction includes the use of water as an inexpensive and environmentally benign reaction medium, absence of base and any additional catalyst, and easy isolation of the product.

Structure and catalytic activity correlation of CoAlPO 4 in the synthesis of N,N-biphenyl urea via alkylation of aniline using dimethyl carbonate

Two sets of cobalt aluminophosphate materials, one at different pH (4.5, 7, 10, and 11.5) and the other containing different percentage of cobalt (0.5–20) were prepared by co-precipitation method. All the materials were characterized by XRD, SEM, 27Al MASS NMR, TGA and DSC, FTIR, for their textural and structural properties. The surface area of the samples was determined by BET method and total surface acidity by n-butylamine titration method. The CoAlPO 4 obtained under acidic pH were found to be crystalline AlPO 4 with nonmicroporous tridymit structure associated with cobalt phosphate, whereas the one obtained under alkaline pH were amorphous aluminophosphate and also associated with cobalt phosphate. Tridymit-AlPO 4 crystals exhibited Al atom in a tetrahedral environment of phosphate groups. In the amorphous material the Al atoms were in a mixed tetrahedral and octahedral environment. The concentration of acid sites were found to be higher in the sample obtained under alkaline pH. This has been attributed due to the partial coordination of hydroxyl groups in the octahedral aluminum sites. The amorphous materials obtained under alkaline pH were found to be thermally stable up to 900 °C. The catalytic activity of all the materials was investigated in aniline alkylation using dimethyl/ethyl carbonates (DMC/DEC) under refluxing conditions. N-methyl/ethyl aniline (NMA/NEA) and biphenyl urea (BPU) were formed as the major products with the catalysts prepared at acidic and alkaline pH, respectively. A good correlation has been observed between the catalytic activity of CoAlPO 4 materials towards their selectivity for NMA/NEA and/or BPU and their textural and structural properties. Reaction conditions such as the amount of the catalyst, duration of the reaction, reusability and efficiency of the catalyst have also been evaluated. CoAlPO 4 prepared under alkaline pH with 5% of cobalt has been found to be the best catalyst for BPU synthesis from aniline and DMC/DEC under refluxing conditions.

Sulfonyl‐phenyl‐ureido Benzamidines: A Novel Structural Class of Potent Antimalarial Agents

AbstractFor Abstract see ChemInform Abstract in Full Text.

Sulfonyl-phenyl-ureido benzamidines: a novel structural class of potent antimalarial agents

The high throughput in silico screening of a virtual library into the structure of the P. falciparum lactate dehydrogenase (LDH) with the 4SCan technology yielded a series of biphenyl urea compounds. These were chemically optimized to a new structural class of potent antimalarial agents. The compounds did not inhibit plasmodium LDH enough to fully explain their potency. Therefore we conclude that an unknown mode of action may be the cause of the antimalarial activity.

A new catalyst for the synthesis of N,N-biphenylurea from aniline and dimethyl carbonate

An environmentally benign method for the synthesis of biphenylurea (BPU) in the presence of ecofriendly catalysts has been reported. Catalytic activity of various metal aluminophosphates, M-AlPO4 (M = V, Fe, Co, Ni and Cu) and cobalt supported on hydrated Al2O3, SiO2 and ZrO2 has been investigated in the synthesis of BPU from aniline and dimethyl carbonate (DMC). All the catalysts used are amorphous. The catalytic activity studies have been carried out in the liquid phase under refluxing conditions. Formation of BPU is found to depend on the type of the catalyst, the molar ratio of aniline to DMC and the duration of the reaction. N-Methylaniline and methyl -N-phenylcarbamate are formed as by-products of the reaction. Of all the catalysts used, Co-AlPO4 has been found to yield the highest percentage of BPU whereas cobalt supported hydrated Al2O3, SiO2 and ZrO2 failed to give any BPU.