Day: October 14, 2022

《New deferiprone derivatives as multi-functional cholinesterase inhibitors: design, synthesis and in vitro evaluation》 was published in European Journal of Medicinal Chemistry in 2020. These research results belong to Bortolami, Martina; Pandolfi, Fabiana; De Vita, Daniela; Carafa, Camilla; Messore, Antonella; Di Santo, Roberto; Feroci, Marta; Costi, Roberta; Chiarotto, Isabella; Bagetta, Donatella; Alcaro, Stefano; Colone, Marisa; Stringaro, Annarita; Scipione, Luigi. Reference of 2,4-Dichloropyrimidine The article mentions the following:

A series of deferiprone derivatives has been synthesized and evaluated in vitro with the hypothesis that they can restore the cholinergic tone and attenuate the dyshomeostasis of the metals mainly involved in the pathol. These compounds were designed as dual binding site AChE inhibitors: they possess an arylalkylamine moiety connected via an alkyl chain to a 3-hydroxy-4-pyridone fragment, to allow the simultaneous interaction with catalytic active site (CAS) and peripheral anionic site (PAS) of the enzyme. Deferiprone moiety and 2-aminopyridine, 2-aminopyrimidine or 2,4-diaminopyrimidine groups have been incorporated into these compounds, in order to obtain mols. potentially able to chelate bio-metals colocalized in Aβ plaques and involved in the generation of radical species. The compounds were tested by enzymic inhibition studies towards EeAChE and eqBChE using Ellman’s method. The most potent EeAChE inhibitor is compound I, with a Ki of 788 +/- 51 nM, while the most potent eqBChE inhibitors are compounds II and III, with Ki values of 182 +/- 18 nM and 258 +/- 25 nM resp. Among the most potent cholinesterases inhibitors, few compounds were able to form complex with iron and in some cases with copper and zinc. Moreover, these compounds were characterized by low toxicity on U-87 MG Cell Line from human brain (glioblastoma astrocytoma). In the part of experimental materials, we found many familiar compounds, such as 2,4-Dichloropyrimidine(cas: 3934-20-1Reference of 2,4-Dichloropyrimidine)

2,4-Dichloropyrimidine(cas: 3934-20-1) is a member of organic chlorides. Almost all organochlorine compounds are synthesized. It is widely used as intermediates, solvents and pesticides of chemical synthetic products.Reference of 2,4-Dichloropyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Huddle, Brandt C.; Grimley, Edward; Chtcherbinine, Mikhail; Buchman, Cameron D.; Takahashi, Cyrus; Debnath, Bikash; McGonigal, Stacy C.; Mao, Shuai; Li, Siwei; Felton, Jeremy; Pan, Shu; Wen, Bo; Sun, Duxin; Neamati, Nouri; Buckanovich, Ronald J.; Hurley, Thomas D.; Larsen, Scott D. published an article in 2021. The article was titled 《Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of aldehyde dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy》, and you may find the article in European Journal of Medicinal Chemistry.Application In Synthesis of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine The information in the text is summarized as follows:

There is strong evidence that inhibition of one or more Aldehyde Dehydrogenase 1A (ALDH1A) isoforms may be beneficial in chemotherapy-resistant ovarian cancer and other tumor types. While many previous efforts have focused on development of ALDH1A1 selective inhibitors, the most deadly ovarian cancer subtype, high-grade serous (HGSOC), exhibits elevated expression of ALDH1A3. Herein, we report continued development of pan-ALDH1A inhibitors to assess whether broad spectrum ALDH1A inhibition is an effective adjunct to chemotherapy in this critical tumor subtype. Optimization of the CM39 scaffold, aided by metabolite ID and several new ALDH1A1 crystal structures, led to improved biochem. potencies, improved cellular ALDH inhibition in HGSOC cell lines, and substantial improvements in microsomal stability culminating in orally bioavailable compounds We demonstrate that two compounds 68 and 69 are able to synergize with chemotherapy in a resistant cell line and patient-derived HGSOC tumor spheroids, indicating their suitability for future in vivo proof of concept experiments In the experiment, the researchers used many compounds, for example, 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4Application In Synthesis 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. Pyrimidine nucleotide derivatives have a wide range of biological applications. For example, pyrimidine derivatives are useful in DNA repair studies involving cancer and epigenetics. Application In Synthesis of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Kampen, Stefanie; Duy Vo, Duc; Zhang, Xiaoqun; Panel, Nicolas; Yang, Yunting; Jaiteh, Mariama; Matricon, Pierre; Svenningsson, Per; Brea, Jose; Loza, Maria Isabel; Kihlberg, Jan; Carlsson, Jens published an article in 2021. The article was titled 《Structure-Guided Design of G-Protein-Coupled Receptor Polypharmacology》, and you may find the article in Angewandte Chemie, International Edition.Recommanded Product: 90213-66-4 The information in the text is summarized as follows:

Many diseases are polygenic and can only be treated efficiently with drugs that modulate multiple targets. However, rational design of compounds with multi-target profiles is rarely pursued because it is considered too difficult, in particular if the drug must enter the central nervous system. Here, a structure-based strategy to identify dual-target ligands of G-protein-coupled receptors is presented. We use this approach to design compounds that both antagonize the A2A adenosine receptor and activate the D2 dopamine receptor, which have excellent potential as antiparkinson drugs. Atomic resolution models of the receptors guided generation of a chem. library with compounds designed to occupy orthosteric and secondary binding pockets in both targets. Structure-based virtual screens identified ten compounds, of which three had affinity for both targets. One of these scaffolds was optimized to nanomolar dual-target activity and showed the predicted pharmacodynamic effect in a rat model of Parkinsonism. In the experimental materials used by the author, we found 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine(cas: 90213-66-4Recommanded Product: 90213-66-4)

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. Recommanded Product: 90213-66-4

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Reference of 2,4-DichloropyrimidineIn 2022 ,《Development of a degrader against oncogenic fusion protein FGFR3-TACC3》 appeared in Bioorganic & Medicinal Chemistry Letters. The author of the article were Shibata, Norihito; Cho, Nobuo; Koyama, Hiroo; Naito, Mikihiko. The article conveys some information:

Fibroblast growth factor receptor 3-transforming acidic coiled-coil containing protein 3 (FGFR3-TACC3), which has been identified in many cancers such as glioblastoma and bladder cancer, is a potent oncogenic fusion protein that induces constitutive activation of FGFR signaling, resulting in uncontrolled cell proliferation. Although several tyrosine kinase inhibitors against FGFR are currently under development, resistance to such types of inhibitors in patients has become a concern. In this study, a chimeric mol. SNIPER(TACC3)-11 I was developed and found to reduce FGFR3-TACC3 levels effectively. Compound I conjugated KHS108 (a TACC3 ligand) to an LCL161 derivative II (an inhibitor of apoptosis protein [IAP] ligand) with a PEG linker (n = 2). Mechanistical anal. showed that cellular IAP1 was required for the reduction of FGFR3-TACC3 levels. Consistent with the decrease in FGFR3-TACC3 levels, compound I suppressed the growth of FGFR3-TACC3 pos. cells. Thus, compound I is a candidate therapeutic with a novel drug modality against cancers that exhibit FGFR3-TACC3-dependent proliferation and exerts pharmacol. effects distinct from FGFR3 kinase inhibitors because it lacks substructures crucial for kinase inhibition. The experimental part of the paper was very detailed, including the reaction process of 2,4-Dichloropyrimidine(cas: 3934-20-1Reference of 2,4-Dichloropyrimidine)

2,4-Dichloropyrimidine(cas: 3934-20-1) 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.Reference of 2,4-Dichloropyrimidine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Computed Properties of C4H2Cl2N2In 2020 ,《Optimization of a series of potent, selective and orally bioavailable SYK inhibitors》 was published in Bioorganic & Medicinal Chemistry Letters. The article was written by Grimster, Neil P.; Gingipalli, Lakshmaiah; Barlaam, Bernard; Su, Qibin; Zheng, XiaoLan; Watson, David; Wang, Haixia; Simpson, Iain; Pike, Andy; Balazs, Amber; Boiko, Scott; Ikeda, Timothy P.; Impastato, Anna C.; Jones, Natalie H.; Kawatkar, Sameer; Kemmitt, Paul; Lamont, Scott; Patel, Joe; Read, Jon; Sarkar, Ujjal; Sha, Li; Tomlinson, Ronald C.; Wang, Haiyun; Wilson, David M.; Zehnder, Troy E.; Wang, Lianghe; Wang, Peng; Goldberg, Frederick W.; Shao, Wenlin; Fawell, Stephen; Dry, Hannah; Dowling, James E.; Edmondson, Scott D.. The article contains the following contents:

Spleen tyrosine kinase (SYK) is a non-receptor cytosolic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signaling, inhibition of SYK has been targeted in a variety of disease areas. Herein, we report the optimization of a series of potent and selective SYK inhibitors, focusing on improving metabolic stability, pharmacokinetics and hERG inhibition. As a result, we identified 30, which exhibited no hERG activity but unfortunately was poorly absorbed in rats and mice. We also identified a SYK chem. probe, 17, which exhibits excellent potency at SYK, and an adequate rodent PK profile to support in vivo efficacy/PD studies. The experimental process involved the reaction of 2,4-Dichloropyrimidine(cas: 3934-20-1Computed Properties of C4H2Cl2N2)

2,4-Dichloropyrimidine(cas: 3934-20-1) 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.Computed Properties of C4H2Cl2N2

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

《Amide-based inhibitors of p38α MAP kinase. Part 2: Design, synthesis and SAR of potent N-pyrimidyl amides》 was written by Tester, Richland; Tan, Xuefei; Luedtke, Gregory R.; Nashashibi, Imad; Schinzel, Kurt; Liang, Weiling; Jung, Joon; Dugar, Sundeep; Liclican, Albert; Tabora, Jocelyn; Levy, Daniel E.; Do, Steven. Quality Control of 2-Chloro-N-ethylpyrimidin-4-amine And the article was included in Bioorganic & Medicinal Chemistry Letters on April 15 ,2010. The article conveys some information:

Optimization of a tri-substituted N-pyridyl amide led to the discovery of a class of potent N-pyrimidyl amide based p38α MAP kinase inhibitors, e.g., I. Initial SAR studies led to the identification of 5-dihydrofuran I as an optimal hydrophobic group. Addnl. side chain modifications resulted in the introduction of hydrogen bond interactions. Through extensive SAR studies, analogs bearing free amino groups and alternatives to the parent (S)-α-Me benzyl moiety were identified. These compounds exhibited improved cellular activities and maintained balance between p38α and CYP3A4 inhibition. In addition to this study using 2-Chloro-N-ethylpyrimidin-4-amine, there are many other studies that have used 2-Chloro-N-ethylpyrimidin-4-amine(cas: 86443-51-8Quality Control of 2-Chloro-N-ethylpyrimidin-4-amine) was used in this study.

2-Chloro-N-ethylpyrimidin-4-amine(cas: 86443-51-8) belongs to anime. Amines have a free lone pair with which they can coordinate to metal centers. Amine–metal bonds are weaker because amines are incapable of backbonding, but they are still important for sensing applications.While stronger than hydrogen bonds, amine–metal bonds are still weaker than both covalent and ionic bonds.Quality Control of 2-Chloro-N-ethylpyrimidin-4-amine

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia