Day: February 22, 2023

Solution structure of the Hop TPR2A domain and investigation of target druggability by NMR, biochemical and in silico approaches was written by Darby, John F.;Vidler, Lewis R.;Simpson, Peter J.;Al-Lazikani, Bissan;Matthews, Stephen J.;Sharp, Swee Y.;Pearl, Laurence H.;Hoelder, Swen;Workman, Paul. And the article was included in Scientific Reports in 2020.Quality Control of 2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indole This article mentions the following:

Heat shock protein 90 (Hsp90) is a mol. chaperone that plays an important role in tumor biol. by promoting the stabilization and activity of oncogenic’ client’ proteins. Inhibition of Hsp90 by small-mol. drugs, acting via its ATP hydrolysis site, has shown promise as a molecularly targeted cancer therapy. Owing to the importance of Hop and other tetratricopeptide repeat (TPR)-containing cochaperones in regulating Hsp90 activity, the Hsp90-TPR domain interface is an alternative site for inhibitors, which could result in effects distinct from ATP site binders. The TPR binding site of Hsp90 cochaperones includes a shallow, pos. charged groove that poses a significant challenge for druggability. Herein, we report the apo, solution-state structure of Hop TPR2A which enables this target for NMR-based screening approaches. We have designed prototype TPR ligands that mimic key native ‘carboxylate clamp’ interactions between Hsp90 and its TPR cochaperones and show that they block binding between Hop TPR2A and the Hsp90 C-terminal MEEVD peptide. We confirm direct TPR-binding of these ligands by mapping 1H-15N HSQC chem. shift perturbations to our new NMR structure. Our work provides a novel structure, a thorough assessment of druggability and robust screening approaches that may offer a potential route, albeit difficult, to address the chem. challenging nature of the Hop TPR2A target, with relevance to other TPR domain interactors. In the experiment, the researchers used many compounds, for example, 2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indole (cas: 16502-01-5Quality Control of 2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indole).

2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indole (cas: 16502-01-5) belongs to indole derivatives. Indole is an important structural motif of various drugs, therapeutic leads besides its prevalence in numerous natural products, agrochemicals, perfumery, and dyes. Moreover, it is known that it controls biofilm formation. However, the role of indole in the cell has not been fully elucidated.Quality Control of 2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indole

Referemce:
Indole alkaloid derivatives as building blocks of natural products from聽Bacillus thuringiensis聽and聽Bacillus velezensis聽and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Pyrroles from azaindoles. A synthesis of porphobilinogen was written by Frydman, Benjamin;Despuy, Maria E.;Rapoport, Henry. And the article was included in Journal of the American Chemical Society in 1965.Synthetic Route of C7H6N2 This article mentions the following:

The synthesis of porphobilinogen in 19% overall yield from 2-methoxy-4-methyl-5-nitropyridine (I) is described. I, m.p. 81掳 位 289 m渭 (蔚 6800), was prepared by treating the chloro derivative with methanolic NaOMe. I with C₂H₅OK and di-Et oxalate gave 93% yield of ethyl 2-methoxy-5-nitro-4-pyridinepyruvate (II), m.p. 97-98掳, 位 287 m渭 (蔚 10,100), 未 7.8 (H-3), 9.1 (H-6), and 7.2 (CH:C(OH)COOR). Hydrogenation of II over Pd-C catalyst and cyclization gave 85% yield of ethyl 5-methoxy-6-azaindole-2-carboxylate (III), m.p. 103-106掳, 位 278 m渭 (蔚 15,000), 287 (17,000), 344 (3600), 未 7.1, 7.2(H-3, H-4), and 8.7 (H-7). Hydrogenation with Pt catalyst yielded III and a substantial amount of 1,2,3,4-tetrahydro-3-hydroxy-6-methoxy-1,7-naphthyridin-2-one, m.p. 215掳 from C₂H₅OH, 位 248 m渭 (14,070), 未 (in CF₃COOH) 3.1 (H-4 脳 2), 4.5 (H-3), 7.0 (H-5) and 8.5 (H-8). III with Me₂NH and paraformaldehyde yielded ethyl 3-dimethylaminomethylene-5-methoxy-6-azaindole-2-carboxylate (IV) di-HCl salt, m.p. 162掳 位 283 m渭 (蔚 12,100), 292 (13,800), 347 (3700), 未 (D₂O) 8.2 (H-7). IV with di-Et sodiomalonate gave the corresponding malonate (V) HCl, m.p. 188掳 位 (蔚 18,600), 294 (20,400), 350 (4600). V was readily converted to 2-methoxy-3-propionic acid-6-azaindole (VI), m.p. 210-215掳, 位 283 m渭 (蔚 13,000), 292 (15,700), 350 (4400). VI on heating at 150掳 with 48% HBr yielded 70% of 2-carboxy-5-oxo-5,6-dihydro-1-H-pyrrolo[2,3-c]pyridine-3-propionic acid (VII), m.p. 280掳 dec., 位 292 m渭 (蔚 4200) and 302 (4400). VII with Pd-C and H in aqueous solution at pH 7 yielded 2-carboxyporphobilinogen lactam in 90% yield, m.p. 295掳 位 276 m渭 (蔚 12,600). In boiling water porphobilinogen lactam (VIII), m.p. 295掳 dec., was obtained in 80% yield. VIII with 2N KOH at 20掳 for 72 hrs. yielded 85% of porphobilinogen hydrate, m.p. 167掳. A similar series of reactions was carried out starting with 2-benzyloxy-4-methyl-5-nitropyridine rather than I. All uv determinations are in EtOH. In the experiment, the researchers used many compounds, for example, 1H-Pyrrolo[2,3-c]pyridine (cas: 271-29-4Synthetic Route of C7H6N2).

1H-Pyrrolo[2,3-c]pyridine (cas: 271-29-4) belongs to indole derivatives. Indole exists overwhelmingly in the 1H-indole form as do other simple indoles.Indole was synthesized in moderate yield via an o-naphthoquinone catalyzed tandem cross-coupling of substituted aniline and benzylamine under aerobic oxidation conditions.Synthetic Route of C7H6N2

Referemce:
Indole alkaloid derivatives as building blocks of natural products from聽Bacillus thuringiensis聽and聽Bacillus velezensis聽and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Natural reversal of pulmonary vascular remodeling and right ventricular remodeling in SU5416/hypoxia-treated Sprague-Dawley rats was written by Zungu-Edmondson, Makhosazane;Shults, Nataliia V.;Melnyk, Oleksiy;Suzuki, Yuichiro J.. And the article was included in PLoS One in 2017.Safety of (Z)-3-((3,5-Dimethyl-1H-pyrrol-2-yl)methylene)indolin-2-one This article mentions the following:

Pulmonary arterial hypertension (PAH) is a lethal disease and improved therapeutic strategies are needed. Increased pulmonary arterial pressure, due to vasoconstriction and vascular remodeling, causes right ventricle (RV) failure and death in patients. The treatment of Sprague-Dawley rats with SU5416 injection and exposure to chronic hypoxia for three weeks followed by maintenance in normoxia promote progressive and severe PAH with pathol. features that resemble human PAH. At 5-17 wk after the SU5416 injection, PAH is developed with pulmonary vascular remodeling as well as RV hypertrophy and fibrosis. The present study investigated subsequent events that occur in these PAH animals. At 35 wk after the SU5416 injection, rats still maintained high RV pressure, but pulmonary vascular remodeling was significantly reduced. Metabolomics anal. revealed that lungs of normal rats and rats from the 35-wk time point had different metabolomics profiles. Despite the maintenance of high RV pressure, fibrosis was resolved at 35-wk. Masson’s trichrome stain and Western blotting monitoring collagen 1 determined 12% fibrosis in the RV at 17-wk, and this was decreased to 5% at 35-wk. The level of myofibroblasts was elevated at 17-wk and normalized at 35-wk. These results suggest that biol. systems possess natural ways to resolve pulmonary and RV remodeling. The resolution of RV fibrosis appears to involve the reduction of myofibroblast- dependent collagen synthesis. Understanding these endogenous mechanisms should help improve therapeutic strategies to treat PAH and RV failure. In the experiment, the researchers used many compounds, for example, (Z)-3-((3,5-Dimethyl-1H-pyrrol-2-yl)methylene)indolin-2-one (cas: 194413-58-6Safety of (Z)-3-((3,5-Dimethyl-1H-pyrrol-2-yl)methylene)indolin-2-one).

(Z)-3-((3,5-Dimethyl-1H-pyrrol-2-yl)methylene)indolin-2-one (cas: 194413-58-6) belongs to indole derivatives. Indole exists overwhelmingly in the 1H-indole form as do other simple indoles. More than 200 indole derivatives have already been marketed as drugs or are under advanced stages of clinical trials.Safety of (Z)-3-((3,5-Dimethyl-1H-pyrrol-2-yl)methylene)indolin-2-one

Referemce:
Indole alkaloid derivatives as building blocks of natural products from聽Bacillus thuringiensis聽and聽Bacillus velezensis聽and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Synthesis of some 1-acetylindoline-5-sulfonyl amino acid derivatives and studies of their antimicrobial activities was written by Zaher, M. R.;Kora, F. A.;Hussein, M. E.;El-Sayed, R. A.;El-Naggar, A. M.. And the article was included in Farmaco, Edizione Scientifica in 1986.Reference of 52206-05-0 This article mentions the following:

Title amino acid derivatives I (R = amino acid residue or corresponding Me ester or hydrazide, dipeptide Me ester residue) were prepared from 1-acetylindoline-5-sulfonyl chloride and amino acids or esters and optional hydrazinolysis or peptide coupling. Most I (27 compounds) showed antimicrobial activity against a variety of microorganisms. In the experiment, the researchers used many compounds, for example, 1-Acetylindoline-5-sulfonyl chloride (cas: 52206-05-0Reference of 52206-05-0).

1-Acetylindoline-5-sulfonyl chloride (cas: 52206-05-0) belongs to indole derivatives. The indole subunit is an almost ubiquitous component of biologically active natural products, and its study has been the focus of research for decades. They are capable of binding to a variety of receptors with high affinity and thus have applications in a wide range of therapeutic areas.Reference of 52206-05-0

Referemce:
Indole alkaloid derivatives as building blocks of natural products from聽Bacillus thuringiensis聽and聽Bacillus velezensis聽and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Conversion of Quinazoline Modulators from Inhibitors to Activators of 尾-Glucocerebrosidase was written by Zheng, Jianbin;Jeon, Sohee;Jiang, Weilan;Burbulla, Lena F.;Ysselstein, Daniel;Oevel, Kristine;Krainc, Dimitri;Silverman, Richard B.. And the article was included in Journal of Medicinal Chemistry in 2019.Computed Properties of C11H12N2 This article mentions the following:

Gaucher’s disease is a lysosomal disease caused by mutations in the 尾-glucocerebrosidase gene (GBA1 and GCase) that have been also linked to increased risk of Parkinson’s disease (PD) and Diffuse Lewy body dementia. Prior studies have suggested that mutant GCase protein undergoes misfolding and degradation, and therefore, stabilization of the mutant protein represents an important therapeutic strategy in synucleinopathies. In this work, we present a structure-activity relationship (SAR) study of quinazoline compounds that serve as inhibitors of GCase. Unexpectedly, we found that N-methylation of these inhibitors transformed them into GCase activators. A systematic SAR study further revealed that replacement of the key oxygen atom in the linker of the quinazoline derivative also contributed to the activity switch. PD patient-derived fibroblasts and dopaminergic midbrain neurons were treated with a selected compound (9q) that partially stabilized GCase and improved its activity. These results highlight a novel strategy for therapeutic development of noninhibitory GCase modulators in PD and related synucleinopathies. In the experiment, the researchers used many compounds, for example, 2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indole (cas: 16502-01-5Computed Properties of C11H12N2).

2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indole (cas: 16502-01-5) belongs to indole derivatives. Indole produced by Proteus, Pseudomonas, Escherichia and other species was shown to be a growth promoting factor in Arabidopsis thaliana. They are capable of binding to a variety of receptors with high affinity and thus have applications in a wide range of therapeutic areas.Computed Properties of C11H12N2

Referemce:
Indole alkaloid derivatives as building blocks of natural products from聽Bacillus thuringiensis聽and聽Bacillus velezensis聽and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Aceperinone dyes for bulk dyeing of Kapron was written by Krasovitskii, B.M.;Kravchenko, E. F.;Shevchenko, E. A.. And the article was included in Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation) in 1963.Safety of 8,9,10,11-Tetrachloro-12H-isoindolo[2,1-a]perimidin-12-one This article mentions the following:

Adding equimol. amounts of 5,6-diaminoacenaphthene and the desired anhydride of an o-phthalic or naphthalic acid to glacial AcOH, refluxing 3-4 hrs., cooling, filtering, and washing with cold AcOH and H₂O gave the following dyes (% yield, m.p., and color given): phthaloaceperinone (I), 62, 287掳, -; tetrachlorophthaloaceperinone (II), 68, 294-5掳 -; naphthaloaceperinone (III), 64, 230掳, light bordeaux; 4(5?)-benzoylnaphthaloaceperinone (IV), 90, 223-4掳, reddish violet. These aceperinones were more deeply colored than the corresponding perinones. The maximum absorbance of I and II was higher and shifted to longer 纬 than that of III. Kapron dyeings obtained with III and IV were more resistant to washing, crocking, and ironing, but less lightfast, than those obtained with the corresponding periones. In the experiment, the researchers used many compounds, for example, 8,9,10,11-Tetrachloro-12H-isoindolo[2,1-a]perimidin-12-one (cas: 20749-68-2Safety of 8,9,10,11-Tetrachloro-12H-isoindolo[2,1-a]perimidin-12-one).

8,9,10,11-Tetrachloro-12H-isoindolo[2,1-a]perimidin-12-one (cas: 20749-68-2) belongs to indole derivatives. In addition to tryptophan, indigo, and indoleacetic acid, numerous compounds obtainable from plant or animal sources contain the indole molecular structure. More than 200 indole derivatives have already been marketed as drugs or are under advanced stages of clinical trials.Safety of 8,9,10,11-Tetrachloro-12H-isoindolo[2,1-a]perimidin-12-one

Referemce:
Indole alkaloid derivatives as building blocks of natural products from聽Bacillus thuringiensis聽and聽Bacillus velezensis聽and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Discovery of novel aminopiperidinyl amide CXCR4 modulators through virtual screening and rational drug design was written by Oum, Yoon Hyeun;Kell, Steven A.;Yoon, Younghyoun;Liang, Zhongxing;Burger, Pieter;Shim, Hyunsuk. And the article was included in European Journal of Medicinal Chemistry in 2020.Product Details of 271-29-4 This article mentions the following:

The C-X-C chemokine receptor type 4 (CXCR4) is a potential therapeutic target for HIV infection, metastatic cancer, and inflammatory autoimmune diseases. In this study, we screened the ZINC chem. database for novel CXCR4 modulators through a series of in silico guided processes. After evaluating the screened compounds for their binding affinities to CXCR4 and inhibitory activities against the chemoattractant CXCL12, we identified a hit compound (ZINC 72372983) showing 100 nM affinity and 69% chemotaxis inhibition at the same concentration (100 nM). To increase the potency of our hit compound, we explored the protein-ligand interactions at an at. level using mol. dynamics simulation which enabled us to design and synthesize a novel compound (Z7R) with nanomolar affinity (IC₅₀ = 1.25 nM) and improved chemotaxis inhibition (78.5%). Z7R displays promising anti-inflammatory activity (50%) in a mouse edema model by blocking CXCR4-expressed leukocytes, being supported by our immunohistochem. study. In the experiment, the researchers used many compounds, for example, 1H-Pyrrolo[2,3-c]pyridine (cas: 271-29-4Product Details of 271-29-4).

1H-Pyrrolo[2,3-c]pyridine (cas: 271-29-4) belongs to indole derivatives. The indole subunit is an almost ubiquitous component of biologically active natural products, and its study has been the focus of research for decades. In addition to indole, the strain-release chemistry worked for numerous substrates including amines, alcohols, thiols, carboxylic acids, imidazoles, and pyrazoles.Product Details of 271-29-4

Referemce:
Indole alkaloid derivatives as building blocks of natural products from聽Bacillus thuringiensis聽and聽Bacillus velezensis聽and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Formation of heterocyclic aromatic amines in spiced pork shoulder: Effects of heat treatment parameters and number of soup cycles was written by Zhang, Yuxia;Zhou, Yajun. And the article was included in Journal of Food Composition and Analysis in 2022.Synthetic Route of C11H8N2 This article mentions the following:

Spiced pork shoulder is a traditional Chinese meat product that is produced by long-term stewing in recycled soup. This study investigated the effects of cooking temperature, cooking time and number of soup cycles on the formation of heterocyclic aromatic amines (HAAs) in spiced pork shoulder. The main HAAs found in spiced pork shoulder was 尾-carboline. When the cooking temperature rose from 70掳C to 100掳C, the total HAAs increased from 27.17 卤 1.76 ng/g to 42.37 卤 0.91 ng/g. When the cooking time was extended from 1 h to 4 h, the total HAAs increased by 50.23%. When the number of soup cycles was 15, the total HAAs in the meat and soup were 40.69 卤 0.28 ng/g and 55.84 卤 1.51 ng/g, resp. Recycling soup may contribute greatly to the contents of HAAs in spiced pork shoulders. The high levels of HAAs in spiced pork shoulders were mainly from the adsorption of the HAAs in the soup onto the surface of the meat and their penetration into the meat. We recommend lowering the cooking temperature and shortening the cooking time to reduce the formation of HAAs in spiced pork shoulder. In addition, it is necessary to study effective methods to inhibit the formation of HAAs in soup. In the experiment, the researchers used many compounds, for example, 9H-Pyrido[3,4-b]indole (cas: 244-63-3Synthetic Route of C11H8N2).

9H-Pyrido[3,4-b]indole (cas: 244-63-3) belongs to indole derivatives. Indole exists overwhelmingly in the 1H-indole form as do other simple indoles. Indole plays a fundamental role for QS in E. coli, being one of the signal molecules responsible for the transcription of a variety of genes (gabT, and tnaB ASTD). Synthetic Route of C11H8N2

Referemce:
Indole alkaloid derivatives as building blocks of natural products from聽Bacillus thuringiensis聽and聽Bacillus velezensis聽and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Characteristics and proteolysis of a Spanish blue cheese made with raw or pasteurised milk was written by Diezhandino, Isabel;Fernandez, Domingo;Combarros-Fuertes, Patricia;Renes, Erica;Fresno, Jose Maria;Tornadijo, Maria Eugenia. And the article was included in International Journal of Dairy Technology in 2022.SDS of cas: 61-54-1 This article mentions the following:

Valdeon cheese is a Spanish Protected Geog. Indication of blue-veined cheese produced on an industrial scale from raw or pasteurised cow and/or goat milk. The aim of this work was to evaluate the impact of pasteurisation on the microbiol., physicochem. and sensory characteristics of cheese. Cheeses made with raw milk showed higher counts of lactobacilli and enterococci, as well as lower values of pH and D-lactic acid and salt/moisture ratio. Cheeses made with pasteurised milk showed greater extent of proteolysis, higher concentration of free amino acids and lower concentration of biogenic amines. Pasteurisation produced more elastic and harder cheeses, but with a lower sensory profile. In the experiment, the researchers used many compounds, for example, 2-(1H-Indol-3-yl)ethanamine (cas: 61-54-1SDS of cas: 61-54-1).

2-(1H-Indol-3-yl)ethanamine (cas: 61-54-1) belongs to indole derivatives. Indole could be stereoselectively alkylated with chiral cyclopentyl sulfone reagent. Due to this activity, the indole ring system has become an important component or intermediate in the synthesis of heterocycles.SDS of cas: 61-54-1

Referemce:
Indole alkaloid derivatives as building blocks of natural products from聽Bacillus thuringiensis聽and聽Bacillus velezensis聽and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Oxidative C-O Cross-Coupling of 1,3-Dicarbonyl Compounds and Their Heteroanalogues with N-Substituted Hydroxamic Acids and N-Hydroxyimides was written by Terent’ev, Alexander O.;Krylov, Igor B.;Timofeev, Vladimir P.;Starikova, Zoya A.;Merkulova, Valentina M.;Ilovaisky, Alexey I.;Nikishin, Gennady I.. And the article was included in Advanced Synthesis & Catalysis in 2013.Application of 1538551-54-0 This article mentions the following:

The oxidative C-O cross-coupling of 1,3-dicarbonyl compounds and their heteroanalogs (2-substituted malononitriles and cyanoacetic esters) with N-substituted hydroxamic acids and N-hydroxyimides was realized. The best results were obtained with the use of manganese(III) acetate [Mn(OAc)₃] or the cobalt(II) acetate catalyst [Co(OAc)₂]/potassium permanganate [KMnO₄] system as the oxidant. E.g., in presence of [Co(OAc)₂]/potassium permanganate, cross-coupling of BuCH(COMe)₂ and N-hydroxyphthalimide gave 77% I. The synthesis can be scaled up to gram quantities of coupling products; yields are 30-94%. The reaction proceeds via a radical mechanism through the formation of nitroxyl radicals from N-substituted hydroxamic acids and N-hydroxyimides. In the experiment, the researchers used many compounds, for example, 1,3-Dioxoisoindolin-2-yl butyrate (cas: 1538551-54-0Application of 1538551-54-0).

1,3-Dioxoisoindolin-2-yl butyrate (cas: 1538551-54-0) belongs to indole derivatives. Indole, also called Benzopyrrole, a heterocyclic organic compound occurring in some flower oils, such as jasmine and orange blossom, in coal tar, and in fecal matter.Indole was synthesized in moderate yield via an o-naphthoquinone catalyzed tandem cross-coupling of substituted aniline and benzylamine under aerobic oxidation conditions.Application of 1538551-54-0

Referemce:
Indole alkaloid derivatives as building blocks of natural products from聽Bacillus thuringiensis聽and聽Bacillus velezensis聽and their antibacterial and antifungal activity study,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles