Month: November 2022

Hamidi, Tewfik published the artcileIdentification of Rpl29 as a major substrate of the lysine methyltransferase Set7/9, Application In Synthesis of 1627607-87-7, the publication is Journal of Biological Chemistry (2018), 293(33), 12770-12780, database is CAplus and MEDLINE.

Set7/9 (also known as Set7, Set9, Setd7, and Kmt7) is a lysine methyltransferase that catalyzes the methylation of multiple substrates, including histone H3 and non-histone proteins. Although not essential for normal development and physiol., Set7/9-mediated methylation events play important roles in regulating cellular pathways involved in various human diseases, making Set7/9 a promising therapeutic target. Multiple Set7/9 inhibitors have been developed, which exhibit varying degrees of potency and selectivity in vitro. However, validation of these compounds in vivo has been hampered by the lack of a reliable cellular biomarker for Set7/9 activity. Here, we report the identification of Rpl29, a ribosomal protein abundantly expressed in all cell types, as a major substrate of Set7/9. We show that Rpl29 lysine 5 (Rpl29K5) is methylated exclusively by Set7/9 and can be demethylated by Lsd1 (also known as Kdm1a). Rpl29 is not a core component of the ribosome translational machinery and plays a regulatory role in translation efficiency. Our results indicate that Rpl29 methylation has no effect on global protein synthesis but affects Rpl29 subcellular localization. Using an Rpl29 methylation-specific antibody, we demonstrate that Rpl29K5 methylation is present ubiquitously and validate that (R)-PFI-2, a Set7/9 inhibitor, efficiently reduces Rpl29K5 methylation in cell lines. Thus, Rpl29 methylation can serve as a specific cellular biomarker for measuring Set7/9 activity.

Journal of Biological Chemistry published new progress about 1627607-87-7. 1627607-87-7 belongs to tetrahydroisoquinoline, auxiliary class Epigenetics,Histone Methyltransferase, name is (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride, and the molecular formula is C23H26ClF4N3O3S, Application In Synthesis of 1627607-87-7.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydroisoquinoline,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Kormos, Chad M. published the artcilePotent and Selective Tetrahydroisoquinoline Kappa Opioid Receptor Antagonists of Lead Compound (3R)-N-[1R)-1-(Cyclohexylmethyl)-2-methylpropyl]-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (CDTic), Synthetic Route of 142335-42-0, the publication is Journal of Medicinal Chemistry (2018), 61(17), 7546-7559, database is CAplus and MEDLINE.

Animal pharmacol. studies suggest that potent and selective κ opioid receptor antagonists have potential as pharmacotherapies targeting depression, anxiety, and substance abuse (opiates, alc., nicotine, cocaine). The authors recently reported lead compound 1 as a new class of κ opioid receptor antagonists with only one basic amine group. Analogs were synthesized and evaluated for their in vitro opioid receptor antagonist properties using a [35S]GTPγS binding assay. All analogs were pure opioid receptor antagonists with no agonist activity. Compounds 1, 8 ((3R)-N-[(1R)-2-Cyclohexyl-1-cyclopropylethyl]-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide), 9 ((3R)-N3-[(1R)-1-(Cyclohexylmethyl)-2-methylpropyl]-1,2,3,4-tetrahydroisoquinoline-3,7-dicarboxamide), 13 ((3R)-N-[(1R)-1-(Cyclopentylmethyl)-2-methylpropyl]-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamide), and 14 (Ke values 0.058-0.64 nM) are highly potent and highly selective for the κ relative to the μ and δ opioid receptors. Favorable calculated physiochem. properties were confirmed in rat PK studies, demonstrating brain penetration for selected compounds 1, 9, and 13. High κ opioid receptor potency and selectivity, and highly favorable calculated physiochem. and PK properties for brain penetration, suggest these compounds should be considered for further development.

Journal of Medicinal Chemistry published new progress about 142335-42-0. 142335-42-0 belongs to tetrahydroisoquinoline, auxiliary class Tetrahydroisoquinoline,Chiral,Carboxylic acid,Amide,Alcohol, name is (S)-2-(tert-Butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, and the molecular formula is C15H19NO5, Synthetic Route of 142335-42-0.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydroisoquinoline,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Barsyte-Lovejoy, Dalia published the artcile(R)-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells, Recommanded Product: (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride, the publication is Proceedings of the National Academy of Sciences of the United States of America (2014), 111(35), 12853-12858, database is CAplus and MEDLINE.

SET domain containing (lysine methyltransferase) 7 (SETD7) is implicated in multiple signaling and disease related pathways with a broad diversity of reported substrates. Here, we report the discovery of (R)-PFI-2-a first-in-class, potent (Kiapp = 0.33 nM), selective, and cell-active inhibitor of the methyltransferase activity of human SETD7-and its 500-fold less active enantiomer, (S)-PFI-2. (R)-PFI-2 exhibits an unusual cofactor-dependent and substrate-competitive inhibitory mechanism by occupying the substrate peptide binding groove of SETD7, including the catalytic lysine-binding channel, and by making direct contact with the donor Me group of the cofactor, S-adenosylmethionine. Chemoproteomics experiments using a biotinylated derivative of (R)-PFI-2 demonstrated dose-dependent competition for binding to endogenous SETD7 in MCF7 cells pretreated with (R)-PFI-2. In murine embryonic fibroblasts, (R)-PFI-2 treatment phenocopied the effects of Setd7 deficiency on Hippo pathway signaling, via modulation of the transcriptional coactivator Yes-associated protein (YAP) and regulation of YAP target genes. In confluent MCF7 cells, (R)-PFI-2 rapidly altered YAP localization, suggesting continuous and dynamic regulation of YAP by the methyltransferase activity of SETD7. These data establish (R)-PFI-2 and related compounds as a valuable tool-kit for the study of the diverse roles of SETD7 in cells and further validate protein methyltransferases as a druggable target class.

Proceedings of the National Academy of Sciences of the United States of America published new progress about 1627607-87-7. 1627607-87-7 belongs to tetrahydroisoquinoline, auxiliary class Epigenetics,Histone Methyltransferase, name is (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride, and the molecular formula is C23H26ClF4N3O3S, Recommanded Product: (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydroisoquinoline,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Tang, Bowen published the artcileInsights into the stereoselectivity of human SETD7 methyltransferase, Recommanded Product: (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride, the publication is RSC Advances (2019), 9(16), 9218-9227, database is CAplus and MEDLINE.

Human SETD7 methyltransferase (hSETD7) is involved in a wide range of physiol. processes, and has been considered as a significant target to develop new drugs. (R)-PFI-2, one hSETD7 inhibitor, could bind to the pocket of substrates with potent (low nanomolar) activity and high selectivity, while its enantiomer (S)-PFI-2 showed 500-fold less activity in IC₅₀ determination Why do this pair of enantiomers, with nearly identical structures, exert tremendously different inhibitory activity. We performed a total of 900 ns long-timescale mol. dynamics (MD) simulations and 80 ps hybrid quantum mechanics/mol. mechanics (QM/MM) MD simulations to understand the mol. mechanism of the stereoselectivity of hSETD7. For each SAM/hSETD7/PFI-2 system, we characterized and compared the residual fluctuation of hSETD7, and generated mol. interaction fingerprints (IFP) to exemplify the propensities of SAM/hSETD7-inhibitor interactions. Based on the QM/MM MD, we accurately captured the difference of hydrogen bonds between the SAM/hSETD7/(R)-PFI-2 and SAM/hSETD7/(S)-PFI-2 systems. Especially the strength of the hydrogen bond between G336 and two inhibitors, which determines the stability of the post-SET loop. The energy barrier for (S)-PFI-2 was much bigger than (R)-PFI-2 from global min. to bioactive conformation as the potential energy surface scanning (PES) showed. Moreover, by estimating the binding affinity and phylogenetic tree anal., we discovered 16 hotspots were essential for binding both enantiomers but the specific mode of interaction between these hotspots and enantiomorphs is different. Our findings reveal the effect of chirality on the inhibition activity of hSETD7 in detail, and provide valuable information for hSETD7 structure-based drug development.

RSC Advances published new progress about 1627607-87-7. 1627607-87-7 belongs to tetrahydroisoquinoline, auxiliary class Epigenetics,Histone Methyltransferase, name is (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride, and the molecular formula is C13H16O2, Recommanded Product: (R)-8-Fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide hydrochloride.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydroisoquinoline,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Ondachi, Pauline W. published the artcilePotent and Selective Tetrahydroisoquinoline Kappa Opioid Receptor Antagonists of Lead Compound (3R)-7-Hydroxy-N-[(1S)-2-methyl-1-(piperidin-1-ylmethyl)propyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (PDTic), COA of Formula: C15H19NO5, the publication is Journal of Medicinal Chemistry (2018), 61(17), 7525-7545, database is CAplus and MEDLINE.

Past studies have shown that it was difficult to discover and develop potent and selective κ opioid receptor antagonists, particularly compounds having potential for clin. development. In this study, we present a structure-activity relation (SAR) study of a recently discovered new class of tetrahydroisoquinoline κ opioid receptor antagonists which led to (3R)-7-hydroxy-N-{(1S)-2-methyl-1-[(-4-methylpiperidine-1-yl)methyl]propyl}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide I (4-Me-PDTic). Compound I had a K_e = 0.37 nM in a [³⁵S]GTPγS binding assay and was 645- and >8100-fold selective for the κ relative to the μ and δ opioid receptors, resp. Calculated log BB and CNS (central nervous system) multiparameter optimization (MPO) and low mol. weight values all predict that 12 will penetrate the brain, and pharmacokinetic studies in rats show that I does indeed penetrate the brain.

Journal of Medicinal Chemistry published new progress about 142335-42-0. 142335-42-0 belongs to tetrahydroisoquinoline, auxiliary class Tetrahydroisoquinoline,Chiral,Carboxylic acid,Amide,Alcohol, name is (S)-2-(tert-Butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, and the molecular formula is C15H19NO5, COA of Formula: C15H19NO5.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydroisoquinoline,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Fukushima, Hiroshi published the artcileSynthesis and structure-activity relationships of potent 1-(2-substituted-aminoacetyl)-4-fluoro-2-cyanopyrrolidine dipeptidyl peptidase IV inhibitors, COA of Formula: C15H19NO5, the publication is Chemical & Pharmaceutical Bulletin (2008), 56(8), 1110-1117, database is CAplus and MEDLINE.

Dipeptidyl peptidase IV (DPP-IV) inhibitors have attracted attention as potential drugs for use in the treatment of type 2 diabetes because they prevent the degradation of glucagon-like peptide-1 (GLP-1) and extend its duration of action. The authors previously reported that 2-cyano-4-fluoropyrrolidines act as potent DPP-IV inhibitors and have been modifying the 1-position of pyrrolidine to obtain more useful inhibitors. An L-tert-butylglycine derivative I was found to be a stable and potent DPP-IV inhibitor that exhibits a glucose lowering effect in vivo. Here, the synthesis of and biol. data on the aforementioned derivatives are reported.

Chemical & Pharmaceutical Bulletin published new progress about 142335-42-0. 142335-42-0 belongs to tetrahydroisoquinoline, auxiliary class Tetrahydroisoquinoline,Chiral,Carboxylic acid,Amide,Alcohol, name is (S)-2-(tert-Butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, and the molecular formula is C15H19NO5, COA of Formula: C15H19NO5.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydroisoquinoline,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Vendeville, Sandrine published the artcileComparison of the inhibition of human and Trypanosoma cruzi prolyl endopeptidases, Safety of (S)-2-(tert-Butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, the publication is Bioorganic & Medicinal Chemistry (2002), 10(6), 1719-1729, database is CAplus and MEDLINE.

Prolyl endopeptidases (PEPs) have been found in numerous species. Inhibitors of human enzyme could correct cognitive deficits in Alzheimer patients while inhibition of Trypanosoma cruzi PEP could prevent invasion phase in Chagas disease. A structure-activity relationship study carried out in a tetrahydroisoquinoline series allowed to obtain potent competitive inhibitors superior to SUAM-1221. Besides, inhibitors expected to act according to an irreversible mechanism revealed to be superior to JPT-4819, for applications linked to human enzyme inhibition.

Bioorganic & Medicinal Chemistry published new progress about 142335-42-0. 142335-42-0 belongs to tetrahydroisoquinoline, auxiliary class Tetrahydroisoquinoline,Chiral,Carboxylic acid,Amide,Alcohol, name is (S)-2-(tert-Butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, and the molecular formula is C13H21BN2O2, Safety of (S)-2-(tert-Butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydroisoquinoline,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Charton, Julie published the artcileOptimized synthesis of tetrahydroisoquinoline-hydantoins, HPLC of Formula: 142335-42-0, the publication is Tetrahedron Letters (2004), 45(38), 7081-7085, database is CAplus.

Several methods have been developed and compared for the solution synthesis of tetrahydroisoquinoline-hydantoin (Tic-hydantoin) derivatives Starting materials were Tic-OH and amines readily available from com. sources. The best yields were observed when the imidazolidine-2,4-dione ring was synthesized in two steps, i.e., reaction of Tic-OH with the appropriate amine and cyclization with 1,1′-carbonyldiimidazole.

Tetrahedron Letters published new progress about 142335-42-0. 142335-42-0 belongs to tetrahydroisoquinoline, auxiliary class Tetrahydroisoquinoline,Chiral,Carboxylic acid,Amide,Alcohol, name is (S)-2-(tert-Butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, and the molecular formula is C15H19NO5, HPLC of Formula: 142335-42-0.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydroisoquinoline,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Zhang, Yingjie published the artcileDesign, synthesis and preliminary activity assay of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as novel Histone deacetylases (HDACs) inhibitors, Recommanded Product: (S)-2-(tert-Butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, the publication is Bioorganic & Medicinal Chemistry (2010), 18(5), 1761-1772, database is CAplus and MEDLINE.

Histone deacetylases (HDACs) are enzymes involved in tumor genesis and development. Herein, we report a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as HDACs inhibitors. The preliminary biol. screening showed that most of our compounds exhibited potent inhibitory activity against HDACs. Within this series, five compounds, 13a (IC₅₀ = 0.58±0.10 μM), 7d (IC₅₀ = 1.00±0.16 μM), 8l (IC₅₀ = 1.06±0.14 μM), 7i (IC₅₀ = 1.17±0.19 μM) and 7a (IC₅₀ = 1.29±0.15 μM) possessed better HDACs inhibitory activity than Vorinostat (IC₅₀ = 1.48±0.20 μM). So these five compounds could be used as novel lead compounds for further design of HDACs inhibitors. The anti-proliferative activities of a few compounds and the structure-activity relationships are also briefly discussed.

Bioorganic & Medicinal Chemistry published new progress about 142335-42-0. 142335-42-0 belongs to tetrahydroisoquinoline, auxiliary class Tetrahydroisoquinoline,Chiral,Carboxylic acid,Amide,Alcohol, name is (S)-2-(tert-Butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, and the molecular formula is C6H17NO3Si, Recommanded Product: (S)-2-(tert-Butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydroisoquinoline,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

Zhang, Yingjie published the artcileDevelopment of Tetrahydroisoquinoline-Based Hydroxamic Acid Derivatives: Potent Histone Deacetylase Inhibitors with Marked in Vitro and in Vivo Antitumor Activities, Application of (S)-2-(tert-Butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, the publication is Journal of Medicinal Chemistry (2011), 54(8), 2823-2838, database is CAplus and MEDLINE.

Inhibition of histone deacetylase (HDAC) results in growth arrest, differentiation, and apoptosis in nearly all tumor cell lines, promoting HDACs as promising targets for antitumor therapy. In our previous study we developed a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as HDAC inhibitors (HDACi), among which compound 7d (I) exhibited promising HDAC8 inhibitory and antiproliferative activities. Herein, we report the design and development of a new class of tetrahydroisoquinoline-bearing hydroxamic acid analogs as potential HDACi and anticancer agents. In vitro biol. evaluation of these compounds showed improved HDAC8 inhibition (compounds 31a and 31b exhibited mid-nM IC₅₀ values against HDAC8) and potent growth inhibition in multiple tumor cell lines. Most importantly, compounds 25e, 34a, and 34b exhibited excellent in vivo anticancer activities in a human breast carcinoma (MDA-MB-231) xenograft model compared with suberoylanilide hydroxamic acid (SAHA), an approved HDACi. Collectively, our results indicate that tetrahydroisoquinoline bearing a hydroxamic acid is an excellent template to develop novel HDACi as potential anticancer agents.

Journal of Medicinal Chemistry published new progress about 142335-42-0. 142335-42-0 belongs to tetrahydroisoquinoline, auxiliary class Tetrahydroisoquinoline,Chiral,Carboxylic acid,Amide,Alcohol, name is (S)-2-(tert-Butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, and the molecular formula is C14H10O4S2, Application of (S)-2-(tert-Butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

Referemce:
https://en.wikipedia.org/wiki/Tetrahydroisoquinoline,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem