Day: November 21, 2022

Pettus, Liping H. published the artcileDiscovery and Optimization of Quinazolinone-pyrrolopyrrolones as Potent and Orally Bioavailable Pan-Pim Kinase Inhibitors, Recommanded Product: 2-Bromo-6,7-dihydro-1H-indol-4(5H)-one, the publication is Journal of Medicinal Chemistry (2016), 59(13), 6407-6430, database is CAplus and MEDLINE.

The high expression of proviral insertion site of Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role in promoting cell survival and proliferation while suppressing apoptosis. The three isoforms of Pim protein appear largely redundant in their oncogenic functions. Thus, a pan-Pim kinase inhibitor is highly desirable. However, cell active pan-Pim inhibitors have proven difficult to develop because Pim-2 has a low K_m for ATP and therefore requires a very potent inhibitor to effectively block the kinase activity at cellular ATP concentrations Herein, the authors report a series of quinazolinone-pyrrolopyrrolones as potent and selective pan-Pim inhibitors. In particular, compound (R)-2-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (17) is orally efficacious in a mouse xenograft model (KMS-12 BM) of multiple myeloma, with 93% tumor growth inhibition at 50 mg/kg QD upon oral dosing.

Journal of Medicinal Chemistry published new progress about 27784-79-8. 27784-79-8 belongs to indole-building-block, auxiliary class Other Aromatic Heterocyclic,Bromide,Ketone, name is 2-Bromo-6,7-dihydro-1H-indol-4(5H)-one, and the molecular formula is C8H8BrNO, Recommanded Product: 2-Bromo-6,7-dihydro-1H-indol-4(5H)-one.

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

Selvakumar, Rajendran published the artcileIdentification of novel NAD(P)H dehydrogenase [quinone] 1 antagonist using computational approaches, Application of 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, the publication is Journal of Biomolecular Structure and Dynamics (2020), 38(3), 682-696, database is CAplus and MEDLINE.

NAD(P)H: quinone oxidoreductase 1 (NQO1) inhibitors are proved as promising therapeutic agents against cancer. This study is to determine potent NAD(P)H-dependent NQO1 inhibitors with new scaffold. Pharmacophore-based three-dimensional (3D) QSAR model has been built based on 45 NQO1 inhibitors reported in the literature. The structure-function correlation coefficient graph represents the relationship between phase activity and phase predicted activity for training and test sets. A QSAR model statistics shows the excellent correlation of the generated model. Pharmacophore hypothesis (AARR) yielded a statistically significant 3D QSASR model with a correlation coefficient of r² = 0.99 as well as an excellent predictive power. From the anal. of pharmacophore-based virtual screening using by SPEC database, 4093 hits were obtained and were further filtered using virtual screening filters (HTVS, SP, XP) through structure based mol. docking. Based on glide energy and docking score, seven lead compounds show better binding affinity compared to the co-crystal inhibitor. The results of induced fit docking and prime/MM-GBSA suggest that leads AN-153/J117103 and AT-138/KB09997 binding with the catalytic site. Further, to understanding the stability of identified lead compounds MD simulations were done. The lead AN-153/J117103 showed the strong binding stable of the protein-ligand complex. Also the computed drug likeness reveals potential of this compound to treat cancer.

Journal of Biomolecular Structure and Dynamics published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C9H20Cl2Si, Application of 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione.

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

Gonzalez-Aragon, David published the artcileES936 stimulates DNA synthesis in HeLa cells independently on NAD(P)H:quinone oxidoreductase 1 inhibition, through a mechanism involving p38 MAPK, SDS of cas: 192820-78-3, the publication is Chemico-Biological Interactions (2010), 186(2), 174-183, database is CAplus and MEDLINE.

The indolequinone ES936 (5-methoxy-1,2-dimethyl-3-[(4-nitrophenol)methyl]-indole-4,7-dione) is a potent mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1). Here, we report that ES936 significantly stimulated thymidine incorporation in sparse cultures of human adenocarcinoma HeLa cells, but was without effect in dense cultures. Stimulation of DNA synthesis was not related with a DNA repair response because an increase in thymidine incorporation was not observed in cells treated with 2,5 bis-[1-aziridyl]-1,4 benzoquinone, a well-established antitumor quinone that causes DNA damage. Conversely, it was related with an increase of cell growth. NQO1 inhibition was not involved in ES936 stimulation of DNA synthesis, because the same response was observed in cells where NQO1 expression had been knocked down by small interfering RNA. Stimulation of DNA synthesis was reverted by treatment with ambroxol, a SOD mimetic, and by pyruvate, an efficient peroxide scavenger, supporting the involvement of alterations in cellular redox state. Pharmacol. inhibition of p38 with either SB203580 or PD169316 completely abolished ES936-stimulated DNA synthesis, indicating the requirement of p38 activity. This is the first report that demonstrates the existence of an ES936-sensitive system which is sep. from NQO1, modulating the redox state and cell growth in HeLa cells through a p38-dependent mechanism. Our results show that the effect ES936 exerts on DNA synthesis may be either pos. or neg. depending on the cellular context and growth conditions.

Chemico-Biological Interactions published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C18H16N2O6, SDS of cas: 192820-78-3.

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

Muldoon, Pretal P. published the artcileInhibition of monoacylglycerol lipase reduces nicotine reward in the conditioned place preference test in male mice, Product Details of C23H23ClN2O4, the publication is Neuropharmacology (2020), 108170, database is CAplus and MEDLINE.

Nicotine, the primary psychoactive component in tobacco, plays a major role in the initiation and maintenance of tobacco dependence and addiction, a leading cause of preventable death worldwide. In this study, we utilized complementary genetic and pharmacol. approaches to test the hypothesis that increasing the levels of the endocannabinoid 2-arachindonoylglycerol (2-AG), will enhance nicotine reward by stimulating neuronal CB1 receptors. Contrary to our hypothesis, we found that inhibition of monoacylglycerol lipase (MAGL), the primary catabolic enzyme of 2-AG, attenuates nicotine conditioned place preference (CPP) in mice, through a non-CB1 receptor-mediated mechanism. In support of our findings, repeated MAGL inhibition did not induce a reduction in CB1 brain receptor levels or hinder function. To explore the potential mechanism of action, we investigated if MAGL inhibition affected other fatty acid levels in our CPP paradigm. Indeed, MAGL inhibition caused a concomitant decrease in arachidonic acid (AA) levels in various brain regions of interest, suggesting an AA cascade-dependent mechanism. This idea is supported by dose-dependent attenuation of nicotine preference by the selective COX-2 inhibitors valdecoxib and LM-4131. Collectively, these findings, along with our reported studies on nicotine withdrawal, suggest that inhibition of MAGL represents a promising new target for the development of pharmacotherapies to treat nicotine dependence.

Neuropharmacology published new progress about 2854-32-2. 2854-32-2 belongs to indole-building-block, auxiliary class GPCR/G Protein,Cannabinoid Receptor, name is 2-(1-(4-Chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-1-morpholinoethanone, and the molecular formula is C23H23ClN2O4, Product Details of C23H23ClN2O4.

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

Nakamura, Hideshi published the artcileConvergent and short-step syntheses of dl-Cypridina luciferin and its analogs based on Pd-mediated cross couplings, Safety of (1-tosyl-1H-Indol-3-yl)boronic acid, the publication is Tetrahedron Letters (2000), 41(13), 2185-2188, database is CAplus.

(±)-Cypridina luciferin and its analogs I (X = NH, O, S) were synthesized from 2-aminopyrazine by an eight-step method that included two regio-selective Pd-mediated cross couplings, and their chemi- and bioluminescent activities were compared. Analogs having a 3-benzofuranyl or a 3-benzothienyl group in the place of a 3-indolyl group showed luciferase affinities similar to Cypridina luciferase but with a lower luminescent efficiency, suggesting that the NH group is unimportant for mol. recognition whereas the indolyl group is crucial for efficient luminescence.

Tetrahedron Letters 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 C15H14BNO4S, Safety of (1-tosyl-1H-Indol-3-yl)boronic acid.

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

Zhang, Dengyou published the artcileDiscovery of novel 2-aminopyridine-3-carboxamides as c-Met kinase inhibitors, Category: indole-building-block, the publication is Bioorganic & Medicinal Chemistry (2012), 20(17), 5169-5180, database is CAplus and MEDLINE.

A series of 2-aminopyridine-3-carboxamide derivatives against c-Met were designed and synthesized by employing bioisosteric replacement of heterocyclic moieties with the amide bond. The structure-activity relationship (SAR) at various positions of the scaffold was explored. In this study, a promising compound (S)-24o (I) with a c-Met IC₅₀ of 0.022 μM was identified. The compound exhibited dose-dependent inhibition of the phosphorylation of c-Met as well as downstream signaling in EBC-1 cells. Furthermore, the interactive binding model of (S)-24o with c-Met was elucidated by virtue of a mol. modeling study.

Bioorganic & Medicinal Chemistry published new progress about 837392-64-0. 837392-64-0 belongs to indole-building-block, auxiliary class Indoline,Boronic acid and ester,Amide,Boronate Esters, name is 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one, and the molecular formula is C12H23N3S, Category: indole-building-block.

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

Patel, Harun M. published the artcileIn silico search of triple mutant T790M/C797S allosteric inhibitors to conquer acquired resistance problem in non-small cell lung cancer (NSCLC): a combined approach of structure-based virtual screening and molecular dynamics simulation, Computed Properties of 1942114-09-1, the publication is Journal of Biomolecular Structure and Dynamics (2021), 39(4), 1491-1505, database is CAplus and MEDLINE.

Third generation EGFR inhibitor osimertinib was approved as the first-line treatment for EGFR T790M mutation-pos. Non-Small Cell Lung Cancer (NSCLC) patients in 2017. However, EGFR tertiary Cys797 to Ser797 (C797S) point mutation emanate rapidly after treatment of osimertinib, which is undruggable mutation to the all existing drugs. Recently, EAI045 fourth-generation allosteric EGFR inhibitor has been reported, which binds away from the ATP-binding site and not rely on Cys 797 binding. Here, we are reporting compound ZINC20531199 by virtual based screening studies as allosteric inhibitor to overcome the EGFR T790M/C797S Tyrosine Kinase (TK) mutation problem. Mol. Dynamics simulation for 10 ns further suggested that docked compound ZINC20531199 was stable into the allosteric pocket of the C797S EGFR tyrosine kinase. In silico pharmacokinetic predictions of the virtually screened compounds are within the defined range described for human use. Results indicate that the virtual screened compounds could be potential leads for the further development of new allosteric EGFR T790M/C797S inhibitors to overcome the problem of drug resistance.

Journal of Biomolecular Structure and Dynamics published new progress about 1942114-09-1. 1942114-09-1 belongs to indole-building-block, auxiliary class Indoline,Thiazole,Fluoride,Amine,Benzene,Amide,Alcohol,Protein Tyrosine Kinase/RTK, name is 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, and the molecular formula is C19H14FN3O3S, Computed Properties of 1942114-09-1.

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

Wesche, Frank published the artcileCombined approach of backbone amide linking and on-resin N-methylation for the synthesis of bioactive and metabolically stable peptides, Recommanded Product: tert-Butyl 3-(2-aminoethyl)-1H-indole-1-carboxylate, the publication is Journal of Medicinal Chemistry (2018), 61(9), 3930-3938, database is CAplus and MEDLINE.

Rhabdopeptides are a large class of nonribosomal peptides from the bacteria Xenorhabdus and Photorhabdus with low micromolar activity against different protozoa, which are the causative agents of several tropical diseases. The development of a facile and flexible synthesis combining backbone amide linking with on-resin peralkylation for the synthesis of permethylated rhabdopeptides is described. This strategy allows the fast generation of permethylated naturally occurring and artificial rhabdopeptides for a structure-activity study. Furthermore, in vitro experiments revealed their superior properties regarding their stability and passive membrane diffusion.

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 C18H28N2O7, Recommanded Product: tert-Butyl 3-(2-aminoethyl)-1H-indole-1-carboxylate.

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

Jang, Ye Jin published the artcileSynthesis and anti-influenza virus activity of 4-oxo- or thioxo-4,5-dihydrofuro[3,4-c]pyridin-3(1H)-ones, Application In Synthesis of 220943-23-7, the publication is Antiviral Research (2014), 66-75, database is CAplus and MEDLINE.

A series of dihydrofuropyridinones I (X = O, S; R¹ = H, Me; R² = Me, Ph; R³ = 5-fluoro-3-indolyl, 2-thienyl, 3-furyl, 3-benzothienyl, etc.) has been synthesized under conventional thermal and microwave irradiation conditions. To investigate the structure-activity relationships, two dozens of the hit analogs were synthesized. One of the hit compounds, I (X = S; R¹ = H; R² = Me; R³ = 5-fluoro-3-indolyl), had half-maximal effective concentrations of 17.4-21.1 μM against influenza A/H1N1, A/H3N2 and B viruses without any cellular toxicity at 900 μM. Among the products, I (X = S; R¹ = H; R² = Me; R³ = 2-benzothienyl, 3-thienyl, 2-thienyl, 5-Me-2-thienyl) and I (X = S; R¹ = R² = Me; R³ = 3-Me-2-thienyl) had anti-influenza viral activity comparable or superior to that of the initial hit. Based on a mode-of-action study, these compounds did not affect virus entry or RNA replication. Instead, they suppressed viral neuraminidase activity. This study is the first to demonstrate that dihydrofuropyridinones could serve as lead compounds for the discovery of alternative influenza virus inhibitors.

Antiviral Research published new progress about 220943-23-7. 220943-23-7 belongs to indole-building-block, auxiliary class Indole,Fluoride,Aldehyde, name is 5-Fluoro-1H-indole-2-carbaldehyde, and the molecular formula is C9H6FNO, Application In Synthesis of 220943-23-7.

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

Abdelbaset, Mahmoud S. published the artcileDiscovery of novel thienoquinoline-2-carboxamide chalcone derivatives as antiproliferative EGFR tyrosine kinase inhibitors, Name: 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, the publication is Bioorganic & Medicinal Chemistry (2019), 27(6), 1076-1086, database is CAplus and MEDLINE.

Novel thienoquinoline carboxamide-chalcone derivatives were prepared via the cyclization of acylated chalcones and 2-mercaptoquinoline-3-carbaldehyde in DMF with K₂CO₃. Thienoquinolines 9a-f, h exhibited promising antiproliferative effect against all the tested cell lines and gave a significant activity as EGFR inhibitors, with IC₅₀ values ranging from 0.5 and 3.2 μM, and compounds 9e and 9f being the most active of the series. They also showed better activity than Erlotinib against melanoma cancer cell line A375. Moreover, compound 9f influenced pre G1 apoptosis and cell cycle arrest at G2/M phase. The binding mode of the best EGFR inhibitor 9e in the EGFR active site revealed that the thienoquinoline ring occupied the ATP-binding site while the chalcone moiety is located in the allosteric site and is responsible for the enhanced activity of these compounds

Bioorganic & Medicinal Chemistry published new progress about 1942114-09-1. 1942114-09-1 belongs to indole-building-block, auxiliary class Indoline,Thiazole,Fluoride,Amine,Benzene,Amide,Alcohol,Protein Tyrosine Kinase/RTK, name is 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide, and the molecular formula is C19H14FN3O3S, Name: 2-(5-Fluoro-2-hydroxyphenyl)-2-(1-oxoisoindolin-2-yl)-N-(thiazol-2-yl)acetamide.

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