Heterocyclic Building Blocks-Naphthyridine

Bein, Kiflai; Ganguly, Koustav; Martin, Timothy M.; Concel, Vincent J.; Brant, Kelly A.; Di, Y. P. Peter; Upadhyay, Swapna; Fabisiak, James P.; Vuga, Louis J.; Kaminski, Naftali; Kostem, Emrah; Eskin, Eleazar; Prows, Daniel R.; Jang, Ann-Soo; Leikauf, George D. published the artcile< Genetic determinants of ammonia-induced acute lung injury in mice>, HPLC of Formula: 1223001-51-1, the main research area is genetic determinant ammonia acute lung injury mice; ARDS; acute lung injury; chemical threat; functional genomics; transcriptomics.

In this study, a genetically diverse panel of 43 mouse strains was exposed to ammonia, and genome-wide association mapping was performed employing a single-nucleotide polymorphism (SNP) assembly. Transcriptomic anal. was used to help resolve the genetic determinants of ammonia-induced acute lung injury. The encoded proteins were prioritized based on mol. function, nonsynonymous SNP within a functional domain or SNP within the promoter region that altered expression. This integrative functional approach revealed 14 candidate genes that included Aatf, Avil, Cep162, Hrh4, Lama3, Plcb4, and Ube2cbp, which had significant SNP associations, and Aff1, Bcar3, Cntn4, Kcnq5, Prdm10, Ptcd3, and Snx19, which had suggestive SNP associations Of these genes, Bcar3, Cep162, Hrh4, Kcnq5, and Lama3 are particularly noteworthy and had pathophysiol. roles that could be associated with acute lung injury in several ways.

American Journal of Physiology published new progress about Actins Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, HPLC of Formula: 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Atwood, Daniel J.; Pokhrel, Deepak; Brown, Carolyn N.; Holditch, Sara J.; Bachu, Dheevena M.; Thorburn, Andrew; Hopp, Katharina; Edelstein, Charles L. published the artcile< Increased mTOR and suppressed autophagic flux in the heart of a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease>, Application of C24H15F3N4O, the main research area is mTOR Pkd1 beclin1 polycystic kidney disease; Autophagy; Autosomal dominant polycystic kidney disease; Cardiac hypertrophy; Heart; mTOR.

Cardiac hypertrophy is common in autosomal dominant polycystic kidney disease (ADPKD) patients. We found increased heart weight in Pkd1RC/RC and Pkd2WS25/+ mouse models of ADPKD. As there is a link between increased heart weight and mammalian target of rapamycin (mTOR), the aim of the study was to determine mTOR complex 1 and 2 signaling proteins in the heart in the Pkd1RC/RC mouse model of PKD. In 70 day old Pkd1RC/RC hearts, on immunoblot anal., there was a large increase in p-AMPKThr172, a known autophagy inducer, and an increase in p-AktSer473 and p-AktThr308, but no increase in other mTORC1/2 proteins (p-S6Ser240/244, p-mTORSer2448). In 150 day old Pkd1RC/RC hearts, there was an increase in mTORC1 (p-S6Ser240/244) and mTOR-related proteins (p-AktThr308, p-GSK3βSer9, p-AMPKThr172). As the mTOR pathway is the master regulator of autophagy, autophagy proteins were measured. There was an increase in p-Beclin-1 (BECN1), an autophagy regulator and activating mol. in Beclin-1-regulated autophagy (AMBRA1), a regulator of Beclin that play a role in autophagosome formation, an early stage of autophagy. There was a defect in the later stage of autophagy, the fusion of the autophagosome with the lysosome, known as autophagic flux, as evidenced by the lack of an increase in LC3-II, a marker of autophagosomes, with the lysosomal inhibitor bafilomycin, in both 70 day old and 150 day old hearts. To determine the role of autophagy in causing increased heart weight, Pkd1RC/RC were treated with 2-deoxyglucose (2-DG) or Tat-Beclin1 peptide, agents known to induce autophagy. 2-DG treatment from 150 to 350 days of age, a time period when increased heart weight developed, did not reduce the increased heart weight Unexpectedly, Tat-Beclin 1 peptide treatment from 70 to 120 days of age resulted in increased heart weight In summary, there is suppressed autophagic flux in the heart at an early age in Pkd1RC/RC mice. Increased mTOR signaling in older mice is associated suppressed autophagic flux. There was a large increase in p-AMPKThr172, a known autophagy inducer, in both young and old mice. 2-DG treatment did not impact increased heart weight and Tat-Beclin1 peptide increased heart weight

Cellular Signalling published new progress about Adult, mammalian. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Application of C24H15F3N4O.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Chen, Kuan-Chung; Lee, Wen-Yuan; Chen, Hsin-Yi; Chen, Calvin Yu-Chian published the artcile< In silico investigation of potential mTOR inhibitors from traditional Chinese medicine for treatment of Leigh syndrome>, Application of C24H15F3N4O, the main research area is human Leigh syndrome mTOR inhibitor traditional Chinese medicine.

A recent research demonstrates that the inhibition of mammalian target of rapamycin mTOR improves survival and health for patients with Leigh syndrome. mTOR proteins can be treated as drug target proteins against Leigh syndrome and other mitochondrial disorders. In this study, we aim to identify potent TCM compounds from the TCM Database@Taiwan as lead compounds of mTOR inhibitors. PONDR-Fit protocol was employed to predict the disordered disposition in mTOR protein before virtual screening. After virtual screening, the MD simulation was employed to validate the stability of interactions between each ligand and mTOR protein in the docking poses from docking simulation. The top TCM compounds, picrasidine M and acerosin, have higher binding affinities with target protein in docking simulation than control. There have H-bonds with residues Val2240 and π interactions with common residue Trp2239. After MD simulation, the top TCM compounds maintain similar docking poses under dynamic conditions. The top two TCM compounds, picrasidine M and acerosin, were extracted from Picrasma quassioides D. Don Benn. and Vitex negundo L. Hence, we propose the TCM compounds, picrasidine M and acerosin, as potential candidates as lead compounds for further study in drug development process with the mTOR protein against Leigh syndrome and other mitochondrial disorders.

BioMed Research International published new progress about Alangium lamarckii. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Application of C24H15F3N4O.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Holditch, Sara J.; Brown, Carolyn N.; Atwood, Daniel J.; Lombardi, Andrew M.; Nguyen, Khoa N.; Toll, Harrison W.; Hopp, Katharina; Edelstein, Charles L. published the artcile< A study of sirolimus and mTOR kinase inhibitor in a hypomorphic Pkd1 mouse model of autosomal dominant polycystic kidney disease>, Electric Literature of 1223001-51-1, the main research area is sirolimus mTOR kinase polycystic kidney disease; apoptosis; autosomal dominant polycystic kidney disease; polycystic; proliferation; sirolimus; torin2.

Autosomal dominant polycystic kidney disease (PKD) is characterized by cyst formation and growth, which are partially driven by abnormal proliferation of tubular cells. Proproliferative mechanistic target of rapamycin (mTOR) complexes 1 and 2 (mTORC1 and mTORC2) are activated in the kidneys of mice with PKD. The aim of the present study was to determine the effects of sirolimus vs. the mTOR kinase inhibitor torin2 on cyst growth and kidney function in the Pkd1 p.R3277C (Pkd1RC/RC) mouse model, a hypomorphic Pkd1 model orthologous to the human condition, and to determine the effects of sirolimus vs. torin2 on mTORC1 and mTORC2 signaling in PKD1/ cells and in the kidneys of Pkd1RC/RC mice. In vitro, both inhibitors reduced mTORC1 and mTORC2 phosphorylated substrates and neg. impacted cellular metabolic activity, as measured by MTT assay. Pkd1RC/RC mice were treated with sirolimus or torin2 from 50 to 120 days of age. Torin2 was as effective as sirolimus in decreasing cyst growth and improving loss of kidney function. Both sirolimus and torin2 decreased phosphorylated S6 protein, phosphorylated eukaryotic translation initiation factor 4E-binding protein 1, phosphorylated Akt, and proliferation in Pkd1RC/RC kidneys. In conclusion, torin2 and sirolimus were equally effective in decreasing cyst burden and improving kidney function and mediated comparable effects on mTORC1 and mTORC2 signaling and proliferation in the Pkd1RC/RC kidney.

American Journal of Physiology published new progress about Animal gene, PKD1 Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Electric Literature of 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Zhuang, Haiwen; Dai, Xudong; Zhang, Xiaoyu; Mao, Zhongqi; Huang, Haijin published the artcile< Sophoridine suppresses macrophage-mediated immunosuppression through TLR4/IRF3 pathway and subsequently upregulates CD8+ T cytotoxic function against gastric cancer>, Synthetic Route of 6882-68-4, the main research area is gastric cancer sophoridine immunosuppression TLR4 IRF3 CD8; CD8(+) T cells; Gastric cancer; Sophoridine; TLR4/IRF3 pathway; Tumor-associated macrophages.

Gastric cancer is one of the most common and deadly neoplasms with limited effective treatments. The emergence of the immunotherapy has brought great expectations for cancer patients. Sophoridine is extracted from the seeds of sophora alopecuroides and has various pharmacol. actions including anti-tumor, anti-inflammatory, anti- arrhythmia and anti-virus. However, the effect of Sophoridine on gastric cancer microenvironment immunity and its underling mechanism remains poorly known. This study was aimed to investigate the effect of Sophoridine on the polarization status of gastric tumor-associated macrophages (TAMs) and its underlying mechanism. We isolated primary bone marrow-derived macrophages (BMDMs) and primary CD8+ T cells to perform coculture assay. Sophoridine educated TAMs polarize to M1-TAMs and suppressed M2-TAMs polarization through TLR4/IRF3 axis. Sophoridine-treated TAMs exhibited stronger pro-inflammatory function through upregulation the expression of INOS, IFN-β and IL-12α, and downregulation the expression of Arg-1, CD206 and IL-10. Sophoridine -primed TAMs increased the proliferation and cytotoxic function of CD8+ T by upregulating the expression of Granzyme-B, TNF-α and Perforin, and downregulated the expression of CD8+ T cells function exhaustion markers PD-1, Tim-3 and Lag-3. Furthermore, Sophoridine inhibited the migration ability of macrophage by decrease the CCR2 expression. Thus, Sophoridine acted on macrophages and CD8+ T cells to reshape gastric cancer immune microenvironment. Our studies provided preclin. basis for clin. application of Sophoridine.

Biomedicine & Pharmacotherapy published new progress about CC chemokine receptor CCR2 Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 6882-68-4 belongs to class naphthyridine, and the molecular formula is C15H24N2O, Synthetic Route of 6882-68-4.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Shang, Hai; Li, Lingyu; Ma, Liyan; Tian, Yu; Jia, Hongmei; Zhang, Tao; Yu, Meng; Zou, Zhongmei published the artcile< Design and synthesis of molecular hybrids of sophora alkaloids and cinnamic acids as potential antitumor agents>, Category: naphthyridine, the main research area is sophora alkaloid cinnamic acid hybrid preparation SAR antitumor apoptosis; antitumor; apoptosis; cinnamic acid; hybrid; sophora alkaloid.

Twenty-five sophora alkaloids-cinnamic acid hybrids, including matrine-cinnamic acid hybrids I (R1 = H, Cl; R2 = H, OMe, Cl, Br; R3 = H, CF3, NO2, etc.; R4 = H, OMe; -R2R3- = -OCH2O-), sophoridine-cinnamic acid hybrids II (R1 = H, Cl; R2 = H, Cl, Br; R3 = H, OMe, NO2, etc.; R4 = H; -R2R3- = -OCH2O-), and sophocarpine-cinnamic acid hybrids III (R1 = H, Cl; R2 = R4 = H; R3 = H, OMe), were designed, synthesized, and evaluated in vitro against three human tumor cell lines (HeLa, HepG2 and A549) with cisplatin as a pos. control. Some matrine-cinnamic acid and sophoridine-cinnamic acid compounds exhibited potent effect against all three cancer cell lines, such as compounds I (R1 = Cl; R2 = R3 = R4 = H), I (R1= R4 = H; R2 = R3 = Cl), I (R1 = R2 =R4= H; R3 = CF3) and I (R1 = R2 = R4 = H; R3 = Cl). The structure-activity relationship study of the synthesized compounds was also performed. Preliminary mechanistic studies indicated that compounds I (R1= R4 = H; R2 = R3 = Cl) and I (R1 = R2 = R4 = H; R3 = Cl) could induce apoptosis in HepG2 cell line. Further, compounds I (R1= R4 = H; R2 = R3 = Cl) and I (R1 = R2 = R4 = H; R3 = Cl) altered mitochondrial membrane potential and produced ROS leading to cell apoptosis of HepG2 cells. Overall, findings suggested that these compounds may provide promising lead compounds for further development as antitumor agents by structural modification.

Molecules published new progress about Alkaloids Role: PAC (Pharmacological Activity), RCT (Reactant), SPN (Synthetic Preparation), THU (Therapeutic Use), BIOL (Biological Study), RACT (Reactant or Reagent), PREP (Preparation), USES (Uses). 6882-68-4 belongs to class naphthyridine, and the molecular formula is C15H24N2O, Category: naphthyridine.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Bhakuni, Rashmi; Shaik, Althaf; Priya, Bhanu; Kirubakaran, Sivapriya published the artcile< Characterization of SPK 98, a Torin2 analog, as ATR and mTOR dual kinase inhibitor>, SDS of cas: 1223001-51-1, the main research area is Torin2 analog ATR mTOR dual kinase inhibitor; ATM; ATR; Cell cycle arrest; DNA damage response; Premature chromatin condensation.

A series of Torin2, a second-generation ATP-competitive inhibitor, analogs were biol. characterized to identify their potential for ATR and mTOR kinase inhibition. Compound SPK 98 was observed to inhibit ATR/mTOR kinase selectively over ATM kinase in HCT 116 cell line. In addition to that, SPK 98 on 30 min incubation with human, mice and rat liver microsomes showed improved properties with an increased half-life (a maximum T 1/2 of 157 min) and internal clearance in mouse as compared to Torin2. Further, SPK 98 was also noticed to indulge in inducing premature chromatin condensation as a result of ATR/mTOR kinase inhibition at 50 nM. In a nutshell, our work presents the identification and characterization of SPK 98, a small mol. inhibitor, which exhibits improved specific inhibition for ATR at a lower concentration than Torin2.

Bioorganic & Medicinal Chemistry Letters published new progress about Antitumor agents (potential as). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, SDS of cas: 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Gruber, Franz S.; Johnston, Zoe C.; Norcross, Neil R.; Georgiou, Irene; Wilson, Caroline; Read, Kevin D.; Gilbert, Ian H.; Swedlow, Jason R.; da Silva, Sarah Martins; Barratt, Christopher L. R. published the artcile< Compounds enhancing human sperm motility identified using a high-throughput phenotypic screening platform>, Electric Literature of 1223001-51-1, the main research area is human sperm motility semen high throughput phenotypic phosphodiesterase inhibitor; drug discovery; high-throughput screening; sperm motility; spermatozoa; subfertility.

Can a high-throughput screening (HTS) platform facilitate male fertility drug discovery. An HTS platform identified a large number of compounds that enhanced sperm motility. Several efforts to find small mols. modulating sperm function have been performed but none have used high-throughput technol. Healthy donor semen samples were used and samples were pooled (3-5 donors per pool). Primary screening was performed singly; dose-response screening was performed in duplicate (using independent donor pools). Spermatozoa isolated from healthy donors were prepared by d. gradient centrifugation and incubated in 384-well plates with compounds (6.25 μM) to identify those compounds with enhancing effects on motility. Approx. 17 000 compounds from the libraries, ReFRAME, Prestwick, Tocris, LOPAC, CLOUD and MMV Pathogen Box, were screened. Dose-response experiments of screening hits were performed to confirm the enhancing effect on sperm motility. Experiments were performed in a university setting. From our primary single concentration screening, 105 compounds elicited an enhancing effect on sperm motility compared to dimethylsulfoxide-treated wells. Confirmed enhancing compounds were grouped based on their annotated targets/target classes. A major target class, phosphodiesterase inhibitors, were identified, in particular PDE10A inhibitors as well as number of compounds not previously known to enhance human sperm motility, such as those related to GABA signalling. Although this approach provides data about the activity of the compound, it is only a starting point. For example, further substantive experiments are necessary to provide a more comprehensive picture of each compound′s activity, the effect on the kinetics of the cell populations and subpopulations, and their potential mechanisms of action. Compounds have been tested with prepared donor spermatozoa, incubated under non-capacitating conditions, and only incubated with compounds for a relatively short period of time. Therefore, the effect of compounds under different conditions, for example in whole semen, for longer incubation times, or using samples from patient groups, may be different and require further study. All experiments were performed in vitro. This phenotypic screening assay identified a large number of compounds that increased sperm motility. In addition to furthering our understanding of human sperm function, for example identifying new avenues for discovery, we highlight potential compounds as promising start-point for a medicinal chem. program for potential enhancement of male fertility. Moreover, with disclosure of the results of screening, we present a substantial resource to inform further work in the field.

Human Reproduction published new progress about Drug discovery. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, Electric Literature of 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Li, Hao; Sun, Wei; Huang, Xiuli; Lu, Xiao; Patel, Paresma R.; Kim, Myunghoon; Orr, Meghan J.; Fisher, Richard M.; Tanaka, Takeshi Q.; McKew, John C.; Simeonov, Anton; Sanderson, Philip E.; Zheng, Wei; Williamson, Kim C.; Huang, Wenwei published the artcile< Efficient Synthesis of 1,9-Substituted Benzo[h][1,6]naphthyridin-2(1H)-ones and Evaluation of their Plasmodium falciparum Gametocytocidal Activities>, HPLC of Formula: 1223001-51-1, the main research area is benzonaphthyridinone preparation antimalarial SAR bromochloroquinolinylacrylate tandem reaction aniline boronate; Torin; benzo[h][1,6]naphthyridin-2(1H)-ones; gametocytocidal activity; malaria; one-pot reaction; quinoline.

A novel three-component, two-step, 1-pot nucleophilic aromatic substitution (SNAr)-intramol. cyclization-Suzuki coupling reaction was developed for the synthesis of benzo[h][1,6]naphthyridin-2(1H)-ones (Torins). On the basis of the new efficiently convergent synthetic route, a library of Torin 2 analogs was synthesized. The antimalarial activities of these compounds were evaluated against asexual parasites using a growth inhibition assay and gametocytes using a viability assay.

ACS Combinatorial Science published new progress about Anilines Role: RCT (Reactant), RACT (Reactant or Reagent). 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, HPLC of Formula: 1223001-51-1.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem

Shaik, Althaf; Bhakuni, Rashmi; Kirubakaran, Sivapriya published the artcile< Design, synthesis, and docking studies of new Torin2 analogs as potential ATR/mTOR kinase inhibitors>, COA of Formula: C24H15F3N4O, the main research area is Torin2 analog ATR mTOR inhibitor anticancer cancer QSAR; ATM; ATR; DNA damage and repair; docking; homology modeling; mTOR; molecular dynamic simulation; p-Chk1S317 (Ser 317), p70 S6KT389 (Thr 389).

Targeting DNA damage and response (DDR) pathway has become an attractive approach in cancer therapy. The key mediators involved in this pathway are ataxia telangiectasia-mutated kinase (ATM) and ataxia telangiectasia-mutated, Rad3-related kinase (ATR). These kinases induce cell cycle arrest in response to chemo- and radio-therapy and facilitate DNA repair via their major downstream targets. Targeting ATP-binding site of these kinases is currently under study. Torin2 is a second generation ATP competitive mTOR kinase inhibitor (EC50 = 250 pmol/L) with better pharmacokinetic profile. Torin2 also exhibits potent biochem. and cellular activity against ATM (EC50 = 28 nmol/L) and ATR (EC50 = 35 nmol/L) kinases. In this study, eight new Torin2 analogs were designed and synthesized through multistep synthesis. All the synthesized compounds were characterized by NMR and mass anal. The newly synthesized analogs were evaluated for their anti-cancer activity via CellTiter-Glo assay. Addnl., compounds 13 and 14 also showed significant inhibition for ATR and mTOR substrates, i.e., p-Chk1 Ser 317 and p70 S6K Thr 389, resp. Compounds 13 and 14 displayed promising anti-cancer activity with HCT-116 cell lines in the preliminary study. Further, a comparative model of ATR kinase was generated using the SWISS-MODEL server and validated using PROCHECK, ProSA anal. Synthesized compounds were docked into the ATP-binding site to understand the binding modes and for the rational design of new inhibitors.

Molecules published new progress about Antitumor agents. 1223001-51-1 belongs to class naphthyridine, and the molecular formula is C24H15F3N4O, COA of Formula: C24H15F3N4O.

Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem