42438-90-4

Usage

Chemical Properties

White to off-white powder

Biochem/physiol Actions

TNCA is a tryptophan derivative that binds the parathyroid Ca2+-sensing receptor (CaSR) extracellular domain (ECD) hinge region between two globular subdomains and acts as a high-affinity CaSR ligand (CaSRL) with co-agonist activity. TNCA is shown to potentiate both Mg++- and Ca++-evoked cellular calcium response (0.1-0.5 mM), as well as Mg++-evoked cellular ERK1/2 phosphorylation in CaSR-expressing HEK293 cells (0.5 mM). AC-265347 (Cat. No. SML0129), on the other hand, is a calcimimetic that functions as a CaSR agonist.

InChI:InChI=1/C12H12N2O2/c15-12(16)10-5-8-7-3-1-2-4-9(7)14-11(8)6-13-10/h1-4,10,13-14H,5-6H2,(H,15,16)/t10-/m0/s1

Upstream product

• 79815-18-2 methyl (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate 
• 64-18-6 formic acid 
• 73-22-3 L-Tryptophan 
• 50-00-0 formaldehyd 
• 73-22-3 L-tryptophan 
• 67-56-1 methanol 
• 83159-19-7 methyl (S)-(-)-2,3,4,9-tetrahydro-1H-pyrido<3,4-b>indole-3-carboxylate hydrochloride 
• 6159-33-7 L-tryptophan hydrochloride 

Downstream Products

• 129201-66-7 2-phenyl-1,3-dioxo-6H-1,2,3,5,11,11a-hexahydroimidazo<1,5-b>-β-carboline 
• 131534-06-0 2-phenyl-1,3-dioxo-6H-1,2,3,5,11,11a-hexahydroimidazo<1,5-b>-β-carboline 
• 78538-74-6 FG 7142 
• 79815-18-2 methyl (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate 
• 80994-42-9 ethyl (S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate 
• 102130-85-8 (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid benzyl ester 
• 945650-60-2 (3S)-N-(Boc-L-alanyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid benzyl ester 

Relevant academic research and scientific papers

Design, synthesis and evaluation of a novel π-π Stacking nano-intercalator as an anti-tumor agent

Based on the knowledge that cyclohexane-1,4-dione, piperazine and β-carboline are the essential building blocks of DNA intercalators, β-carboline-3-carboxylic acid is a π-π stack-like DNA intercalator, and β-carboline derivatives can form nanoparticles, this paper hypothesized that (2′S,5′S)-tetrahydropyrazino[1′,2′:1,6]- di{2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole}-1′,4′-dione (THPDTPI) would be a π-π stacking lead nano-intercalator. The docking investigation found that THPDTPI can intercalate into DNA in a π-π stacking manner. The simple condensation of 3S-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid provided THPDTPI in good yield and high purity. The TEM, SEM and AFM imaging visualized that THPDTPI formed nanoparticles in ultrapure water, in the solid state and in rat plasma. The Faraday-Tyndall effect proved that THPDTPI exhibited nano-properties in pH 2.0 and pH 7.0 water. Spectrophotometric assays suggested that the interaction model of THPDTPI and CT DNA was π-π stacking intercalation. In vivo THPDTPI dose-dependently slowed the tumor growth of S180 mice with a minimal effective dose of 0.01 μmol kg-1 per day. In vitro THPDTPI exhibited anti-proliferation activities on S180 and HeLa cells with IC50 values of 0.39 and 3.5 μM, respectively. Even when the single dose was raised up to 10 000 fold of the minimal effective dose, i.e. 100 μmol kg-1, THPDTPI still did not show liver, kidney and systemic toxicity in mice. These findings provide a strategy for designing THPDTPI-like π-π stacking nano-intercalators.

Fluorescence of a rotationally constrained tryptophan derivative, 3-carboxy-1,2,3,4-tetrahydro-2-carboline

Despite a plethora of work on tryptophan photophysics, the origin of the complex fluorescence decay kinetics is still unknown. A question remains whether the two fluorescence lifetimes of the tryptophan zwitterion are due to ground-state and therefore excited-state heterogeneity resulting from rotameric forms. To test the conformer model, we synthesized a tryptophan derivative, 3-carboxy-1,2,3,4-tetrahydro-2-carboline, which restricts rotation of the alanyl side chain. The constraint limits the number of conformations available to the molecule without greatly affecting the electronic properties. The absorption and emission spectra and the pK of the amino group are similar to those of tryptophan. The fluorescence decay of the constrained derivative is an apparent monoexponential. The zwitterion has a lifetime of 6.2 ± 0.2 ns and the anion has a lifetime of 4.7 ± 0.2 ns at 25°C. Global analysis of time-resolved emission spectral data for the zwitterion reveals a double-exponential decay, which may reflect two stable conformations of the partially unsaturated six-membered ring. This is discussed in detail in the following paper.

Synthesis and crystal structure analysis of 9-phenyl-β-carboline

An efficient method is described for the synthesis of 9-phenyl-9H-pyrido[3,4-b]indole and 9-(4-chlorophenyl)-9H-pyrido[3,4-b]indole by employing a catalytic amount of CuI (10 mole%) without any ligand. The single crystal of 9-phenyl-9H-pyrido[3,4-b]indole

Histone demethylating agents as potential S-adenosyl-l-methionine-competitors

Histone H3 methylation on K9 and/or K27 depends on histone lysine methyltransferases (KMTs). EZH2, one of the components of the PRC2 complex, catalyzes the trimethylation of histone H3K27, which is associated with transcriptional repression and tumor development. H3K9me3 mediated gene silencing may result from other KDMs such as G9a/GLP, SUV39H1-2, SETDB1, CCLD8 and RIZ1. Their disturbance leads to defective cell mitosis. It is therefore desirable to find small molecules that are able to decrease H3K9 and K27 tagging to reinitiate gene transcription. Most KDM inhibitors are still based on SAM co-factor competition/modulation. Herein, functional screening of a diversity library proved to be a useful tool for finding new specific KDM inhibitors; the use of SAM-based pharmacophoric models facilitated the understanding of their possible mechanism of action.

Highly diastereoselective synthesis of 1-carbamoyl-4-aminoindoloazepinone derivatives via the Ugi reaction

A one-pot procedure for the highly diastereoselective synthesis of 1-carbamoyl-4-amino-1,2,4,5-tetrahydroindolo[2,3-c]azepin-3-one derivatives is described. Using 2-formyl-L-tryptophan as a bifunctional building block, a catalyst-free Ugi-three-component

Discovery of furyl/thienyl β-carboline derivatives as potent and selective PDE5 inhibitors with excellent vasorelaxant effect

Based on our previous studies and predictive docking results, furans and thiophenes were introduced to the privileged tetrahydro-β-carboline scaffold to generate more potent and selective PDE5 inhibitors. A total of 66 novel furyl/thienyl tetrahydro-β-carboline derivatives were designed, synthesized and evaluated for PDE5 inhibition. Tetrahydro-β-carboline-piperazinedione 19f and tetrahydro-β-carboline-hydantoin 26b with optimized pendant 5-ethylfuran/5-ethylthiophene were identified as the most potent PDE5 inhibitors, and showed high selectivity towards PDE5 versus other PDE isozymes, especially PDE6 and PDE11. Further vasorelaxant activity assessments revealed that these PDE5 inhibitors also exhibited significant angiectasis on the norepinephrine-precontracted 3rd-order mesenteric arteries (110–150 μm) via NO–sGC–cGMP pathway, implying their further application for the treatment of vascular diseases.

Structure-based discovery of (S)-2-amino-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione as low nanomolar, orally bioavailable autotaxin inhibitor

Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, syn

Discovery and preliminary mechanism of 1-carbamoyl β-carbolines as new antifungal candidates

Natural β-carboline alkaloids are ideal models for the discovery of pharmaceutically important entities. Various 1-substituted β-carbolines were synthesized from commercially inexpensive tryptophan and demonstrated significant in vitro antifungal activity against G. graminis. Significantly, compound 4m (EC50 = 0.45 μM) with carboxamide at 1-position displayed the best efficacy and nearly 20 folds enhancement in antifungal potential compared to Silthiopham (EC50 = 8.95 μM). Moreover, compounds 6, 7, and 4i exhibited excellent in vitro antifungal activities and in vivo protective and curative activities against B. cinerea and F. graminearum. Preliminary mechanism studies revealed that compound 4m caused reactive oxygen species accumulation, cell membrane destruction, and deregulation of histone acetylation. These findings indicated that 1-carbamoyl β-carboline can be selected as a promising model for the discovery of novel and broad-spectrum fungicide candidates.

Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile

Side-chain-constrained amino acids are useful tools to modulate the biological properties of peptides. In this study, we applied side-chain constraints to apelin-13 (Ape13) by substituting the Pro12 and Phe13 positions, affecting the binding affinity and signaling profile on the apelin receptor (APJ). The residues 1Nal, Trp, and Aia were found to be beneficial substitutions for Pro12, and the resulting analogues displayed high affinity for APJ (Ki 0.08-0.18 nM vs Ape13 Ki 0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Dbzg; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds 47 (Pro12-Phe13 replaced by Aia-Phe, Ki 0.08 nM) and 53 (Pro12-Phe13 replaced by 1Nal-Dbzg, Ki 0.08 nM) are the most potent Ape13 analogues activating the Gα12 pathways (53, EC50 Gα12 2.8 nM vs Ape13, EC50 43 nM) known to date, displaying high affinity, resistance to ACE2 cleavage as well as improved pharmacokinetics in vitro (t1/2 5.8-7.3 h in rat plasma) and in vivo.

Asymmetric Total Synthesis of Sarpagine and Koumine Alkaloids

We report here a concise, collective, and asymmetric total synthesis of sarpagine alkaloids and biogenetically related koumine alkaloids, which structurally feature a rigid cage scaffold, with L-tryptophan as the starting material. Two key bridged skeleton-forming reactions, namely tandem sequential oxidative cyclopropanol ring-opening cyclization and ketone α-allenylation, ensure concurrent assembly of the caged sarpagine scaffold and installation of requisite derivative handles. With a common caged intermediate as the branch point, by taking advantage of ketone and allene groups therein, total synthesis of five sarpagine alkaloids (affinisine, normacusine B, trinervine, Na-methyl-16-epipericyclivine, and vellosimine) with various substituents and three koumine alkaloids (koumine, koumimine, and N-demethylkoumine) with more complex cage scaffolds has been accomplished.