Category: 721401-43-0

Zhao, Yujun; Bai, Longchuan; Liu, Liu; McEachern, Donna; Stuckey, Jeanne A.; Meagher, Jennifer L.; Yang, Chao-Yie; Ran, Xu; Zhou, Bing; Hu, Yang; Li, Xiaoqin; Wen, Bo; Zhao, Ting; Li, Siwei; Sun, Duxin; Wang, Shaomeng published the artcile< Structure-Based Discovery of 4-(6-Methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (CD161) as a Potent and Orally Bioavailable BET Bromodomain Inhibitor>, Safety of Isoquinolin-8-ylboronic acid, the main research area is quinolinyl pyrimidoindolyl dimethylisoxazole preparation oral BET bromodomain inhibitor.

A series of 9H-pyrimido[4,5-b]indole-containing compounds was designed and synthesized to obtain potent and orally bioavailable BET inhibitors. By incorporation of an indole or a quinoline moiety to the 9H-pyrimido[4,5-b]indole core, we identified a series of small mols. showing high binding affinities to BET proteins and low nanomolar potencies in inhibition of cell growth in acute leukemia cell lines. One such compound, 4-(6-methoxy-2-methyl-4-(quinolin-4-yl)-9H-pyrimido[4,5-b]indol-7-yl)-3,5-dimethylisoxazole (I) has excellent microsomal stability and good oral pharmacokinetics in rats and mice. Orally administered, I achieves significant antitumor activity in the MV4;11 leukemia and MDA-MB-231 triple-neg. breast cancer xenograft models in mice. Determination of the cocrystal structure of I with BRD4 BD2 provides a structural basis for its high binding affinity to BET proteins. Testing its binding affinities against other bromodomain-containing proteins shows that I is a highly selective inhibitor of BET proteins. These data show that I is a potent, selective, and orally active BET inhibitor.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 721401-43-0 belongs to class isoquinoline, and the molecular formula is C9H8BNO2, Safety of Isoquinolin-8-ylboronic acid.

Referemce:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

Liao, Lan-Shan; Tan, Lin-Jie; Chen, Yin; Yang, Qi-Yuan; Choudhary, Muhammad Iqbal; Pan, Ying-Ming; Tang, Hai-Tao; Su, Gui-Fa; Liang, Hong; Chen, Zhen-Feng published the artcile< One-pot synthesis of oxoaporphines as potent antitumor agents and investigation of their mechanisms of actions>, Reference of 721401-43-0, the main research area is oxoporphine derivative preparation antitumor agents; Antitumor activity; Apoptosis; Cell cycle; Oxoaporphine.

An efficient one-pot reaction for the synthesis of oxoaporphine alkaloids has been developed. Twenty-three compounds of oxoaporphine alkaloids were prepared and assessed for their antitumor activities. Most compounds inhibited the growth of T-24 tumor cells in vitro. Particularly, I displayed the most potent activity with an IC50 value of 0.5μM, which was 19-fold more potent than the parent compound 4. The substitution at C3-position of oxoaporphine core by -NO2 significantly enhanced the anticancer activity. Mechanism studies indicated that II and I induced cell cycle arrest at G2/M phase; in contrast, III induced cell cycle arrest at the S phase. Increase of mitochondrial ROS/Ca2+ and decrease of MMP, accompanied by activation of caspase-3/9, were observed in T-24 cells after exposure to compounds I, II and III, suggesting that the mitochondrial pathway was involved in the induced apoptosis. Moreover, compound I effectively inhibited tumor growth in a mouse xenograft model bearing T-24.

European Journal of Medicinal Chemistry published new progress about Alkaloids Role: PAC (Pharmacological Activity), SPN (Synthetic Preparation), BIOL (Biological Study), PREP (Preparation). 721401-43-0 belongs to class isoquinoline, and the molecular formula is C9H8BNO2, Reference of 721401-43-0.

Referemce:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

Cheng, Yunfeng; Ni, Nanting; Yang, Wenqian; Wang, Binghe published the artcile< A New Class of Fluorescent Boronic Acids That Have Extraordinarily High Affinities for Diols in Aqueous Solution at Physiological pH>, Application of C9H8BNO2, the main research area is fluorescent boronate high affinity diol aqueous solution physiol pH.

The boronic acid group is an important recognition moiety for sensor design. Herein, the authors report a series of isoquinolinylboronic acids that have extraordinarily high affinities for diol-containing compounds at physiol. pH. In addition, 5- and 8-isoquinolinylboronic acids also showed fairly high binding affinities towards D-glucose (Ka=42 and 46 M-1, resp.). For the first time, weak but encouraging binding of cis-cyclohexanediol was found for these boronic acids. Such binding was coupled with significant fluorescence changes. Furthermore, 4- and 6-isoquinolinylboronic acids also showed the ability to complex Me α-D-glucopyranose (Ka=3 and 2 M-1, resp.).

Chemistry – A European Journal published new progress about Affinity. 721401-43-0 belongs to class isoquinoline, and the molecular formula is C9H8BNO2, Application of C9H8BNO2.

Referemce:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

Berthel, Steven J.; Marks, Ian M.; Yin, Xuefeng; Mischke, Steven G.; Orzechowski, Lucja; Pezzoni, Gabriella; Sala, Franca; Vassilev, Lyubomir T. published the artcile< Identification of phenyl-pyridine-2-carboxylic acid derivatives as novel cell cycle inhibitors with increased selectivity for cancer cells>, Application In Synthesis of 721401-43-0, the main research area is phenylpyridine carboxylate derivative preparation structure activity antitumor cell cycle; Ro414439 cell cycle antitumor breast cancer mitosis structure activity.

Ro 41-4439, a phenyl-pyridine-2-carboxylic acid derivative, was identified by a cell-based screening approach that exploits the differences between normal and cancer cells in their sensitivity to cytotoxic agents. This compound showed low micromolar antiproliferative activity and cytotoxicity against a broad panel of human cancer cell lines in vitro, and over 10-fold selectivity to cancer cells when tested in parallel with a panel of proliferating normal human cells. Cytotoxicity of Ro 41-4439 is due to arrest of cell cycle progression in mitosis followed by induction of apoptosis. Four-week treatment of nude mice bearing established mammary tumor xenografts (MDA-MB-435) with well-tolerated doses of the compound showed 73% inhibition of tumor growth. Limited exploration of structure-activity relationships involving side chain length, and aryl and pyridine rings allowed for the identification of more potent analogs.

Anti-Cancer Drugs published new progress about Antitumor agents. 721401-43-0 belongs to class isoquinoline, and the molecular formula is C9H8BNO2, Application In Synthesis of 721401-43-0.

Referemce:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

Favalli, Nicholas; Bassi, Gabriele; Bianchi, Davide; Scheuermann, Jorg; Neri, Dario published the artcile< Large screening of DNA-compatible reaction conditions for Suzuki and Sonogashira cross-coupling reactions and for reverse amide bond formation>, COA of Formula: C9H8BNO2, the main research area is alkyne pinacol borane boronic acid DNA synthesis carboxylic acid; Suzuki Sonogashira cross coupling reverse amide formation DNA compatible; DNA-compatible reactions; DNA-encoded libraries; Reverse amide bond formation; Sonogashira cross-coupling; Suzuki cross-coupling.

Progress in DNA-encoded chem. library synthesis and screening crucially relies on the availability of DNA-compatible reactions, which proceed with high yields and excellent purity for a large number of possible building blocks. In the past, exptl. conditions have been presented for the execution of Suzuki and Sonogashira cross-coupling reactions on-DNA. In this article, our aim was to optimize Suzuki and Sonogashira reactions, comparing our results to previously published procedures. We have tested the performance of improved conditions using 606 building blocks (including boronic acids, pinacol boranes and terminal alkynes), achieving >70% conversion for 84% of the tested mols. Moreover, we describe efficient exptl. conditions for the on-DNA synthesis of amide bonds, starting from DNA derivatives carrying a carboxylic acid moiety and 300 primary, secondary and aromatic amines, as amide bonds are frequently found in DNA-encoded chem. libraries thanks to their excellent DNA compatibility.

Bioorganic & Medicinal Chemistry published new progress about Boronic acids Role: RCT (Reactant), SPN (Synthetic Preparation), RACT (Reactant or Reagent), PREP (Preparation). 721401-43-0 belongs to class isoquinoline, and the molecular formula is C9H8BNO2, COA of Formula: C9H8BNO2.

Referemce:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

Li, Shasha; Pissarnitski, Dmitri; Nowak, Timothy; Wleklinski, Michael; Krska, Shane W. published the artcile< Merging Late-Stage Diversification with Solid-Phase Peptide Synthesis Enabled by High-Throughput On-Resin Reaction Screening>, HPLC of Formula: 721401-43-0, the main research area is solid phase peptide synthesis high throughput experimentation; Suzuki Miyaura coupling peptide boronic acid library.

An integrated workflow is described that combines micromole-scale high-throughput experimentation (HTE) reaction screening and solid-phase peptide synthesis (SPPS) to enable rapid synthetic method development for on-resin peptide diversification. Using this new approach, we have identified several sets of robust Suzuki-Miyaura coupling conditions with complementary scope that collectively display broad coverage with respect to both resin-bound peptide substrates containing aryl halide side chains and (hetero)arylboronic acid coupling partners. We have also demonstrated the utility of this integrated SPPS/chem. diversification method by synthesizing a multidimensional library of diverse peptides in high yields.

ACS Catalysis published new progress about Amino acids Role: CMB (Combinatorial Study), RCT (Reactant), RACT (Reactant or Reagent). 721401-43-0 belongs to class isoquinoline, and the molecular formula is C9H8BNO2, HPLC of Formula: 721401-43-0.

Referemce:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

Kimura, Hidenori; Suda, Hitoshi; Kassai, Momoe; Endo, Mika; Deai, Yoko; Yahata, Masahiro; Miyajima, Mari; Isobe, Yoshiaki published the artcile< N-(6-phenylpyridazin-3-yl)benzenesulfonamides as highly potent, brain-permeable, and orally active kynurenine monooxygenase inhibitors>, Electric Literature of 721401-43-0, the main research area is Huntington disease pyridazinylsulfonamide kynurenine monooxygenase inhibitor neuroprotection; 3-HK; BBB; Brain permeable; Huntington’s disease; KMO; KYNA; Kynurenine monooxygenase; Kynurenine pathway; R6/2.

Huntington’s disease (HD) is one of the serious neurodegenerative diseases and no disease modifiers are available to date. The correction of unbalanced kynurenine pathway metabolites may be useful to treat disease progression and kynurenine monooxygenase (KMO) is considered an ideal drug target. A couple of KMO inhibitors have been reported, but their brain permeability was very poor. We found pyridazinylsulfonamide as a novel lead compound, and it was optimized to the brain-permeable and highly potent KMO inhibitor 12, which was equipotent with CHDI-340246 and superior to CHDI-340246 in terms of brain penetration. Compound 12 was effective in R6/2 mice (HD model mice), i.e. neuroprotective kynurenic acid was increased, whereas neurotoxic 3-hydroxykynurenine was suppressed. In addition, impaired cognitive function was improved. Therefore, the brain-permeable KMO inhibitor was considered to be a disease modifier for HD treatment.

Bioorganic & Medicinal Chemistry Letters published new progress about Ataxia. 721401-43-0 belongs to class isoquinoline, and the molecular formula is C9H8BNO2, Electric Literature of 721401-43-0.

Referemce:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

Ni, Nanting; Laughlin, Sarah; Wang, Yingji; Feng, You; Zheng, Yujun; Wang, Binghe published the artcile< Probing the general time scale question of boronic acid binding with sugars in aqueous solution at physiological pH>, Computed Properties of 721401-43-0, the main research area is boronate sugar carbohydrate.

The boronic acid group is widely used in chemosensor design due to its ability to reversibly bind diol-containing compounds The thermodn. properties of the boronic acid-diol binding process have been investigated extensively. However, there are few studies of the kinetic properties of such binding processes. In this report, stopped-flow method was used for the first time to study the kinetic properties of the binding between three model arylboronic acids, 4-, 5-, and 8-isoquinolinylboronic acids, and various sugars. With all the boronic acid-diol pairs examined, reactions were complete within seconds. The kon values with various sugars follow the order of D-fructose > D-tagatose > D-mannose > D-glucose. This trend tracks the thermodn. binding affinities for these sugars and demonstrates that the ‘on’ rate is the key factor determining the binding constant

Bioorganic & Medicinal Chemistry published new progress about Boronic acids Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 721401-43-0 belongs to class isoquinoline, and the molecular formula is C9H8BNO2, Computed Properties of 721401-43-0.

Referemce:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

Yu, Mingfeng; Teo, Theodosia; Yang, Yuchao; Li, Manjun; Long, Yi; Philip, Stephen; Noll, Benjamin; Heinemann, Gary K.; Diab, Sarah; Eldi, Preethi; Mekonnen, Laychiluh; Anshabo, Abel T.; Rahaman, Muhammed H.; Milne, Robert; Hayball, John D.; Wang, Shudong published the artcile< Potent and orally bioavailable CDK8 inhibitors: Design, synthesis, structure-activity relationship analysis and biological evaluation>, Related Products of 721401-43-0, the main research area is pyridine preparation structure activity relationship biol evaluation CDK8 inhibitor; CDK8 inhibitor; Drug-like properties; Pharmacokinetics; Structure-activity relationship; Toxicity.

CDK8 regulates transcription either by phosphorylation of transcription factors or, as part of a four-subunit kinase module, through a reversible association of the kinase module with the Mediator complex, a highly conserved transcriptional coactivator. Deregulation of CDK8 has been found in various types of human cancer, while the role of CDK8 in suppressing anti-cancer response of natural killer cells is being understood. Currently, CDK8-targeting cancer drugs are highly sought-after. Herein authors detail the discovery of a series of novel pyridine-derived CDK8 inhibitors. Medicinal chem. optimization gave rise to I (AU1-100), a potent CDK8 inhibitor with oral bioavailability. The compound inhibited the proliferation of MV4-11 acute myeloid leukemia cells with the kinase activity of cellular CDK8 dampened. No systemic toxicol. was observed in the mice treated with I. These results warrant further pre-clin. studies of I as an anti-cancer agent.

European Journal of Medicinal Chemistry published new progress about Antitumor agents. 721401-43-0 belongs to class isoquinoline, and the molecular formula is C9H8BNO2, Related Products of 721401-43-0.

Referemce:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

Chilamari, Maheshwerreddy; Immel, Jacob R.; Bloom, Steven published the artcile< General Access to C-Centered Radicals: Combining a Bioinspired Photocatalyst with Boronic Acids in Aqueous Media>, HPLC of Formula: 721401-43-0, the main research area is radical preparation photocatalyzed oxidation boronic acid catalyst reaction mechanism; conjugate addition reaction radical Michael acceptor.

Carbon-centered radicals are indispensable building blocks for modern synthetic chem. In recent years, visible light photoredox catalysis has become a promising avenue to access C-centered radicals from a broad array of latent functional groups, including boronic acids. Herein, we present an aqueous protocol wherein water features a starring role to help transform aliphatic, aromatic, and heteroaromatic boronic acids to C-centered radicals with a bioinspired flavin photocatalyst. These radicals are used to deliver a diverse pool of alkylated products, including three pharmaceutically relevant compounds, via open-shell conjugate addition to disparate Michael acceptors. The mechanism of the reaction is investigated by computational studies, deuterium labeling, radical-trapping experiments, and spectroscopic anal.

ACS Catalysis published new progress about Alkylation (deborylative-alkylation). 721401-43-0 belongs to class isoquinoline, and the molecular formula is C9H8BNO2, HPLC of Formula: 721401-43-0.

Referemce:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem