Design, Synthesis and Binding Affinity Evaluation of Cytochrome P450 1B1 Targeted Chelators

2021 ◽  
Vol 21 ◽  
Author(s):  
Dongmei Chen ◽  
Qiqi Fan ◽  
Ting Xu ◽  
Jinyun Dong ◽  
Jiahua Cui ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Binding Affinity ◽  
Binding Affinities ◽  
Cell Level ◽  
Design Synthesis ◽  
Inhibitor Complex ◽  
Cytochrome P450 1B1 ◽  
Positron Emission ◽  
Competition Study ◽  
Erod Assay

Background: Cytochrome P450 1B1 (CYP1B1) is specifically expressed in a variety of tumors which makes it a promise imaging target of tumor. Objective: We aimed to design and synthesize CYP1B1 targeted chelators for the potential application in positron emission tomography (PET) imaging of tumor. Methods: 1,4,7-triazacyclononane-1,4-diiacetic acid (NODA) was connected to the CYP1B1 selective inhibitor we developed before through polyethylene glycol (PEG) linkers with different lengths. The inhibitory activities of chelators 6a-c against CYP1 family were evaluated by 7-ethoxyresorufin o-deethylation (EROD) assay. The manual docking between the chelators and the CYP1B1 are conducted subsequently. To determine the binding affinities of 6a-c to CYP1B1 in cells, we further performed a competition study at the cell level. Results: Among three chelators, 6a with the shortest linker showed the best inhibitory activity against CYP1B1. In the following molecular simulation study, protein-inhibitor complex of 6a showed the nearest F-heme distance which is consistent with the results of enzymatic assay. Finally, the cell based competitive assay proved the binding affinity of 6a-c to CYP1B1 enzyme. Conclusion: We designed and synthesized a series of chelators which can bind to CYP1B1 enzyme in cancer cells.To our knowledge, this work is the first attempt to construct CYP1B1 targeted chelators for radiolabeling and we hope it will prompt the application of CYP1B1 imaging in tumor detection.

ChemInform Abstract: Design, Synthesis, and Discovery of Novel trans-Stilbene Analogues as Potent and Selective Human Cytochrome P450 1B1 Inhibitors.

ChemInform ◽  
2010 ◽  
Vol 33 (22) ◽  
pp. no-no
Author(s):  
Sanghee Kim ◽  
Hyojin Ko ◽  
Jae Eun Park ◽  
Sungkyu Jung ◽  
Sang Kwang Lee ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Design Synthesis ◽  
Cytochrome P450 1B1 ◽  
Human Cytochrome ◽  
Trans Stilbene ◽  
Stilbene Analogues

Design, Synthesis, and Binding Affinities of Potential Positron Emission Tomography (PET) Ligands for Visualization of Brain Dopamine D3Receptors

2006 ◽  
Vol 49 (1) ◽  
pp. 358-365 ◽  
Author(s):  
Marcello Leopoldo ◽  
Enza Lacivita ◽  
Paola De Giorgio ◽  
Nicola A. Colabufo ◽  
Mauro Niso ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Emission Tomography ◽  
Binding Affinities ◽  
Brain Dopamine ◽  
Design Synthesis ◽  
Positron Emission

Design, Synthesis, and Discovery of Noveltrans-Stilbene Analogues as Potent and Selective Human Cytochrome P450 1B1 Inhibitors

2002 ◽  
Vol 45 (1) ◽  
pp. 160-164 ◽  
Author(s):  
Sanghee Kim ◽  
Hyojin Ko ◽  
Jae Eun Park ◽  
Sungkyu Jung ◽  
Sang Kwang Lee ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Design Synthesis ◽  
Cytochrome P450 1B1 ◽  
Human Cytochrome ◽  
Stilbene Analogues

Phenanthridine Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Design, Synthesis and Biological Evaluation

2020 ◽  
Vol 16 ◽  
Author(s):  
Reema Abu Khalaf ◽  
Shorooq Alqazaqi ◽  
Maram Aburezeq ◽  
Dima Sabbah ◽  
Ghadeer Albadawi ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Biological Evaluation ◽  
Ligand Docking ◽  
Biological Assessment ◽  
Hypoglycemic Agents ◽  
Binding Affinities ◽  
Oral Hypoglycemic Agents ◽  
Design Synthesis ◽  
Dpp Iv

Background: Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduces the deterioration of gut-derived endogenous incretin hormones that are secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of pancreas. Objective: In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors was carried out. The target compounds were docked to study the molecular interactions and binding affinities against DPP-IV enzyme. Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed. Results: In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 µM concentration, where compound 3d harboring ortho-fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669 and Y752 backbones. Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.

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