Day: November 23, 2022

Schoning, Verena published the artcileThe hepatotoxic potential of protein kinase inhibitors predicted with Random Forest and Artificial Neural Networks, Formula: C19H21N3O3S, the publication is Toxicology Letters (2018), 145-148, database is CAplus and MEDLINE.

Protein kinases (PKs) play a role in many pivotal aspects of cellular function. Dysregulation and mutations of protein kinases are involved in the development of different diseases, which might be treated by inhibition of the corresponding kinase. Protein kinase inhibitors (PKIs) are generally well tolerated, but unexpected and serious adverse events on the heart, lung, kidney and liver were observed clin. In this study, the structure-activity relationship of PKIs in relation to hepatotoxicity was investigated. A dataset of 165 PKIs was compiled and the probability of human hepatotoxicity with two different machine learning algorithms (Random Forest and Artificial Neural Networks) was analyzed. The estimated probability of hepatotoxicity was generally high for single PKIs. However, depending on the target kinase of the PKI, a difference in hepatotoxic potential could be observed The similarity of the PKIs to each other is caused by the conserved site of action of the protein kinases. Hepatotoxicity may therefore always be an issue in PKIs.

Toxicology Letters published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C19H21N3O3S, Formula: C19H21N3O3S.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Tobrman, Tomas published the artcileAluminum chloride promoted cross-coupling of trisubstituted enol phosphates with organozinc reagents en route to stereoselective synthesis of tamoxifen and its analogues, Product Details of C15H14BNO4S, the publication is European Journal of Organic Chemistry (2016), 2016(29), 5037-5044, database is CAplus.

In the presence of Pd(S-Phos)₂Cl₂ [S-Phos = (2′,6′-dimethoxy-1,1-biphenyl-2-yl)dicyclohexylphosphine], aluminum chloride acts as a promoter for the diastereoselective Negishi coupling reactions of arylzinc chlorides or tribenzylaluminum (generated in situ) with enol phosphates to yield aryl alkenes with high stereoselectivities; using dibromoalkenyl phosphates, tri- and tetraaryl alkenes were prepared stereoselectively. Using this method, tamoxifen and two analogs were prepared stereoselectively in >98:2 diastereoselectivities.

European Journal of Organic Chemistry published new progress about 149108-61-2. 149108-61-2 belongs to indole-building-block, auxiliary class Indole,Boronic acid and ester,Sulfamide,Benzene,Boronic Acids,Boronic Acids,Boronic acid and ester,, name is (1-tosyl-1H-Indol-3-yl)boronic acid, and the molecular formula is C10H15NO, Product Details of C15H14BNO4S.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Majima, Riko published the artcileSynthetic experiments in the indole group. VII. Nitration and bromination of β-indolecarboxylic ester and a new synthesis of the dye of the purple of antiquity, Computed Properties of 10242-03-2, the publication is Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1930), 2237-45, database is CAplus.

cf. C. A. 20, 758. A repetition of the work of Oddo and Sessa (C. A. 5, 2638) not only confirmed the earlier observation that, contrary to the statements of O. and S., Et β-indolecarboxylate (I) is formed by the action of ClCO₂Et on indolylmagnesium iodide but also showed that di-Et N, β-indoledicarboxylate (II) is formed at the same time; to obtain II in good yield it is well to use 2 mols. ClCO₂Et per mol. of indole. Addition of concentrated HNO₃ to I in cold AcOH gives chiefly Et 6-nitroindole-3-carboxylate (III), saponified by KOH to the free and (IV) which with hot quinoline gives 6-nitroindole (V). The position of the NO₂ group was established by oxidation of the salt of IV with aqueous KMnO₄ to 2,4-H₂N(O₂N)C₆H₃-CO₂H. With HCl and SnCl₂ in AcOH III readily yields the 3-amino ester (VI). V similarly gives the amorphous and very unstable 6-aminoindole (VII). I is readily brominated in AcOH, giving chiefly either Et 6-bromoindole-3-carboxylate (VIII) or the 5,6-di-Br ester (IX), depending on the conditions. The free di-Br acid (X) can be further converted into 5,6-dibromoindole (XI). X with CrO₃ in AcOH gives a red 5,6-dibromoisatin (XII), m. above 290°, which on distillation with KOH yields a Br₂C₆H₃NH₂, m. 79-80° (of the known Br₂C₆H₃NH₂, the 3,4-compound, m. 80.4°, comes closest in its properties to the one obtained from XII). XII on further oxidation with CrO₃ in AcOH gives a dibromoisatoic acid (XIII) which with concentrated HCl yields 4,5,2-Br₂(H₂N)C₆H₂CO₂H, m. 227-8°. In the same way VIII gave 6-bromoisatin (XIV), different from Borsche and Jacobs’ synthetic 5-Br compound With 03 in alk. solution, VIII readily gives 6,6′-dibromoindigo (XV), thus further confirming the structure of VIII. II (1.1 g. from 3 g. indole through the Mg compound with 2 mols. ClCO₂Et), less soluble in alc. than I, m. 102-3°. The yield of I has been increased to over 78% by slowly adding 11 g. ClCO₂Et to the Mg derivative from 11 g. indole in cold Et₂O. III, light yellowish needles, m. 198-9°. IV, yellow, becomes opaque at 227°, decomposes around 275-8°; its alkali salts dissolve in H₂O with orange-red color. V, yellow, m. 139-40.5°. VI, m. 149-50°; HCl salt; chloroplatinate. β-Indolealdehyde in AcOH with HNO₃ (d. 1.4) gives an addition product, C₉H₇ON.HNO₃, decomposes 94°; with excess of HNO₃ on the H₂O bath is obtained a nitro-β-indolealdehyde, light yellow, m. around 290° (decomposition), turns brownish in the air. VIII, m. 134-7°; free acid, m. 212°. IX (85% from 2 g. I and 4 g. Br), m. 223-5°. X, m. 255-7°; if, in the saponification of IX, the boiling with excess of ale. KOH is continued 10 hrs. the product is XI, m. 154°. XII, m. 290°, shows the indopbenin reaction, gives with dilute NaOH a dark violet precipitate which redissolves with yellow color on heating and acids reppt. the original XII. XIV, orange-red, m. 256-8°. 5,5′,6,6′-Tetrabrornoindigo, is obtained from IX with O₃; it dyes silk in somewhat less reddish shades than XV, the chief constituent of the purple of the ancients.

Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen published new progress about 10242-03-2. 10242-03-2 belongs to indole-building-block, auxiliary class Indole,Nitro Compound,Carboxylic acid,Indole, name is 6-Nitro-1H-indole-3-carboxylic acid, and the molecular formula is C9H6N2O4, Computed Properties of 10242-03-2.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Zischler, Johannes published the artcileAlcohol-Enhanced Cu-Mediated Radiofluorination, COA of Formula: C14H18BNO2, the publication is Chemistry – A European Journal (2017), 23(14), 3251-3256, database is CAplus and MEDLINE.

The potential of many ¹⁸F-labeled (hetero)aromatics for applications in positron emission tomog. remains underexplored because convenient procedures for their radiosynthesis are lacking. Consequently, simple methods to prepare radiofluorinated (hetero)arenes are highly sought after. Herein, we report the beneficial effect of primary and secondary alcs. on Cu-mediated ¹⁸F-labeling. This observation contradicts the assumption that such alcs. are inappropriate solvents for aromatic fluorination. Therefore, we developed a protocol for rapid radiolabeling of an extraordinarily broad scope of boronic and stannyl substrates under general reaction conditions. Notably, radiofluorinated indoles, phenols, and anilines were synthesized directly from the corresponding unprotected precursors. Furthermore, the novel method enabled the preparation of radiofluorinated tryptophans, [¹⁸F]F-DPA, [¹⁸F]DAA1106, 6-[¹⁸F]FDA, and 6-[¹⁸F]FDOPA.

Chemistry – A European Journal published new progress about 642494-36-8. 642494-36-8 belongs to indole-building-block, auxiliary class Indole,Boronic acid and ester,Indole,Boronate Esters,Boronic acid and ester, name is 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole, and the molecular formula is C9H16BNO2, COA of Formula: C14H18BNO2.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Okamoto, Masako published the artcileVirtual screening and further development of novel ALK inhibitors, Safety of SU6656, the publication is Bioorganic & Medicinal Chemistry (2011), 19(10), 3086-3095, database is CAplus and MEDLINE.

Anaplastic lymphoma kinase (ALK) has been in the spotlight in recent years as a promising new target for therapy of non-small-cell lung cancer (NSCLC). Since the identification of the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene in some NSCLC patients was reported in 2007, various research groups have been seeking ALK inhibitors. Above all, crizotinib (PF-02341066) has been under clin. trial, and its therapeutic efficacy of inhibiting ALK in NSCLC has been reported. Among anticancer drugs, drug resistance appears frequently necessitating various kinds of inhibitors. We identified novel ALK inhibitors by virtual screening from the public chem. library collected by the Chem. Biol. Research Initiative (CBRI) at the University of Tokyo, and inhibitors that are more potent were developed.

Bioorganic & Medicinal Chemistry published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C19H21N3O3S, Safety of SU6656.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Simpson, Levi S. published the artcileA cleavable scaffold strategy for the synthesis of one-bead one-compound cyclic peptoid libraries that can be sequenced by tandem mass spectrometry, SDS of cas: 167015-84-1, the publication is Tetrahedron Letters (2012), 53(18), 2341-2344, database is CAplus and MEDLINE.

Many macrocyclic depsipeptides or related compounds have interesting medicinal properties and often display more favorable pharmacokinetic properties than linear analogs. Therefore, there is considerable interest in the development of large combinatorial libraries of macrocyclic peptidomimetic compounds However, such mols. cannot be easily sequenced by tandem mass spectrometry, making it difficult to identify hits isolated from library screens using one bead one compound libraries. Here we report a strategy to solve this problem by placing a methionine in both the linker connecting the cyclic mol. to the bead as well as within the cycle itself. Treatment with CNBr both linearizes the mol. at a specific position and releases the mol. from the bead, making its characterization by tandem MALDI mass spectrometry straightforward.

Tetrahedron Letters published new progress about 167015-84-1. 167015-84-1 belongs to indole-building-block, auxiliary class Indols, name is tert-Butyl 3-(2-aminoethyl)-1H-indole-1-carboxylate, and the molecular formula is C23H23ClN2O4, SDS of cas: 167015-84-1.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Spangler, Jillian E. published the artcileα-Arylation of Saturated Azacycles and N-Methylamines via Palladium(II)-Catalyzed C(sp³)-H Coupling, COA of Formula: C14H12BNO4S, the publication is Journal of the American Chemical Society (2015), 137(37), 11876-11879, database is CAplus and MEDLINE.

In the presence of Pd(O₂CCF₃)₂, N-(thiopivaloyl) nitrogen heterocycles such as I (R = H; X = CH₂, CH₂CH₂CH₂) underwent chemoselective and regioselective arylation with arylboronic acids R¹B(OH)₂ (R¹ = Ph, 2-MeC₆H₄, 3-MeC₆H₄, 4-MeC₆H₄, 3-MeOC₆H₄, 4-MeOC₆H₄, 4-AcNHC₆H₄, 4-F₃COC₆H₄, 3,4-Cl₂C₆H₃, 4-ClC₆H₄, 3-ClC₆H₄, 2-FC₆H₄, 4-FC₆H₄, 4-F₃CC₆H₄, 4-AcC₆H₄, 3-AcC₆H₄, 5-benzofuranyl, 1-PhSO₂-4-indolyl, 1-PhSO₂-5-indolyl, 6-F-3-pyridinyl, 2-F-4-pyridinyl, 6-Cl-3-pyridinyl, 6-MeO-3-pyridinyl, 2-MeO-4-pyridinyl) mediated by 1,4-benzoquinone in tert-amyl alc. with KHCO₃ to give monoarylated heterocycles such as (thiopivaloyl)arylpyrrolidines I (R = R¹; R¹ = Ph, 2-MeC₆H₄, 3-MeC₆H₄, 4-MeC₆H₄, 3-MeOC₆H₄, 4-MeOC₆H₄, 4-AcNHC₆H₄, 4-F₃COC₆H₄, 3,4-Cl₂C₆H₃, 4-ClC₆H₄, 3-ClC₆H₄, 2-FC₆H₄, 4-FC₆H₄, 4-F₃CC₆H₄, 4-AcC₆H₄, 3-AcC₆H₄, 5-benzofuranyl, 1-PhSO₂-4-indolyl, 1-PhSO₂-5-indolyl, 6-F-3-pyridinyl, 2-F-4-pyridinyl, 6-Cl-3-pyridinyl, 6-MeO-3-pyridinyl, 2-MeO-4-pyridinyl; X = CH₂) and (thiopivaloyl)phenylhexahydroazepine I (R = Ph; X = CH₂CH₂CH₂). Unsym. trans-2,5-diaryl-1-(thiopivaloyl)pyrrolidines were prepared in >20:1 dr in one pot using this method. Tertiary N-methylthiopivalamides t-BuC(:S)N(Me)R² (R² = Me, n-Pr, PhCH₂, PhCH₂CH₂, cyclohexyl, Ph, 4-FC₆H₄, 4-ClC₆H₄) underwent chemoselective and regioselective arylation with arylboronic acids (R³ = Ph, 1-PhSO₂-5-indolyl, 5-benzofuranyl, 6-MeO-3-pyridinyl) under similar conditions to yield (arylmethyl)thiopivalamides t-BuC(:S)N(CH₂R³)R² (R² = Me, n-Pr, PhCH₂, PhCH₂CH₂, cyclohexyl, Ph, 4-FC₆H₄, 4-ClC₆H₄; R³ = Ph, 1-PhSO₂-5-indolyl, 5-benzofuranyl, 6-MeO-3-pyridinyl). The structure of a trans-(fluorophenyl)(methoxyphenyl)thiopivaloylpyrrolidine was determined by X-ray crystallog.

Journal of the American Chemical Society published new progress about 480438-51-5. 480438-51-5 belongs to indole-building-block, auxiliary class Indole,Boronic acid and ester,Sulfamide,Benzene,Boronic Acids,Boronic Acids,Boronic acid and ester,, name is (1-(Phenylsulfonyl)-1H-indol-5-yl)boronic acid, and the molecular formula is C6H3ClFNO2, COA of Formula: C14H12BNO4S.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Walpole, C. published the artcile2-Nitrophenylcarbamoyl-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N- methylamide (SDZ NKT 343), a Potent Human NK₁ Tachykinin Receptor Antagonist with Good Oral Analgesic Activity in Chronic Pain Models, Application In Synthesis of 167015-84-1, the publication is Journal of Medicinal Chemistry (1998), 41(17), 3159-3173, database is CAplus and MEDLINE.

A lead compound which had sub-micromolar affinity for the rabbit NK₁ receptor but negligible affinity for rat NK₁ receptors, 2-MeOC₆H₄CH₂NHCS-Pro-NHCHPh₂, was discovered by directed screening. 2-Substitution in the ring of the benzylthiourea substituent in the initial lead was found to be important, and halogens (Cl, Br) in this position were found to improve affinity for the human receptor. The activity of a series of 2-halo-substituted benzylthioureas was then optimized by modification of the proline diphenylmethyl amide, guided by a simple conceptual model based on structural overlay between these early antagonists and NK₁ selective peptides. In this way, aromatic amino acid amides were identified which had improved affinity with respect to the starting diphenylmethyl (DPM) amides. The first sub-nanomolar ligand for the human NK₁ receptor which arose from this series, I, combined a 2-chlorobenzylthiourea unit with a 2-naphthylalanine amide. Contemporaneously it was discovered that the benzylthiourea unit could be simplified to a phenylthiourea providing that an appropriate 2-substituent was also incorporated. Combination of these two series gave 2-NO₂ phenylthiourea analogs which led directly to the analogous urea, II (SDZ NKT 343), a highly potent ligand for the human NK₁ receptor (K_i = 0.16 nM). In addition to its high in vitro potency, II proved to be a potent orally active analgesic in guinea pig models of chronic inflammatory and neuropathic pain. The nature of the 2-aryl substituent was found to be critical for oral activity in this series. Clin. evaluation of II as a novel analgesic agent is currently underway.

Journal of Medicinal Chemistry published new progress about 167015-84-1. 167015-84-1 belongs to indole-building-block, auxiliary class Indols, name is tert-Butyl 3-(2-aminoethyl)-1H-indole-1-carboxylate, and the molecular formula is C4H6BrFO2, Application In Synthesis of 167015-84-1.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Paveliev, Mikhail published the artcileAcute brain trauma in mice followed by longitudinal two-photon imaging, Synthetic Route of 330161-87-0, the publication is Journal of Visualized Experiments (2014), e51559/1-e51559/8, database is CAplus and MEDLINE.

Although acute brain trauma often results from head damage in different accidents and affects a substantial fraction of the population, there is no effective treatment for it yet. Limitations of currently used animal models impede understanding of the pathol. mechanism. Multiphoton microscopy allows studying cells and tissues within intact animal brains longitudinally under physiol. and pathol. conditions. Here, we describe two models of acute brain injury studied by means of two-photon imaging of brain cell behavior under posttraumatic conditions. A selected brain region is injured with a sharp needle to produce a trauma of a controlled width and depth in the brain parenchyma. Our method uses stereotaxic prick with a syringe needle, which can be combined with simultaneous drug application. We propose that this method can be used as an advanced tool to study cellular mechanisms of pathophysiol. consequences of acute trauma in mammalian brain in vivo. In this video, we combine acute brain injury with two preparations: cranial window and skull thinning. We also discuss advantages and limitations of both preparations for multisession imaging of brain regeneration after trauma.

Journal of Visualized Experiments published new progress about 330161-87-0. 330161-87-0 belongs to indole-building-block, auxiliary class Protein Tyrosine Kinase/RTK,Src, name is SU6656, and the molecular formula is C19H21N3O3S, Synthetic Route of 330161-87-0.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles