Month: October 2022

The author of 《Design, synthesis and biological evaluation of AZD9291 derivatives as selective and potent EGFRL858R/T790M inhibitors》 were Zhao, Bingbing; Xiao, Zhen; Qi, Jianguo; Luo, Rong; Lan, Zhou; Zhang, Yanzhuo; Hu, Xiaohan; Tang, Qidong; Zheng, Pengwu; Xu, Shan; Zhu, Wufu. And the article was published in European Journal of Medicinal Chemistry in 2019. Application In Synthesis of 2,4-Dichloropyrimidine The author mentioned the following in the article:

Third-generation epidermal growth factor receptor (EGFR)L858R/T790M inhibitors are still the main drugs for the treatment of advanced non-small cell lung cancer (NSCLC), and these drugs have achieved remarkable clin. efficacy. However, there are still many patients suffering from drug-resistant mutations and drug side effects caused by NSCLC. In this study, guided by the mol. simulation, we applied a structure-based drug design strategy (SBDD) and optimized the structure to obtain a series of potent and selective EGFRL858R/T790M inhibitors. The most potent compound 18e demonstrated excellent kinase inhibitory activity and selectivity for EGFRL858R/T790M double mutants and the IC50 value reached nanomolar level. The selectivity of 18e against wild-type EGFR was near to 200-fold. In addition, compound 18e also inhibited H1975 cells proliferation at G2/M phase and induced apoptosis at a concentration of 0.25 μM, which makes it more valuable for potential lung cancer research. In the part of experimental materials, we found many familiar compounds, such as 2,4-Dichloropyrimidine(cas: 3934-20-1Application In Synthesis of 2,4-Dichloropyrimidine)

2,4-Dichloropyrimidine(cas: 3934-20-1) is a member of organic chlorides. Organic chloride content in crude oil can be detected through specialized laboratory analysis. Care and attention are essential while sampling and testing.Application In Synthesis of 2,4-Dichloropyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

The author of 《I-8, a novel inhibitor of mutant IDH1, inhibits cancer progression in vitro and in vivo》 were Jia, Panli; Wu, Yao; Du, Hongzhi; Yang, Lijun; Zhang, Zhibo; Ma, Tianfang; Li, Sun; Yuan, Shengtao; Lu, Ligong; Zha, Xiaoming. And the article was published in European Journal of Pharmaceutical Sciences in 2019. Application In Synthesis of 2,4-Dichloropyrimidine The author mentioned the following in the article:

Isocitrate dehydrogenase 1 mutations have been discovered in an array of hematol. malignancies and solid tumors. These mutations could cause the production of high levels of 2-hydroxyglutarate, which in turn implicated in epigenetic changes and impaired cell differentiation. Here, we described the characterization of compound I-8, a novel mutant IDH1 inhibitor, both in vitro and in vivo. Compound I-8 specifically inhibited 2-HG production, reduced histone methylation levels, induced differentiation and depleted stem characteristics in engineered and endogenous IDH1 mutant cells. In addition, oral administration of I-8 also significantly suppressed 2-HG production and histone methylation with dose of 150 mg/kg. And I-8 treatment also could induce differentiation and attenuate stem characteristics in tumor tissue. Together, these studies indicated that compound I-8 has clin. potential in tumor therapies as a effective mutant IDH1 inhibitor, and provided scientific guidance for the development of mutant IDH1 inhibitor in the future. In addition to this study using 2,4-Dichloropyrimidine, there are many other studies that have used 2,4-Dichloropyrimidine(cas: 3934-20-1Application In Synthesis of 2,4-Dichloropyrimidine) was used in this study.

2,4-Dichloropyrimidine(cas: 3934-20-1) is a member of organic chlorides. Organic chloride content in crude oil can be detected through specialized laboratory analysis. Care and attention are essential while sampling and testing.Application In Synthesis of 2,4-Dichloropyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Jiang, Xiangyi; Huang, Boshi; Olotu, Fisayo A.; Li, Jing; Kang, Dongwei; Wang, Zhao; De Clercq, Erik; Soliman, Mahmoud E. S.; Pannecouque, Christophe; Liu, Xinyong; Zhan, Peng published their research in European Journal of Medicinal Chemistry in 2021. The article was titled 《Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: Discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp3 values and favorable drug-like properties》.Name: 2,4-Dichloropyrimidine The article contains the following contents:

A series of novel diarylpyrimidine derivatives I [R1 = cyano, 2-cyanovinyl; R = thiomorpholino, 1-oxo-1,4-thiazinan-4-yl, 1,1-dioxo-1,4-thiazinan-4-yl, etc.] targeted the tolerant region I of the NNRTI binding pocket were designed, synthesized and biol. evaluated as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with favorable drug-like properties was studied. The most active inhibitor I [R1 = 2-cyanovinyl; R = 1,1-dioxo-1,4-thiazinan-4-yl] exhibited outstanding antiviral activity against most of the viral panel, being about 2-fold (wild-type, EC50 = 0.0021μM), 1.7-fold (K103N, EC50 = 0.0019μM), and slightly more potent (E138K, EC50 = 0.0075μM) than the NNRTI drug etravirine (ETR). Addnl., I [R1 = 2-cyanovinyl; R = 1,1-dioxo-1,4-thiazinan-4-yl] was endowed with relatively low cytotoxicity (CC50 = 18.52μM). More importantly, I [R1 = 2-cyanovinyl; R = 1,1-dioxo-1,4-thiazinan-4-yl] possessed improved drug-like properties compared to those of ETR with an increased F sp3 (Fraction of sp3 carbon atoms) value. Furthermore, the mol. dynamics simulation and mol. docking studies were implemented to reveal the binding mode of I [R1 = 2-cyanovinyl; R = 1,1-dioxo-1,4-thiazinan-4-yl] in the binding pocket. Taken together, I [R1 = 2-cyanovinyl; R = 1,1-dioxo-1,4-thiazinan-4-yl] was a promising lead compound that was worth further investigation. In the experimental materials used by the author, we found 2,4-Dichloropyrimidine(cas: 3934-20-1Name: 2,4-Dichloropyrimidine)

2,4-Dichloropyrimidine(cas: 3934-20-1) is a member of organic chlorides. Organic chloride content in crude oil can be detected through specialized laboratory analysis. Care and attention are essential while sampling and testing.Name: 2,4-Dichloropyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Chen, Tianpeng; Wei, Yingying; Zhu, Gaoyang; Zhao, Huajun; Zhang, Xingxian published an article in 2021. The article was titled 《Design, synthesis and structure-activity relationship studies of 4-indole-2-arylaminopyrimidine derivatives as anti-inflammatory agents for acute lung injury》, and you may find the article in European Journal of Medicinal Chemistry.Computed Properties of C4H2Cl2N2 The information in the text is summarized as follows:

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), a clin. high mortality disease, has not been effectively treated till now, and the development of anti-acute lung injury drugs is imminent. Acute lung injury was efficiently treated by inhibiting the cascade of inflammation, and reducing the inflammatory response in the lung. A series of novel compounds with highly efficient inhibiting the expression of inflammatory factors were designed by using 4-indolyl-2-aminopyrimidine as the core skeleton. Totally eleven 4-indolyl-2-arylaminopyrimidine derivatives were designed and synthesized. As well, the related anti-ALI activity of these compounds was evaluated. Compounds I and II showed a superior activity among these compounds, and the inhibition rate of IL-6 and IL-8 release ranged from 62% to 77%, and from 65% to 72%, resp. Furthermore, most of compounds had no significant cytotoxicity in vitro. The infiltration of inflammatory cells into lung tissue significantly reduced by using compound II (20 mg/kg) in the ALI mice model, which achieved the effect of protecting lung tissue and improving ALI. In addition, the inflammatory response was inhibited by using compound II through inhibiting phosphorylation of p-38 and ERK in MAPK signaling pathway, and resulted in protective effect on ALI. These data indicated that compound II showed good anti-inflammatory activity in vitro and in vivo, which was expected to become a leading compound for the treatment of ALI. In the experiment, the researchers used many compounds, for example, 2,4-Dichloropyrimidine(cas: 3934-20-1Computed Properties of C4H2Cl2N2)

2,4-Dichloropyrimidine(cas: 3934-20-1) is a member of organic chlorides. Organic chloride content in crude oil can be detected through specialized laboratory analysis. Care and attention are essential while sampling and testing.Computed Properties of C4H2Cl2N2

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Barbosa da Silva, Elany; Rocha, Debora A.; Fortes, Isadora S.; Yang, Wenqian; Monti, Ludovica; Siqueira-Neto, Jair L.; Caffrey, Conor R.; McKerrow, James; Andrade, Saulo F.; Ferreira, Rafaela S. published an article in 2021. The article was titled 《Structure-Based Optimization of Quinazolines as Cruzain and TbrCATL Inhibitors》, and you may find the article in Journal of Medicinal Chemistry.Reference of 2,4-Dichloropyrimidine The information in the text is summarized as follows:

The cysteine proteases, cruzain and TbrCATL (rhodesain), are therapeutic targets for Chagas disease and Human African Trypanosomiasis, resp. Among the known inhibitors for these proteases, N4-benzyl-N2-phenylquinazoline-2,4-diamine (1a I [R1 = phenyl; R2 = benzyl] in this study), as a competitive cruzain inhibitor (Ki = 1.4μM) was described. The synthesis and biol. evaluation of 22 analogs I [R1 = Ph, 4-OH-Ph, 2-pyridyl; R2 = benzyl, Ph, 3-Cl-Ph, etc] of I [R1 = phenyl; R2 = benzyl], containing modifications in the quinazoline core, and in the substituents in positions 2 and 4 of this ring was described. The analogs I demonstrate low micromolar inhibition of the target proteases and cidal activity against Trypanosoma cruzi with up to two log selectivity indexes in counterscreens with myoblasts. Fourteen compounds were active against Trypanosoma brucei at low to mid micromolar concentrations During the optimization of I [R1 = phenyl; R2 = benzyl], structure-based design and prediction of physicochem. properties were employed to maintain potency against the enzymes while removing colloidal aggregator characteristics observed for some mols. in this series.2,4-Dichloropyrimidine(cas: 3934-20-1Reference of 2,4-Dichloropyrimidine) was used in this study.

2,4-Dichloropyrimidine(cas: 3934-20-1) is a member of organic chlorides. Organic chloride content in crude oil can be detected through specialized laboratory analysis. Care and attention are essential while sampling and testing.Reference of 2,4-Dichloropyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

In 2022,Yang, Tingting; Zhang, Wenjuan; Cao, Shengjie; Sun, Shiyang; Cai, Xu; Xu, Lei; Li, Pengyun; Zheng, Zhibing; Li, Song published an article in European Journal of Medicinal Chemistry. The title of the article was 《Discovery of highly potent and selective EGFRT790M/L858R TKIs against NSCLC based on molecular dynamic simulation》.Synthetic Route of C4H2Cl2N2 The author mentioned the following in the article:

Epidermal growth factor receptor (EGFR) is the most attractive target for drug research in non-small cell lung cancer (NSCLC). There have been three generation drugs developed to treat of NSCLC. The third-generation EGFR tyrosine kinase inhibitors (TKIs) Rociletinib and Osimertinib (AZD9291) achieved remarkable clin. efficacy. However, due to the inhibitory activity against the wild-type EGFR, the side effect of associated skin rash and gastrointestinal toxicity appeared. Thus, there is still an urgent need to develop novel inhibitors with potent inhibitory activity and high selectivity for T790M-containing EGFR over EGFRWT. Herein, guided by the mol. dynamic simulation results, a series of potent and selective Osimertinib derivatives were designed, synthesized and evaluated. The promising compounds N-(2-((2-((4-bromobenzyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide, N-(2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)-4-bromo-N-methylbenzamide, N-(2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)-N-methyl-but-2-ynamide, N-(4-methoxy-2-(methyl(2-(methyl(prop-2-yn-1-yl)amino)ethyl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide and N-(2-((2-(benzyl(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide demonstrated excellent kinase inhibitory activity and high selectivity for EGFRT790M/L858R mutant. The selectivity of N-(2-((2-((4-bromobenzyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide to EGFRT790M/L858R was the highest in the current known compounds near to 2500-fold. In addition, the compound N-(2-((2-((4-bromobenzyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide showed considerable activity against NCI-H1975 and HCC827 cells, arrested NCI-H1975 cell cycle at the G2/M stage and significantly induced apoptosis in NCI-H1975 cell. These encouraged results indicated that N-(2-((2-((4-bromobenzyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide will be used as a candidate targeting EGFRT790M/L858R for further pharmacodynamic and pharmacokinetic studies, and all these studies provide important clues for the discovery of potent EGFRT790M/L858R inhibitors with high selectivity. The experimental process involved the reaction of 2,4-Dichloropyrimidine(cas: 3934-20-1Synthetic Route of C4H2Cl2N2)

2,4-Dichloropyrimidine(cas: 3934-20-1) is a member of organic chlorides. Organic chloride content in crude oil can be detected through specialized laboratory analysis. Care and attention are essential while sampling and testing.Synthetic Route of C4H2Cl2N2

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Safety of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidineIn 2020 ,《Purine/purine isoster based scaffolds as new derivatives of benzamide class of HDAC inhibitors》 appeared in European Journal of Medicinal Chemistry. The author of the article were Nepali, Kunal; Chang, Ting-Yu; Lai, Mei-Jung; Hsu, Kai-Cheng; Yen, Yun; Lin, Tony Eight; Lee, Sung-Bau; Liou, Jing-Ping. The article conveys some information:

This study reports the design, synthesis and evaluation of a series of histone deacetylase (HDAC) inhibitors I (X = Cl, methylazanyl, (3-chloro-4-fluorophenyl)azanyl, etc.; Y = Cl, NH2, (2,4,6-trichloro-3,5-dimethoxyphenyl)azanyl; Z = N, CH; R = H, F) containing purine/purine isoster as a capping group and an N-(2-aminophenyl)-benzamide unit. In vitro cytotoxicity studies reveal that benzamide I (X = (3-chloro-4-fluorophenyl)azanyl; Y = NH2; Z = N; R = H) (A) suppressed the growth of triple-neg. breast cancer cells MDA-MB-231 (IC50 = 1.48μM), MDA-MB-468 (IC50 = 0.65μM), and liver cancer cells HepG2 (IC50 = 2.44μM), better than MS-275 and Chidamide. Compared to the well-known HDAC inhibitor SAHA, (A) showed a higher toxicity (IC50 = 0.33μM) in three leukemic cell lines, K-562, KG-1 and THP-1. Moreover, (A) was found to be equally virulent in the HDAC-sensitive and -resistant gastric cell lines, YCC11 and YCC3/7, resp., indicating the potential of (A) to overcome HDACi resistance. Furthermore, substantial inhibitory effects more pronounced than MS-275 and Chidamide were displayed by (A) towards HDAC1, 2 and 3 isoforms with IC50 values of 0.108, 0.585 and 0.563μM resp. Compound (A) also exhibited a potent antitumor efficacy in human MDA-MB-231 breast cancer xenograft mouse model, providing a potential lead for the development of anticancer agents. In the experiment, the researchers used 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4Safety of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine)

2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4) belongs to pyrimidine. The pyrimidine ring system has wide occurrence in nature as substituted and ring fused compounds and derivatives, including the nucleotides cytosine, thymine and uracil, thiamine (vitamin B1) and alloxan. Safety of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Related Products of 3764-01-0In 2021 ,《Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies》 appeared in Journal of Medicinal Chemistry. The author of the article were Soares de Melo, Candice; Singh, Vinayak; Myrick, Alissa; Simelane, Sandile B.; Taylor, Dale; Brunschwig, Christel; Lawrence, Nina; Schnappinger, Dirk; Engelhart, Curtis A.; Kumar, Anuradha; Parish, Tanya; Su, Qin; Myers, Timothy G.; Boshoff, Helena I. M.; Barry, Clifton E. III; Sirgel, Frederick A.; van Helden, Paul D.; Buchanan, Kirsteen I.; Bayliss, Tracy; Green, Simon R.; Ray, Peter C.; Wyatt, Paul G.; Basarab, Gregory S.; Eyermann, Charles J.; Chibale, Kelly; Ghorpade, Sandeep R.. The article conveys some information:

Phenotypic screening of a Medicines for Malaria Venture compound library against Mycobacterium tuberculosis (Mtb) identified a cluster of pan-active 2-pyrazolylpyrimidinones. The biol. triage of these actives using various tool strains of Mtb suggested a novel mechanism of action. The compounds were bactericidal against replicating Mtb and retained potency against clin. isolates of Mtb. Although selected MmpL3 mutant strains of Mtb showed resistance to these compounds, there was no shift in the min. inhibitory concentration (MIC) against a mmpL3 hypomorph, suggesting mutations in MmpL3 as a possible resistance mechanism for the compounds but not necessarily as the target. RNA transcriptional profiling and the checkerboard board 2D-MIC assay in the presence of varying concentrations of ferrous salt indicated perturbation of the Fe-homeostasis by the compounds Structure-activity relationship studies identified potent compounds with good physicochem. properties and in vitro microsomal metabolic stability with moderate selectivity over cytotoxicity against mammalian cell lines. After reading the article, we found that the author used 2,4,6-Trichloropyrimidine(cas: 3764-01-0Related Products of 3764-01-0)

2,4,6-Trichloropyrimidine(cas: 3764-01-0) is a member of organic chlorides. Organic chlorides are compounds containing a carbon-chlorine bond, which are widely used in the oil field as a wax dissolver. They are generally not present in crude oils and are typically the result of additives, cleaning solutions or chemicals used for oil recovery.Related Products of 3764-01-0

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Quality Control of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidineIn 2019 ,《Design, synthesis and biological evaluation of novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potential FAK inhibitors and anticancer agents》 appeared in European Journal of Medicinal Chemistry. The author of the article were Wang, Ruifeng; Chen, Yixuan; Zhao, Xiangxin; Yu, Sijia; Yang, Bowen; Wu, Tianxiao; Guo, Jing; Hao, Chenzhou; Zhao, Dongmei; Cheng, Maosheng. The article conveys some information:

A series of 7H-pyrrolo[2,3-d]pyrimidine derivatives possessing a dimethylphosphine oxide moiety I (20a-i, R5, R6, R7 = H, R3 = acylamino, sulfamoyl, phosphonomethyl, carbamoyl, amino; 25a-h, R3 = 4-piperidinylaminocarbonyl, R5 = H, halo, alkoxy, CF3, R6 = H, Me, F, R7 = H, F) and II (22a-g, R4 = Me. CHF2CH2, MeOCH2CH2, tetrahydropyranyl, piperidinyl, CH2CONMe2) were designed, synthesized and evaluated as novel Focal adhesion kinase (FAK) inhibitors. Most compounds potently suppressed the enzymic activities of FAK, with IC50 values in the 10-8-10-9 M range, and potently inhibited the proliferation of breast (MDA-MB-231) and lung (A549) cancer cell lines. The representative compound 25b (R5 = OMe, R6 = R7 = H) exhibited potent enzyme inhibition (IC50 = 5.4 nM) and good selectivity when tested on a panel of 26 kinases. Compound 25b exhibited antiproliferative activity against A549 cells (IC50 = 3.2 μM) and relatively less cytotoxicity to a normal human cell line HK2. Compound 25b also induced apoptosis and suppressed the migration of A549 cells in a concentration-dependent manner. Further profiling of compound 25b revealed it had good metabolic stability in mouse, rat and human liver microsomes in vitro and showed weak inhibitory activity against various subtypes of human cytochrome P 450. The docking study of compound 25b was performed to elucidate its possible binding modes and to provide a structural basis for further structure-guided design of FAK inhibitors. In the experimental materials used by the author, we found 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4Quality Control of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine)

2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4) belongs to pyrimidine. The pyrimidine ring system has wide occurrence in nature as substituted and ring fused compounds and derivatives, including the nucleotides cytosine, thymine and uracil, thiamine (vitamin B1) and alloxan. Quality Control of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia