Month: October 2022

Liu, Xuesong; Wang, Beilei; Chen, Cheng; Qi, Ziping; Zou, Fengming; Wang, Junjie; Hu, Chen; Wang, Aoli; Ge, Juan; Liu, Qingwang; Yu, Kailin; Hu, Zhenquan; Jiang, Zongru; Wang, Wei; Wang, Li; Wang, Wenchao; Ren, Tao; Bai, Mingfeng; Liu, Qingsong; Liu, Jing published the artcile< Discovery of (E)-N1-(3-Fluorophenyl)-N3-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)malonamide (CHMFL-KIT-033) as a Novel c-KIT T670I Mutant Selective Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs)>, Reference of 229009-40-9, the main research area is CHMFL KIT033 preparation cKIT T670I kinase inhibitor gastrointestinal tumor.

Gain-of-function mutations of c-KIT kinase play crucial pathol. roles for the gastrointestinal stromal tumors (GISTs). Despite the success of imatinib as the first-line treatment of GISTs, dozens of drug-acquired resistant mutations emerge, and c-KIT T670I is one of the most common mutants among them. Although several kinase inhibitors are capable of overcoming the T670I mutant, none of them can achieve the selectivity over the c-KIT wild-type (wt), which also plays important roles in a variety of physiol. functions such as hematopoiesis. Starting from axitinib, through fragment hybrid type II kinase inhibitor design approach, we have discovered a novel inhibitor 24, which not only exhibits potent activity to c-KIT T670I mutant but also achieves 12-fold selectivity over c-KIT weight Compound 24 displays good antiproliferative effects against c-KIT T670I mutant-driven GIST cell lines (GIST-T1/T670I and GIST-5R) and also exhibits suitable in vivo pharmacokinetic profiles as well as dose-dependent antitumor efficacy. This study provides a proof of concept for developing a c-KIT mutant selective inhibitor that theor. can render a better therapeutic window.

Journal of Medicinal Chemistry published new progress about Antiproliferative agents. 229009-40-9 belongs to class piperazines, and the molecular formula is C11H17BN2O2, Reference of 229009-40-9.

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

Nishizawa, Akihiro; Takahira, Tsuyoshi; Yasui, Kosuke; Fujimoto, Hayato; Iwai, Tomohiro; Sawamura, Masaya; Chatani, Naoto; Tobisu, Mamoru published the artcile< Nickel-Catalyzed Decarboxylation of Aryl Carbamates for Converting Phenols into Aromatic Amines>, Computed Properties of 197638-83-8, the main research area is phenol conversion aromatic amine nickel catalyzed decarboxylation carbamate; polystyrene supported phosphine ligand nickel catalyzed decarboxylation carbamate.

Herein, we describe a new catalytic approach to accessing aromatic amines from an abundant feedstock, namely phenols. The most reliable catalytic method for converting phenols to aromatic amines uses an activating group, such as a trifluoromethane sulfonyl group. However, this activating group is eliminated as a leaving group during the amination process, resulting in significant waste. Our nickel-catalyzed decarboxylation reaction of aryl carbamates forms aromatic amines with carbon dioxide as the only byproduct. As this amination proceeds in the absence of free amines, a range of functionalities, including a formyl group, are compatible. A bisphosphine ligand immobilized on a polystyrene support (PS-DPPBz) is key to the success of this reaction, generating a catalytic species that is significantly more active than simple nonsupported variants.

Journal of the American Chemical Society published new progress about Amination (decarboxylative amination). 197638-83-8 belongs to class piperazines, and the molecular formula is C16H22N2O3, Computed Properties of 197638-83-8.

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

Ivashchenko, Andrey A.; Ivanenkov, Yan A.; Aladinskiy, Vladimir A.; Karapetian, Ruben N.; Koryakova, Angela G.; Ryakhovskiy, Alexey A.; Mitkin, Oleg D.; Kravchenko, Dmitry V.; Savchuk, Nikolai P.; Zagribelnyy, Bogdan A.; Ivashchenko, Alexander V. published the artcile< Synthesis, biological evaluation and in silico modeling of novel pan-genotypic NS5A inhibitors>, Safety of 4-(4-Methyl-1-piperazinyl)phenylboronic Acid, the main research area is peptide linked bisimidazole preparation NS5A inhibitor mol modeling SAR; Combinatorial synthesis; HCV; In silico modeling; Medicinal chemistry; NS5A inhibitors.

A series of novel small-mol. pan-genotypic hepatitis C virus (HCV) NS5A inhibitors with picomolar activity containing 2-[(2S)-pyrrolidin-2-yl]-5-[4-(4-{2-[(2S)-pyrrolidin-2-yl]-1H-imidazol-5-yl}buta-1,3-diyn-1-yl)aryl]-1H-imidazole core was designed based on mol. modeling study and SAR anal. The constructed in silico model and docking study provide a deep insight into the binding mode of this type of NS5A inhibitors. Based on the predicted binding interface authors have prioritized the most crucial diversity points responsible for improving antiviral activity. The synthesized mols. were tested in a cell-based assay, and compound I exhibited an EC50 value in the range of 2.9-34 pM against six genotypes of NS5A HCV, including gT3a, and demonstrated favorable pharmacokinetic profile in rats. This lead compound can be considered as an attractive candidate for further clin. evaluation.

Bioorganic & Medicinal Chemistry published new progress about Alkadiynes Role: PAC (Pharmacological Activity), PKT (Pharmacokinetics), PRP (Properties), RCT (Reactant), SPN (Synthetic Preparation), THU (Therapeutic Use), BIOL (Biological Study), RACT (Reactant or Reagent), PREP (Preparation), USES (Uses). 229009-40-9 belongs to class piperazines, and the molecular formula is C11H17BN2O2, Safety of 4-(4-Methyl-1-piperazinyl)phenylboronic Acid.

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

Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Kosmopoulou, Magda; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; Brandon, Alexis de Haven; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian published the artcile< Optimization of Imidazo[4,5-b]pyridine-Based Kinase Inhibitors: Identification of a Dual FLT3/Aurora Kinase Inhibitor as an Orally Bioavailable Preclinical Development Candidate for the Treatment of Acute Myeloid Leukemia>, Electric Literature of 197638-83-8, the main research area is imidazopyridine FLT3 Aurora kinase inhibitor preparation orally bioavailable; antitumor activity imidazopyridine acute myeloid leukemia.

Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (I), a potent inhibitor of Aurora kinases (Aurora-A Kd = 7.5 nM, Aurora-B Kd = 48 nM), FLT3 kinase (Kd = 6.2 nM), and FLT3 mutants including FLT3-ITD (Kd = 38 nM) and FLT3(D835Y) (Kd = 14 nM). FLT3-ITD causes constitutive FLT3 kinase activation and is detected in 20-35% of adults and 15% of children with acute myeloid leukemia (AML), conferring a poor prognosis in both age groups. In an in vivo setting, I strongly inhibited the growth of a FLT3-ITD-pos. AML human tumor xenograft (MV4-11) following oral administration, with in vivo biomarker modulation and plasma free drug exposures consistent with dual FLT3 and Aurora kinase inhibition. Compound I, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was selected as a preclin. development candidate for the treatment of human malignancies, in particular AML, in adults and children.

Journal of Medicinal Chemistry published new progress about Acute myeloid leukemia. 197638-83-8 belongs to class piperazines, and the molecular formula is C16H22N2O3, Electric Literature of 197638-83-8.

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

Zhou, Min; Ni, Chuanfa; Zeng, Yuwen; Hu, Jinbo published the artcile< Trifluoromethyl Benzoate: A Versatile Trifluoromethoxylation Reagent>, Application In Synthesis of 229009-40-9, the main research area is trifluoromethyl benzoate versatile trifluoromethoxylation reagent; trifluoromethoxylation halogenation aryne.

Trifluoromethyl benzoate (TFBz) is developed as a new shelf-stable trifluoromethoxylation reagent, which can be easily prepared from inexpensive starting materials using KF as the only fluorine source. The synthetic potency of TFBz is demonstrated by trifluoromethoxylation-halogenation of arynes, nucleophilic substitution of alkyl (pseudo)halides, cross-coupling with aryl stannanes, and asym. difunctionalization of alkenes. The unprecedented trifluoromethoxylation-halogenation of arynes proceeds smoothly at room temperature with the aid of a crown ether-complexed potassium cation, which significantly stabilizes the trifluoromethoxide anion derived from TFBz.

Journal of the American Chemical Society published new progress about Alkynes, arynes Role: RCT (Reactant), RACT (Reactant or Reagent). 229009-40-9 belongs to class piperazines, and the molecular formula is C11H17BN2O2, Application In Synthesis of 229009-40-9.

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

Shallal, Hassan M.; Faridi, Jesika S.; Russu, Wade A. published the artcile< Anti-tumor pyrimidinylpiperazines bind to the prosurvival Bcl-2 protein family member Bcl-XL>, Product Details of C13H19BrN4O2, the main research area is pyrimidinylpiperazine preparation Bcl XL protein inhibitor anticancer; piperazine pyrimidinyl preparation Bcl XL protein inhibitor anticancer.

Overexpression of prosurvival or underexpression of pro-death Bcl-2 family proteins can lead to cancer cell resistance to chemotherapy and radiation treatment. Inhibition of the prosurvival Bcl-2 family proteins has become a strategy for cancer therapy and inhibitors are currently being evaluated in the clinic both as single agents and in combination with established drugs. Here, we describe the design, synthesis, and evaluation of pyrimidinylpiperazines I (R = Et, X = H, F, OH, NO2, Y = H, Br, Cl, 1H-pyrazol-4-yl; R = PhCH2, X = H, F, OH, NO2, NH2, Y = H, Br, Cl, 1H-pyrazol-4-yl) that were discovered to be inhibitors of the prosurvival Bcl-2 protein family member Bcl-XL. This study identified compound I (R = PhCH2, X = H, Y = 1H-pyrazol-4-yl), which demonstrated a GI50 value of 8.4 μM against A549 lung adenocarcinoma cells and a binding affinity Ki value for Bcl-XL of 127 nM.

Bioorganic & Medicinal Chemistry Letters published new progress about Antitumor agents. 374930-88-8 belongs to class piperazines, and the molecular formula is C13H19BrN4O2, Product Details of C13H19BrN4O2.

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

He, Chunxian; Preiss, Laura; Wang, Bin; Fu, Lei; Wen, Hui; Zhang, Xiang; Cui, Huaqing; Meier, Thomas; Yin, Dali published the artcile< Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-Dimethylaminomethyl)phenyl)quinoline-Derived Antitubercular Lead Compounds>, Synthetic Route of 229009-40-9, the main research area is quinoline dimethylaminomethyl phenyl preparation antitubercular activity; ATP synthase; Mycobacterium tuberculosis; bedaquiline; multidrug resistance; pulmonary tuberculosis.

Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chem. synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound’s structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogs were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chem. less complex, lower-cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non-ATP synthase related targets.

ChemMedChem published new progress about ATPase inhibitors. 229009-40-9 belongs to class piperazines, and the molecular formula is C11H17BN2O2, Synthetic Route of 229009-40-9.

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

Bachovchin, Kelly A.; Sharma, Amrita; Bag, Seema; Klug, Dana M.; Schneider, Katherine M.; Singh, Baljinder; Jalani, Hitesh B.; Buskes, Melissa J.; Mehta, Naimee; Tanghe, Scott; Momper, Jeremiah D.; Sciotti, Richard J.; Rodriguez, Ana; Mensa-Wilmot, Kojo; Pollastri, Michael P.; Ferrins, Lori published the artcile< Improvement of aqueous solubility of lapatinib-derived analogues: identification of a quinolinimine lead for human African trypanosomiasis drug development>, Recommanded Product: tert-Butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate, the main research area is trypanosomiasis parasiticide quinolinimine lapatinib pharmacokinetics Trypanosoma brucei.

Lapatinib, an approved epidermal growth factor receptor inhibitor, was explored as a starting point for the synthesis of new hits against Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). Previous work culminated in I, which was part of a series typically associated with poor aqueous solubility In this report, we present various medicinal chem. strategies that were used to increase the aqueous solubility and improve the physicochem. profile without sacrificing antitrypanosomal potency. To rank trypanocidal hits, a new assay (summarized in a cytocidal effective concentration (CEC50)) was established, as part of the lead selection process. Increasing the sp3 carbon content of I resulted in II (0.19 μM EC50 against T. brucei and 990 μM aqueous solubility). Further chem. exploration of II yielded III, a trypanocidal quinolinimine (EC50: 0.013 μM; aqueous solubility: 880 μM; and CEC50: 0.18 μM). Compound III reduced parasitemia 109 fold in trypanosome-infected mice; it is an advanced lead for HAT drug development.

Journal of Medicinal Chemistry published new progress about Homo sapiens. 374930-88-8 belongs to class piperazines, and the molecular formula is C13H19BrN4O2, Recommanded Product: tert-Butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate.

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