Discovery of biphenyl-aryl ureas as novel VEGFR-2 inhibitors. Part 4: Exploration of diverse hinge-binding fragments

Su, Ping; Wang, Jinfeng; Shi, Yunfei; Pan, Xiaoyan; Shao, Ruili; Zhang, Jie

doi:10.1016/j.bmc.2015.04.071

Cited by 17 publications

(6 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The dataset illustrated in Table was implemented to construct the Atom‐based 3D QSAR. The statistical parameters of the PLS regression model have summarized in Table .…”

Section: Resultsmentioning

confidence: 99%

Design of Potential Inhibitors and Prediction of their Activity by the Structural Insight of VEGFR2 Inhibitors: Atom‐based 3D‐QSAR, Fingerprint‐based 2D QSAR and Off‐target analysis.

et al. 2020

View full text Add to dashboard Cite

VEGF−A is a crucial factor of angiogenesis process in tumor cells. It mediates its biological function through VEGFR2. Therefore, VEGFR2 is a promising target to suppress angiogenesis. Till date, 8‐FDA approved VEGFR2 inhibitors are available but correlated with serious side effects due to off‐target activity of compounds. Hence, these findings alarmed us to find the favorable features of compounds and association of compounds to the serious side effects. To address these question, an Atom‐based 3D and fingerprint‐based 2D QSAR models were constructed. The results of these models assisted us to design the hits 5 a and 6 a with favorable features from the inactive Compound 52 of diaryl urea analogs (IC50=53 μM). The designed hits were subjected for docking, binding free energy calculation, ADME and hERG toxicity in comparison of Compound 52 of diaryl urea analogs. On the contrary to hit 5a and Compound 52 of diaryl urea analogs, hit 6 a possessed crucial interactions with ASP1046 and GLU885 along with acceptable ADMET profile which was affirmed by Molecular Dynamics simulation study. The best hit 6 a was also subjected first time to off‐target analysis employing PoSSuM database.

show abstract

“…The dataset illustrated in Table was implemented to construct the Atom‐based 3D QSAR. The statistical parameters of the PLS regression model have summarized in Table .…”

Section: Resultsmentioning

confidence: 99%

Design of Potential Inhibitors and Prediction of their Activity by the Structural Insight of VEGFR2 Inhibitors: Atom‐based 3D‐QSAR, Fingerprint‐based 2D QSAR and Off‐target analysis.

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The key intermediate (5) was prepared from commercially available 2-amino-5-bromopyridine (4). Subsequently, the title commands (CDAU-1~CDAU-11) were prepared from (3a-3k) and (5) by Pd-catalyzed Suzuki coupling reaction22.…”

Section: Resultsmentioning

confidence: 99%

Discovery of multi-target receptor tyrosine kinase inhibitors as novel anti-angiogenesis agents

Wang

Zhang

Pan

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Recently, we have identified a biphenyl-aryl urea incorporated with salicylaldoxime (BPS-7) as an anti-angiogenesis agent. Herein, we disclosed a series of novel anti-angiogenesis agents with BPS-7 as lead compound through combining diarylureas with N-pyridin-2-ylcyclopropane carboxamide. Several title compounds exhibited simultaneous inhibition effects against three pro-angiogenic RTKs (VEGFR-2, TIE-2 and EphB4). Some of them displayed potent anti-proliferative activity against human vascular endothelial cell (EA.hy926). In particular, two potent compounds (CDAU-1 and CDAU-2) could be considered as promising anti-angiogenesis agents with triplet inhibition profile. The biological evaluation and molecular docking results indicate that N-pyridin-2-ylcyclopropane carboxamide could serve as a hinge-binding group (HBG) for the discovery of multi-target anti-angiogenesis agents. CDAU-2 also exhibited promising anti-angiogenic potency in a tissue model for angiogenesis.

show abstract

“…As is well-known, an amine functionality is compatible with both the Suzukir eactionw ith ab ispinacolated erivative or ab oronic acid. [19] Consequently,t he coupling of 4a and 15 under standard Suzuki conditions provided the tripod-shaped molecule 16 (Scheme 7). Finally,t he amine group was successfully converted into an azide by treatment with sodium azide and sodium nitrite in acidic THF,t hus obtaining compound 1a.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Covalent Grafting of Tripod‐Shaped Oligo(p‐phenylene)s End‐Capped with Azide Groups

et al. 2016

View full text Add to dashboard Cite

Here we report the synthesis and characterization of several tripod-shaped oligo(p-phenylene)s molecules with legs composed of five and three phenylene units, compounds 1 and 2,r espectively.I nt heses tructures, each leg is end-capped with an azide group andt he terminal functional arm contains an acetylene or bromine group. The presented synthesis has as the key step aP d-catalyzedS uzukic rosscoupling reaction. In particular,t he iodine derivative from the silicon core molecule reacts with the appropriate oligo(p-phenylene) boron derivative, thus generating the final tripod-shaped structure. The azide end-capped leg is specifically designed for its covalentincorporation on alkynyl terminated silicon surfaces in an easy and reproducible way. As ap reliminarys tudy,w ep resent the nanostructuration of tripod 2a on alkynyl-functionalized silicon waferst hrough copper-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction.

show abstract

Discovery of biphenyl-aryl ureas as novel VEGFR-2 inhibitors. Part 4: Exploration of diverse hinge-binding fragments

Cited by 17 publications

References 18 publications

Design of Potential Inhibitors and Prediction of their Activity by the Structural Insight of VEGFR2 Inhibitors: Atom‐based 3D‐QSAR, Fingerprint‐based 2D QSAR and Off‐target analysis.

Design of Potential Inhibitors and Prediction of their Activity by the Structural Insight of VEGFR2 Inhibitors: Atom‐based 3D‐QSAR, Fingerprint‐based 2D QSAR and Off‐target analysis.

Discovery of multi-target receptor tyrosine kinase inhibitors as novel anti-angiogenesis agents

Synthesis and Covalent Grafting of Tripod‐Shaped Oligo(p‐phenylene)s End‐Capped with Azide Groups

Contact Info

Product

Resources

About