Month: October 2022

Henning, Nathaniel J.; Boike, Lydia; Spradlin, Jessica N.; Ward, Carl C.; Liu, Gang; Zhang, Erika; Belcher, Bridget P.; Brittain, Scott M.; Hesse, Matthew J.; Dovala, Dustin; McGregor, Lynn M.; Valdez Misiolek, Rachel; Plasschaert, Lindsey W.; Rowlands, David J.; Wang, Feng; Frank, Andreas O.; Fuller, Daniel; Estes, Abigail R.; Randal, Katelyn L.; Panidapu, Anoohya; McKenna, Jeffrey M.; Tallarico, John A.; Schirle, Markus; Nomura, Daniel K. published the artcile< Deubiquitinase-targeting chimeras for targeted protein stabilization>, Application of C6H12N2O, the main research area is cystic fibrosis deubiquitinase chimera protein stabilization.

Many diseases are driven by proteins that are aberrantly ubiquitinated and degraded. These diseases would be therapeutically benefited by targeted protein stabilization (TPS). Here we present deubiquitinase-targeting chimeras (DUBTACs), heterobifunctional small mols. consisting of a deubiquitinase recruiter linked to a protein-targeting ligand, to stabilize the levels of specific proteins degraded in a ubiquitin-dependent manner. Using chemoproteomic approaches, we discovered the covalent ligand EN523 that targets a non-catalytic allosteric cysteine C23 in the K48-ubiquitin-specific deubiquitinase OTUB1. We showed that a DUBTAC consisting of our EN523 OTUB1 recruiter linked to lumacaftor, a drug used to treat cystic fibrosis that binds ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR), robustly stabilized ΔF508-CFTR protein levels, leading to improved chloride channel conductance in human cystic fibrosis bronchial epithelial cells. We also demonstrated stabilization of the tumor suppressor kinase WEE1 in hepatoma cells. Our study showcases covalent chemoproteomic approaches to develop new induced proximity-based therapeutic modalities and introduces the DUBTAC platform for TPS. [graphic not available: see fulltext]

Nature Chemical Biology published new progress about Amino acids Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 22476-74-0 belongs to class piperazines, and the molecular formula is C6H12N2O, Application of C6H12N2O.

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Yang, Wei; Liu, Xiaolong; Song, Chunli; Ji, Sen; Yang, Jianhong; Liu, Yang; You, Jing; Zhang, Jie; Huang, Shenzhen; Cheng, Wei; Shao, Zhenhua; Li, Linli; Yang, Shengyong published the artcile< Structure-activity relationship studies of phenothiazine derivatives as a new class of ferroptosis inhibitors together with the therapeutic effect in an ischemic stroke model>, Quality Control of 229009-40-9, the main research area is SAR preparation phenothiazine derivative ferroptosis ischemic stroke BBB; Ferroptosis inhibitor; Ischemic stroke; Promethazine derivatives; Structure-activity relationship.

Ferroptosis is a new type of programmed cell death discovered recently and has been demonstrated to be involved in a number of human diseases such as ischemic stroke. Ferroptosis inhibitors are expected to have potential to treat these diseases. Herein, we report the identification of promethazine derivatives as a new type of ferroptosis inhibitors. Structure-activity relationship (SAR) analyses led to the discovery of the most potent compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine (51), which showed an EC50 (half maximal effective concentration) value of 0.0005μM in the erastin-induced HT1080 cell ferroptosis model. In the MCAO (middle cerebral artery occlusion) ischemic stroke model, 51 presented an excellent therapeutic effect. This compound also displayed favorable pharmacokinetic properties, in particular, a good ability to permeate the blood-brain barrier. Overall, 51 could be a promising lead compound for the treatment of ferroptosis related diseases and deserves further investigations.

European Journal of Medicinal Chemistry published new progress about Blood-brain barrier (permeation). 229009-40-9 belongs to class piperazines, and the molecular formula is C11H17BN2O2, Quality Control of 229009-40-9.

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

De Savi, Chris; Waterson, David; Pape, Andrew; Lamont, Scott; Hadley, Elma; Mills, Mark; Page, Ken M.; Bowyer, Jonathan; Maciewicz, Rose A. published the artcile< Hydantoin based inhibitors of MMP13-Discovery of AZD6605>, Application of C13H19BrN4O2, the main research area is piperidine ether aryl piperazine hydantoin inhibitor MMP13 osteoarthritis; Cyp P450; Hydantoin; Lead optimisation; MMP13; Zinc binder.

Piperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chem. campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimizing MMP13 potency, solubility and DMPK properties while maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug.

Bioorganic & Medicinal Chemistry Letters published new progress about Enzyme inhibitors. 374930-88-8 belongs to class piperazines, and the molecular formula is C13H19BrN4O2, Application of C13H19BrN4O2.

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Song, Fengbin; Xu, Guozhang; Gaul, Michael D.; Zhao, Baoping; Lu, Tianbao; Zhang, Rui; DesJarlais, Renee L.; DiLoreto, Karen; Huebert, Norman; Shook, Brian; Rentzeperis, Dennis; Santulli, Rosie; Eckardt, Annette; Demarest, Keith published the artcile< Design, synthesis and structure activity relationships of indazole and indole derivatives as potent glucagon receptor antagonists>, Category: piperazines, the main research area is design synthesis SAR indazole indole derivative glucagon receptor antagonist; Diabetes mellitus; Glucagon; Glucagon receptor antagonist; Indazole; Indole.

A novel series of indazole/indole derivatives were discovered as glucagon receptor (GCGR) antagonists through scaffold hopping based on two literature leads: MK-0893 and LY-2409021. Further structure-activity relationship (SAR) exploration and optimization led to the discovery of multiple potent GCGR antagonists with excellent pharmacokinetic properties in mice and rats, including low systemic clearance, long elimination half-life, and good oral bioavailability. These potent GCGR antagonists could be used for potential treatment of type II diabetes.

Bioorganic & Medicinal Chemistry Letters published new progress about Conformation (conformational overlay with LY-2409021). 229009-40-9 belongs to class piperazines, and the molecular formula is C11H17BN2O2, Category: piperazines.

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Gazzard, Lewis; Appleton, Brent; Chapman, Kerry; Chen, Huifen; Clark, Kevin; Drobnick, Joy; Goodacre, Simon; Halladay, Jason; Lyssikatos, Joseph; Schmidt, Stephen; Sideris, Steve; Wiesmann, Christian; Williams, Karen; Wu, Ping; Yen, Ivana; Malek, Shiva published the artcile< Discovery of the 1,7-diazacarbazole class of inhibitors of checkpoint kinase 1>, SDS of cas: 229009-40-9, the main research area is crystal structure diazacarbazole preparation checkpoint kinase inhibitor; ChK1; Checkpoint; Diazacarbazole; GNE-783; Structure-based design.

Checkpoint kinase 1 (ChK1) is activated in response to DNA damage, acting to temporarily block cell cycle progression and allow for DNA repair. It is envisaged that inhibition of ChK1 will sensitize tumor cells to treatment with DNA-damaging therapies, and may enhance the therapeutic window. High throughput screening identified carboxylate-containing diarylpyrazines as a prominent hit series, but with limited biochem. potency and no cellular activity. Through a series of SAR investigations and x-ray crystallog. anal. the critical role of polar contacts with conserved waters in the kinase back pocket was established. Structure-based design, guided by in silico modeling, transformed the series to better satisfy these contacts and the novel 1,7-diazacarbazole class of inhibitors was discovered. Here the authors present the genesis of this novel series and the identification of GNE-783 I, a potent, selective and orally bioavailable inhibitor of ChK1.

Bioorganic & Medicinal Chemistry Letters published new progress about Antitumor agents. 229009-40-9 belongs to class piperazines, and the molecular formula is C11H17BN2O2, SDS of cas: 229009-40-9.

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Yin, Huanhuan; Dong, Jingjing; Cai, Yingchun; Shi, Ximeng; Wang, Hao; Liu, Guixia; Tang, Yun; Liu, Jianwen; Ma, Lei published the artcile< Design, synthesis and biological evaluation of chalcones as reversers of P-glycoprotein-mediated multidrug resistance>, Recommanded Product: 1-Boc-4-(4-Formylphenyl)piperazine, the main research area is chalcone design synthesis anticancer reversers glycoprotein multidrug resistance; Chalcones; Inhibitors docking; Multidrug resistance reversers; P-glycoprotein inhibitors; Structure-activity relationship.

Overexpression of P-glycoprotein (P-gp) is one of the major causes for multidrug resistance (MDR), which has become a major obstacle in cancer therapy. One hopeful approach to reverse the MDR is to develop inhibitors of P-gp in expression and/or function. Here, we designed and synthesized a series of chalcone derivatives as P-gp inhibitors and evaluated their potential reversal activities against MDR. Among them, the most active compound I had little intrinsic cytotoxicity and showed the highest activity (RF = 50.19) in reversing DOX resistance in MCF-7/DOX cells. Further studies demonstrated that I could increase intracellular accumulation of DOX and inhibit expression of P-gp at mRNA and protein levels. More importantly, I significantly enhanced the efficacy of DOX against the tumor xenografts bearing MCF-7/DOX cells with the precondition of unchanged body weight Therefore, I might represent a promising lead to develop MDR reversal agents for cancer chemotherapy.

European Journal of Medicinal Chemistry published new progress about Antitumor agents. 197638-83-8 belongs to class piperazines, and the molecular formula is C16H22N2O3, Recommanded Product: 1-Boc-4-(4-Formylphenyl)piperazine.

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Papagni, Antonio; Del Buttero, Paola; Bertarelli, Chiara; Miozzo, Luciano; Moret, Massimo; Pryce, Mary T.; Rizzato, Silvia published the artcile< Novel fluorinated amino-stilbenes and their solid-state photodimerization>, Quality Control of 197638-83-8, the main research area is fluorinated aminostilbene solid state photodimerization.

We synthesized a series of polyfluoroaminostilbenes in satisfactory yields by Wittig reaction of 4-piperazinylbenzalhehydes with pentafluorobenzylidenetriphenylphosphorane and we analyzed the photochem. behavior of these stilbenes in the solid state; thanks to arene-perfluoroarene π-π interactions, some of them have shown a good propensity to give the corresponding cyclobutane photodimers in quant. yields. The photocyclization is reversible both in solution and in polymeric matrix, affording the corresponding stilbenes with different cis-trans stereoselectivity.

New Journal of Chemistry published new progress about [2+2] Photocycloaddition reaction. 197638-83-8 belongs to class piperazines, and the molecular formula is C16H22N2O3, Quality Control of 197638-83-8.

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Antonow, Dyeison; Cooper, Nectaroula; Howard, Philip W.; Thurston, David E. published the artcile< Parallel Synthesis of a Novel C2-Aryl Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) Library>, SDS of cas: 229009-40-9, the main research area is pyrrolobenzodiazepine aryl parallel synthesis Suzuki coupling microwave irradiation.

A 66-membered library of C2-aryl pyrrolo[2,1-c][1,4]benzodiazepines I [R = Ph, 4-MeOC6H4, 3-H2NC6H4, 2-F3CC6H4, 4-(4-methyl-1-piperazinyl)phenyl, 2-thienyl, 4-pyridyl, 2-naphthyl, etc.] has been successfully prepared by parallel synthesis via Suzuki coupling using polystyrene-bound Pd(PPh3)4 as catalyst and polystyrene-bound diethanolamine as scavenger under microwave irradiation Library members were obtained in sufficient yields (up to 91%) and purity (85-98% crude) for biol. evaluation.

Journal of Combinatorial Chemistry published new progress about Boronic acids Role: RCT (Reactant), RACT (Reactant or Reagent). 229009-40-9 belongs to class piperazines, and the molecular formula is C11H17BN2O2, SDS of cas: 229009-40-9.

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Tintori, Cristina; Brai, Annalaura; Dasso Lang, Maria Chiara; Deodato, Davide; Greco, Antonia Michela; Bizzarri, Bruno Mattia; Cascone, Lorena; Casian, Alexandru; Zamperini, Claudio; Dreassi, Elena; Crespan, Emmanuele; Maga, Giovanni; Vanham, Guido; Ceresola, Elisa; Canducci, Filippo; Arien, Kevin K.; Botta, Maurizio published the artcile< Development and in Vitro Evaluation of a Microbicide Gel Formulation for a Novel Non-Nucleoside Reverse Transcriptase Inhibitor Belonging to the N-Dihydroalkyloxybenzyloxopyrimidines (N-DABOs) Family>, Synthetic Route of 197638-83-8, the main research area is HIV1 antiviral gel dihydroalkyloxybenzyl oxopyrimidine.

Preventing HIV transmission by the use of a vaginal microbicide is a topic of considerable interest in the fight against AIDS. Both a potent anti-HIV agent and an efficient formulation are required to develop a successful microbicide. In this regard, mols. able to inhibit the HIV replication before the integration of the viral DNA into the genetic material of the host cells, such as entry inhibitors or reverse transcriptase inhibitors (RTIs), are ideal candidates for prevention purpose. Among RTIs, S- and N-dihydroalkyloxybenzyloxopyrimidines (S-DABOs and N-DABOs) are interesting compounds active at nanomolar concentration against wild type of RT and with a very interesting activity against RT mutations. Herein, novel N-DABOs were synthesized and tested as anti-HIV agents. Furthermore, their mode of binding was studied by mol. modeling. At the same time, a vaginal microbicide gel formulation was developed and tested for one of the most promising candidates.

Journal of Medicinal Chemistry published new progress about Anti-HIV agents. 197638-83-8 belongs to class piperazines, and the molecular formula is C16H22N2O3, Synthetic Route of 197638-83-8.

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics

Verma, Sanjeev K.; Ghorpade, Ramarao; Pratap, Ajay; Kaushik, M. P. published the artcile< CDI-mediated monoacylation of symmetrical diamines and selective acylation of primary amines of unsymmetrical diamines>, HPLC of Formula: 76535-74-5, the main research area is CDI monoacylation sym diamine acylation amine unsym.

A highly efficient and green protocol for monoacylation of sym. diamines and chemoselective acylation of primary amines of unsym. diamines was developed.

Green Chemistry published new progress about Acylation. 76535-74-5 belongs to class piperazines, and the molecular formula is C9H19ClN2O2, HPLC of Formula: 76535-74-5.

Referemce:
Piperazine – Wikipedia,
Piperazines – an overview | ScienceDirect Topics