16013-85-7Relevant academic research and scientific papers
Optimization of 4,6-Disubstituted Pyrido[3,2-d]pyrimidines as Dual MNK/PIM Inhibitors to Inhibit Leukemia Cell Growth
Han, Yu,Zhang, Huimin,Wang, Shuxiang,Li, Bo,Xing, Kun,Shi, Yuntao,Cao, Hongxue,Zhang, Jian,Tong, Tong,Zang, Jie,Guan, Lihong,Gao, Xiaoxiao,Wang, Yuetong,Liu, Dan,Huang, Min,Jing, Yongkui,Zhao, Linxiang
, p. 13719 - 13735 (2021/10/01)
Mitogen-activated protein kinase-interacting kinases (MNKs) and provirus integration in maloney murine leukemia virus kinases (PIMs) are downstream enzymes of cell proliferation signaling pathways associated with the resistance of tyrosine kinase inhibitors. MNKs and PIMs have complementary effects to regulate cap-dependent translation of oncoproteins. Dual inhibitors of MNKs and PIMs have not been developed. We developed a novel 4,6-disubstituted pyrido[3,2-d]pyrimidine compound 21o with selective inhibition of MNKs and PIMs. The IC50’s of 21o to inhibit MNK1 and MNK2 are 1 and 7 nM and those to inhibit PIM1, PIM2, and PIM3 are 43, 232, and 774 nM, respectively. 21o inhibits the growth of myeloid leukemia K562 and MOLM-13 cells with GI50’s of 2.1 and 1.2 μM, respectively. 21o decreases the levels ofp-eIF4E andp-4EBP1, the downstream products of MNKs and PIMs, as well as cap-dependent proteins c-myc, cyclin D1, and Mcl-1. 21o inhibits the growth of MOLM-13 cell xenografts without causing evident toxicity. 21o represents an innovative dual MNK/PIM inhibitor with a good pharmacokinetic profile.
4, 6-disubstituted pyridine [3, 2-d] pyrimidine compound as well as preparation and application thereof
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Paragraph 0100-0103, (2020/04/02)
The invention belongs to the technical field of medicines. The invention relates to the field of pharmaceutical chemistry, in particular to a 4, 6-disubstituted pyridine [3, 2-d] pyrimidine compound and pharmaceutically acceptable salt thereof, a preparation method of the compound, a pharmaceutical composition taking the compound as an active ingredient, and application of the compound in preparation of an MNK inhibitor and drugs for treating and/or preventing various cancers and/or metabolic diseases. The present invention relates to compounds represented by formulas I, II, III or IV, and pharmaceutically acceptable salts, hydrates, solvates and metabolites thereof, wherein the variables are described in the claims and the description.
N-Nitroheterocycles: Bench-Stable Organic Reagents for Catalytic Ipso-Nitration of Aryl- And Heteroarylboronic Acids
Budinská, Alena,Katayev, Dmitry,Passera, Alessandro,Zhang, Kun
supporting information, (2020/03/30)
Photocatalytic and metal-free protocols to access various aromatic and heteroaromatic nitro compounds through ipso-nitration of readily available boronic acid derivatives were developed using non-metal-based, bench-stable, and recyclable nitrating reagents. These methods are operationally simple, mild, regioselective, and possess excellent functional group compatibility, delivering desired products in up to 99% yield.
Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection
Shah, Khushbu,Queener, Sherry,Cody, Vivian,Pace, Jim,Gangjee, Aleem
supporting information, p. 1874 - 1880 (2019/06/08)
Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (pj) can lead to serious health consequences in patients with an immunocompromised system. Trimethoprim (TMP), used as first-line therapy in combination with sulfamethoxazole, is a selective but only moderately potent pj dihydrofolate reductase (pjDHFR) inhibitor, whereas non-clinical pjDHFR inhibitors, such as, piritrexim and trimetrexate are potent but non-selective pjDHFR inhibitors. To meet the clinical needs for a potent and selective pjDHFR inhibitor for PCP treatment, fourteen 6-substituted pyrido[3,2-d]pyrimidines were developed. Comparison of the amino acid residues in the active site of pjDHFR and human DHFR (hDHFR) revealed prominent amino acid differences which could be exploited to structurally design potent and selective pjDHFR inhibitors. Molecular modeling followed by enzyme assays of the compounds revealed 15 as the best compound of the series with an IC50 of 80 nM and 28-fold selectivity for inhibiting pjDHFR over hDHFR. Compound 15 serves as the lead analog for further structural variations to afford more potent and selective pjDHFR inhibitors.
Preparation method of 2,6-dichloro-3-nitropyridine
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Paragraph 0040-0045, (2019/10/01)
The invention relates to a 2,6-Dichloro-3-Preparation method of nitropyridine. The method uses 2-Nitroacetate and 2-Halogenated acrylates are catalyzed by organic bases for 1,4-Addition reaction followed by cyclization reaction with ammonia to obtain 2,6-Dihydroxy-3-Nitropyridine is then reacted with a chlorinating reagent to produce 2,6-Dichloro-3-Nitropyridine. The invention does not use concentrated sulfuric acid and nitric acid, the used raw materials are cheap and easily available, the operation is simple and convenient, the conditions are mild, the amount of waste water is small, the invention is safe and environment-friendly and the cost is low.
MONOCYCLIC, THIENO, PYRIDO, AND PYRROLO PYRIMIDINE COMPOUNDS AND METHODS OF USE AND MANUFACTURE OF THE SAME
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Page/Page column 33-34, (2017/03/21)
The present invention provides monocyclic, thieno, pyrido and pyrrolo pyrimidine compounds. Pharmaceutical compositions comprising one or more of these compounds and optionally comprising a pharmaceutically acceptable salt or hydrate of one or more of the compounds are provided. Preferably, these pharmaceutical compositions further comprise at least one pharmaceutically acceptable carrier. Methods of treating a patient having cancer are provided wherein a therapeutically effective amount of one or more of these compounds or pharmaceutical compositions are administered to the patient.
A 5 (4H)-pyridone combines furazane oxide synthesis method
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Paragraph 0032-0033, (2017/04/11)
The invention discloses a synthesis method of 4H-pyridofuroxan-5-one (III, also known as 4H, 5H-(1, 2, 5) oxadiazole (3, 4-b) pyridin-5-one-1-oxide). The synthesis method comprises the following steps (see the following reaction formula): enabling 2-amino-3-nitro-6-chloropyridine (I) to react with potassium (or sodium and the like) fluoride in a water-containing alcohol type solution, or enabling I to react with a nitrite in acetone to prepare 2-amino-3-nitro-6-hydroxypyridine (II); then performing oxidation and condensation reaction under alkaline conditions to prepare III. The synthesis process disclosed by the invention is simple and convenient to operate, and suitable for relatively large-scale production of III; a new way is provided for preparing anti-virus and anti-tumor compounds with the effect of releasing nitric oxide (NO).
Oxidation potentials of N-modified derivatives of the analgesic flupirtine linked to potassium KV7 channel opening activity but not hepatocyte toxicity
Lemmerhirt, Christian J.,Rombach, Mirko,Bodtke, Anja,Bednarski, Patrick J.,Link, Andreas
, p. 368 - 379 (2015/02/05)
Openers of neuronal voltage-gated potassium channels (KV) are of interest as therapeutic agents for treating pain (flupirtine) and epilepsy (retigabine). In an effort to better understand the mechanisms of action and toxicity of flupirtine, we synthesized nine novel analogues with varying redox behavior. Flupirtine can be oxidatively metabolized into azaquinone di-imines; thus, the oxidation potentials of flupirtine and its analogues were measured by cyclic voltammetry. KV7.2/3 (KCNQ2/3) opening activity was determined by an established assay with HEK293 cells overexpressing these channels. A link was found between the oxidation potentials of the compounds and their EC50 values for potassium channel opening activity. On the other hand, no correlation was observed between oxidation potentials and cytotoxicity in cultures of transgenic mouse hepatocytes (TAMH). These results support the idea that oxidative metabolites of flupirtine contribute to the mechanism of action, similar to what was recently proposed for acetaminophen (paracetamol), but not to hepatotoxicity.
INHIBITORS OF DNA GYRASE FOR THE TREATMENT OF BACTERIAL INFECTIONS
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Page/Page column 47, (2014/05/07)
The present invention relates to compounds which specifically inhibit bacterial DNA Gyrase and can be used for the treatment of respiratory tract infections.
