Month: October 2022

Heffron, Timothy P.; Wei, Bin Qing; Olivero, Alan; Staben, Steven T.; Tsui, Vickie; Do, Steven; Dotson, Jennafer; Folkes, Adrian J.; Goldsmith, Paul; Goldsmith, Richard; Gunzner, Janet; Lesnick, John; Lewis, Cristina; Mathieu, Simon; Nonomiya, Jim; Shuttleworth, Stephen; Sutherlin, Daniel P.; Wan, Nan Chi; Wang, Shumei; Wiesmann, Christian; Zhu, Bing-Yan published the artcile< Rational Design of Phosphoinositide 3-Kinase α Inhibitors That Exhibit Selectivity over the Phosphoinositide 3-Kinase β Isoform>, Synthetic Route of 18740-39-1, the main research area is PI3K alpha inhibitor preparation antitumor.

Of the four class I phosphoinositide 3-kinase (PI3K) isoforms, PI3Kα has justly received the most attention for its potential in cancer therapy. Herein we report our successful approaches to achieve PI3Kα vs PI3Kβ selectivity for two chem. series. In the thienopyrimidine series of inhibitors, we propose that select ligands achieve selectivity derived from a hydrogen bonding interaction with Arg770 of PI3Kα that is not attained with the corresponding Lys777 of PI3Kβ. In the benzoxepin series of inhibitors, the selectivity observed can be rationalized by the difference in electrostatic potential between the two isoforms in a given region rather than any specific interaction.

Journal of Medicinal Chemistry published new progress about Antitumor agents. 18740-39-1 belongs to class pyrimidines, and the molecular formula is C6H2Cl2N2S, Synthetic Route of 18740-39-1.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Zhu, Wufu; Chen, Chen; Sun, Chengyu; Xu, Shan; Wu, Chunjiang; Lei, Fei; Xia, Hui; Tu, Qidong; Zheng, Pengwu published the artcile< Design, synthesis and docking studies of novel thienopyrimidine derivatives bearing chromone moiety as mTOR/PI3Kα inhibitors>, Recommanded Product: 2,4-Dichlorothieno[2,3-d]pyrimidine, the main research area is thienopyrimidine preparation mTOR PI3Kalpha inhibitor treatment cancer; hydrazinylthienopyrimidine chromenecarboxaldehyde condensation; Chromone; Cytotoxicity; Docking; PI3Kα; Synthesis; Thienopyrimidine; mTOR.

Two series of thienopyrimidine derivatives, e.g, I and II, bearing chromone moiety were designed and synthesized. All the compounds were evaluated for inhibitory activity against mTOR kinase at a concentration of 10uM. Four selected compounds were further evaluated for the IC50 values against mTOR kinase, PI3Kα kinase and two cancer cell lines. One of the target compounds exhibited moderate to excellent mTOR/PI3Kα kinase inhibitory activity and cytotoxicity. The most promising compound II showed good inhibitory activity against mTOR/PI3Kα kinase and good antitumor potency for H460 and PC-3 cell lines with IC50 values of 0.16 ± 0.03 μM, 2.35 ± 0.19 μM, 1.20 ± 0.23 μM and 0.85 ± 0.04 μM, which were 8.6, >5, 7.9 and 19.1 times more active than compound I (1.37 ± 0.07 μM, >10 μM, 9.52 ± 0.29 μM, 16.27 ± 0.54 μM), resp. Structure-activity relationships (SARs) and docking studies indicated that the chromone moiety is necessary for the potent antitumor activity and cytotoxicity of these compounds Substitution of the chromone moiety at the 6-position has a significant impact to the inhibitory activity, in particular a carboxylic acid group, produced the best potency.

European Journal of Medicinal Chemistry published new progress about Antitumor agents. 18740-39-1 belongs to class pyrimidines, and the molecular formula is C6H2Cl2N2S, Recommanded Product: 2,4-Dichlorothieno[2,3-d]pyrimidine.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Roecker, Anthony J.; Mercer, Swati P.; Harrell, C. Meacham; Garson, Susan L.; Fox, Steven V.; Gotter, Anthony L.; Prueksaritanont, Thomayant; Cabalu, Tamara D.; Cui, Donghui; Lemaire, Wei; Winrow, Christopher J.; Renger, John J.; Coleman, Paul J. published the artcile< Discovery of dual orexin receptor antagonists with rat sleep efficacy enabled by expansion of the acetonitrile-assisted/diphosgene-mediated 2,4-dichloropyrimidine synthesis>, Product Details of C6H2Cl2N2S, the main research area is orexin receptor antagonist sleep acetonitrile diphosgene dichloropyrimidine; Antagonist; Bioactivation; Orexin; Pyrimidine; Sleep.

Recent clin. studies have demonstrated that dual orexin receptor antagonists (OX1R and OX2R antagonists or DORAs) represent a novel treatment option for insomnia patients. Previously we have disclosed several compounds in the diazepane amide DORA series with excellent potency and both preclin. and clin. sleep efficacy. Addnl. SAR studies in this series were enabled by the expansion of the acetonitrile-assisted, diphosgene-mediated 2,4-dichloropyrimidine synthesis to novel substrates providing an array of Western heterocycles. These heterocycles were utilized to synthesize analogs in short order with high levels of potency on orexin 1 and orexin 2 receptors as well as in vivo sleep efficacy in the rat.

Bioorganic & Medicinal Chemistry Letters published new progress about Drug bioavailability. 18740-39-1 belongs to class pyrimidines, and the molecular formula is C6H2Cl2N2S, Product Details of C6H2Cl2N2S.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Watterson, Scott H.; Xiao, Zili; Dodd, Dharmpal S.; Tortolani, David R.; Vaccaro, Wayne; Potin, Dominique; Launay, Michele; Stetsko, Dawn K.; Skala, Stacey; Davis, Patric M.; Lee, Deborah; Yang, Xiaoxia; McIntyre, Kim W.; Balimane, Praveen; Patel, Karishma; Yang, Zheng; Marathe, Punit; Kadiyala, Pathanjali; Tebben, Andrew J.; Sheriff, Steven; Chang, Chieh Ying Y.; Ziemba, Theresa; Zhang, Huiping; Chen, Bang-Chi; DelMonte, Albert J.; Aranibar, Nelly; McKinnon, Murray; Barrish, Joel C.; Suchard, Suzanne J.; Murali Dhar, T. G. published the artcile< Small Molecule Antagonist of Leukocyte Function Associated Antigen-1 (LFA-1): Structure-Activity Relationships Leading to the Identification of 6-((5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic Acid (BMS-688521)>, Safety of Ethyl 2-chloropyrimidine-5-carboxylate, the main research area is spirocyclic hydantoin derivative preparation LFA1 antagonist SAR.

Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or αLβ2, belongs to the β2 integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion mols. 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclin. animal studies and clin. data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunol. target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clin. compound (1, I), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clin. trials.

Journal of Medicinal Chemistry published new progress about Homo sapiens. 89793-12-4 belongs to class pyrimidines, and the molecular formula is C7H7ClN2O2, Safety of Ethyl 2-chloropyrimidine-5-carboxylate.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Vikram, Venugopalarao; Amperayani, Karteek rao; Ummidi, Venkata Ravi Sankar; Parimi, Umadevi published the artcile< Synthesis, Anti-Microbial Activity, and Docking Studies of Novel N-Pyridine Substituted 2-Chlorothieno[2,3-d]pyrimidine Derivatives>, Synthetic Route of 18740-39-1, the main research area is pyridine substituted chloro thienopyrimidinamine preparation antibacterial antifungal docking; acetyl coenzyme carboxylase inhibitor pyridine substituted chloro thienopyrimidinamine preparation.

A series of novel N-pyridine substituted 2-chloro-thieno[2,3-d]pyrimidin-4-amine derivatives I [Ar = 2-pyridyl, (3-methyl-2-pyridyl), (5-chloro-2-pyridyl), etc.] had been synthesized and characterized by 1H and 13C NMR spectrometry. All the compounds had been docked against acetyl-CoA carboxylase enzyme and also tested for their in vitro antimicrobial activity on Gram-pos. (Micrococcus luteus, staphylococcus aureus) and Gram-neg. bacteria (Salmonella typhi, klebsiella pneumoniae) and anti-fungal activity on aspergillus niger and fusarium oxysporum. All synthesized compounds have demonstrated moderate activity and two products have exhibited good antibacterial and antifungal activity.

Russian Journal of General Chemistry published new progress about Acetyl-coenzyme A carboxylase inhibitors. 18740-39-1 belongs to class pyrimidines, and the molecular formula is C6H2Cl2N2S, Synthetic Route of 18740-39-1.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Spratt, Thomas E.; De los Santos, Hannah published the artcile< Reaction of O6-alkylguanine-DNA alkyltransferase with O6-methylguanine analogs: evidence that the oxygen of O6-methylguanine is protonated by the protein to effect methyl transfer>, Application In Synthesis of 84955-32-8, the main research area is alkylguanine DNA alkyltransferase methylguanine analog.

The DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) repairs the promutagenic O6-methylguanine lesion by transferring the Me group to a cysteine residue on the protein. A mechanism in which AGT activates the guanyl moiety as a leaving group by protonation of a heteroatom on guanine was probed by reacting AGT with analogs of O6-methylguanine in which the heteroatoms were changed. The initial rates of reaction were measured at various substrate concentrations in 50 mM Hepes, 1 mM EDTA, 1 mM DTT, and 10% glycerol, pH 7.8 at 37). The kinact (h-1) and Kin (mM) were determined for O6-methylguanine (1.66, 1.51) 0.32), 6-methoxypurine (1.07, 10.6), S6-methyl-6-thioguanine (0.63, 1.17), 6-methylthiopurine (no reaction), Se6-methyl-6-selenoguanine (1.76, 10.6), 6-methylselenopurine (2.51, 15.7), O6-methyl-1-deazaguanine (1.71, 14.8), O6-methyl-3-deazaguanine (1.90, 2.54), and O6-methyl-7-deazaguanine (1.97, 2.56). These results indicate that replacement of the nitrogens does not affect the kinact parameter but the Kin is increased upon removal of the exocyclic amino group and the nitrogen at the 1-position. Replacement of the oxygen with sulfur decreases the kinact, and replacement with selenium increases the Kin. The results are consistent with a mechanism in which O6-methylguanine binds to the active site of AGT with hydrogen bonds to the oxygen, the exocyclic amino group, and the nitrogen at the 1-position of the substrate. The Me group is then displaced from the guanine as a proton is transferred to the oxygen, neutralizing the charge on the leaving group.

Biochemistry published new progress about 84955-32-8. 84955-32-8 belongs to class pyrimidines, and the molecular formula is C7H8N4O, Application In Synthesis of 84955-32-8.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia

Jat, Bhagchand; Santra, Swapna; Santra, Prasanta Kumar published the artcile< Synthesis and evaluation of antimicrobial activity of pyrimidine derivatives>, Formula: C6H2Cl2N2S, the main research area is pyridinylpropylphenylamino fused pyrimidine preparation antibacterial agrochem antifungal activity.

Synthesis, characterization and evaluation of antimicrobial activity of novel pyrimidine derivatives containing O, N, and S in the ring was reported. Pyrimidine derivatives were prepared in three steps. In the first step, chalcones containing -NO2 functional group were synthesized using Claisen-Schmidt condensation of aromatic aldehydes with 2-acetyl pyridine/3-acetylpyridine in methanol in the presence of aqueous NaOH. In the second step, -NO2 group was reduced to -NH2 group. Resulting compounds containing -NH2 functional group were reacted with different dichlorothienopyrimidines and dichlorofuropyrimidines in the presence of N,N-diisopropylethylamine to obtain pyrimidine derivatives Antibacterial and antifungal activity of pyrimidine derivatives were studied in-vitro. Antibacterial and antifungal activity of the newly synthesized pyrimidine derivatives will definitely inspire future researchers for the preparation of new analogs.

Asian Journal of Pharmaceutical and Clinical Research published new progress about Agrochemical fungicides. 18740-39-1 belongs to class pyrimidines, and the molecular formula is C6H2Cl2N2S, Formula: C6H2Cl2N2S.

Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia