2506-10-7Relevant academic research and scientific papers
THE N-9, C-1 DIANION OF TETRAHYDRO-β-CARBOLINES. REGIOSELECTIVE ALKYLATION LEADING TO INDOLE ALKALOID SYSTEMS
Meyers, A. I.,Loewe, Mallory F.
, p. 2641 - 2644 (1984)
By treatment of β-carboline formamidine (1) with potassium hydride followed by an alkyl lithium reagent, both the pyrrole proton (N-9) and the proton at C-1 are removed.The resulting dianion (3) alkylates cleanly at C-1 and ultimately at N-9 or N-2.
Formation of tetrahydroharman (1-methyl-1,2,3,4-tetrahydro-beta-carboline) by Helicobacter pylori in the presence of ethanol and tryptamine
Callaway, James C.,Airaksinen, Mauno M.,Salmela, Katja S.,Salaspuro, Mikko
, p. 1817 - 1821 (1996)
Helicobacter pylori contains alcohol dehydrogenase which oxidizes ethanol to acetaldehyde. In the present study, H. pylori cytosol was incubated in a buffered media at pH 6.0 and 7.4 in the presence of ethanol and tryptamine. Under these conditions, tetrahydroharman (1-methyl-tetrahydro-β-carboline) was produced as a condensation product of tryptamine and acetaldehyde. At pH 6.0, 20.60 ± 5.00% of the added tryptamine was converted to tetrahydroharman, while 27.00 ± 4.80% (mean ± SD) was converted at pH 7.4. Similar reactions between acetaldehyde and other dietary amines seem likely. Such biogenic alkaloids, if formed in vivo, might contribute to the dysphoric effects of alcohol.
Excited-state prototropic reactions of tetrahydroharmane
Carmona, Carmen,Balon, Manuel,Munoz, Maria A.,Guardado, Pilar
, p. 2239 - 2244 (1996)
Steady-state and time-resolved fluorescence measurements of THHN (9H-1-methyl-1,2,3,4-tetrahydropyrido[3,4-b]indole), have been carried out as a function of the acidity or basicity of the medium. In these media, four different THHN species have been detected, namely: dication (DC), cation (C), neutral (N) and anion (A). Attempts have been made to determine the excited state pKa* values for the three prototropic processes: N-A, C-N and DC-C reactions. The dicationic and anionic forms, observed outside the 0-14 pH range, are extremely weakly fluorescent species and only the second-order rate constants for the protonation and deprotonation processes, respectively, could be determined. In the case of the C-N process, studied in near-neutral media, excited-state proton exchange is much slower than fluorescence emission and the inflection points in the fluorimetric titration curves correspond quite closely to the ground state pKaG.
Bromal-derived tetrahydro-β-carbolines as neurotoxic agents: Chemistry, impairment of the dopamine metabolism, and inhibitory effects on mitochondrial respiration
Bringmann, Gerhard,Feineis, Doris,Brueckner, Ralph,Blank, Michael,Peters, Karl,Peters, Eva-Maria,Reichmann, Heinz,Janetzky, Bernd,Grote, Christoph,Clement, Hans-Willi,Wesemann, Wolfgang
, p. 1467 - 1478 (2000)
The mammalian alkaloids tryptoline (1) and eleagnine (2) as well as the highly halogenated (X=F, Cl, Br) tetrahydro-β-carbolines (THβCs) 3-5, structurally similar to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 6), were found to have a common feature of inducing a severe impairment of the nigrostriatal dopamine metabolism and inhibiting complex I of the mitochondrial respiratory chain highly selectively. Within the series of compounds tested, 1-tribromomethyl-1,2,3,4-tetrahydro-β-carboline ('TaBro', 5), which was prepared in high yields from the biogenic amine tryptamine ('Ta', 7) and the unnatural aldehyde bromal ('Bro', 8) by a Pictet-Spengler cyclization reaction, turned out to be the most potent toxin in vitro and in vivo. As demonstrated by voltammetric measurements on rats, for all the THβCs 1-5 investigated, intranigral application of a single dose of 10μg resulted in a significant reduction of the dopaminergic activity in the striatum, with the strongest effect being observed for TaBro (5). Using rat brain homogenates, again 5 (IC50=200μM) as well as its dehydrohalogenation product 11 (IC50=150μM) exhibited the most pronounced inhibitory potential on mitochondrial respiration. The halogen-free THβCs 1 and 2 as well as the MPTP metabolite 1-methyl-4-phenylpyridinium ion (MPP+), by contrast, showed only a moderate inhibition at concentrations in the millimolar range (e.g. for MPP+: IC50=3.5mM). For an elucidation of the role of hydrophobic portion in the inhibitory action against complex I activity, several N-acyl derivatives (15-21) of 5 were synthesized and tested. An X-ray diffraction study on the 3-dimensional structure of trifluoroacetylated highly halogenated THβCs (12-14) revealed the tetrahydropyrido part to adopt a nearly planarized half-chair conformation. Because of the steric demand of the trihalogenmethyl moiety (CF333), the N-substituent is dramatically pushed out of that ring 'plane'. Copyright (C) 2000 Elsevier Science Ltd.
Tandem cleavage of hydrogenated β- and γ-carbolines - New practical synthesis of tetrahydroazocino[4,5-b]indoles and tetrahydroazocino[5, 4-b]indoles showing acetylcholinesterase inhibitory activity
Voskressensky, Leonid G.,Borisova, Tatiana N.,Kulikova, Larisa N.,Varlamov, Alexej V.,Catto, Marco,Altomare, Cosimo,Carotti, Angelo
, p. 3128 - 3135 (2004)
Hydrogenated γ-carbolines underwent tandem piperidine ring cleavage on treatment with dimethyl acetylenedicarboxylate (DMAD) or ethyl propiolate (EP) in the presence of alcohols, producing 3-alkoxymethyl-substituted indoles in high yields. These compounds were cyclized to tetrahydroazocino[4,5-b]indoles in the presence of AlCl3. Hydrogenated β-carbolines produced tetrahydroazocino [5,4-b]indoles directly upon treatment with EP in ethanol. The resulting azocinoindole derivatives were subjected to a preliminary evaluation of their in vitro acetylcholinesterase (AChE) inhibitory activities. Most of them were found to inhibit AChE with IC50 values in the micromolar range, compound 17 being the most potent (IC50 = 8.7 μm). Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
TCCA-mediated oxidative rearrangement of tetrahydro-β-carbolines: Facile access to spirooxindoles and the total synthesis of (±)-coerulescine and (±)-horsfiline
Sathish, Manda,Sakla, Akash P.,Nachtigall, Fabiane M.,Santos, Leonardo S.,Shankaraiah, Nagula
, p. 16537 - 16546 (2021/05/19)
Multi-reactive centered reagents are beneficial in chemical synthesis due to their advantage of minimal material utilization and formation of less by-products. Trichloroisocyanuric acid (TCCA), a reagent with three reactive centers, was employed in the synthesis of spirooxindoles through the oxidative rearrangement of various N-protected tetrahydro-β-carbolines. In this protocol, low equivalents of TCCA were required to access spirooxindoles (up to 99% yield) with a wide substrate scope. Furthermore, the applicability and robustness of this protocol were proven for the gram-scale total synthesis of natural alkaloids such as (±)-coerulescine (1) and (±)-horsfiline (2) in excellent yields.
Inverted Binding of Non-natural Substrates in Strictosidine Synthase Leads to a Switch of Stereochemical Outcome in Enzyme-Catalyzed Pictet-Spengler Reactions
Eger, Elisabeth,Simon, Adam,Sharma, Mahima,Yang, Song,Breukelaar, Willem B.,Grogan, Gideon,Houk,Kroutil, Wolfgang
supporting information, p. 792 - 800 (2020/01/31)
The Pictet-Spengler reaction is a valuable route to 1,2,3,4-tetrahydro-β-carboline (THBC) and isoquinoline scaffolds found in many important pharmaceuticals. Strictosidine synthase (STR) catalyzes the Pictet-Spengler condensation of tryptamine and the aldehyde secologanin to give (S)-strictosidine as a key intermediate in indole alkaloid biosynthesis. STRs also accept short-chain aliphatic aldehydes to give enantioenriched alkaloid products with up to 99% ee STRs are thus valuable asymmetric organocatalysts for applications in organic synthesis. The STR catalysis of reactions of small aldehydes gives an unexpected switch in stereopreference, leading to formation of the (R)-products. Here we report a rationale for the formation of the (R)-configured products by the STR enzyme from Ophiorrhiza pumila (OpSTR) using a combination of X-ray crystallography, mutational, and molecular dynamics (MD) studies. We discovered that short-chain aldehydes bind in an inverted fashion compared to secologanin leading to the inverted stereopreference for the observed (R)-product in those cases. The study demonstrates that the same catalyst can have two different productive binding modes for one substrate but give different absolute configuration of the products by binding the aldehyde substrate differently. These results will guide future engineering of STRs and related enzymes for biocatalytic applications.
Application of metal free aromatization to total synthesis of perlolyrin, flazin, eudistomin U and harmane
Santhanam, Srinath,Ramu, Abinaya,Baburaj, Baskar,Kalpatu Kuppusamy, Balasubramanian
, p. 2121 - 2127 (2020/03/04)
Application of our recently reported metal free reaction conditions to the total synthesis of the four different and selective biologically interesting β-carboline natural products is reported. Using this simple methodology, flazin, perlolyrine, eudistomin U and harmane containing heteroaryl and alkyl substituents at C1 position were synthesized in good yields. (Figure presented.).
Design, synthesis and biological evaluation of novel carboline-cinnamic acid hybrids as multifunctional agents for treatment of Alzheimer's disease
Feng, Feng,Jiang, Pan,Li, Qi,Liao, Qinghong,Liu, Wenyuan,Qu, Wei,Sun, Haopeng,Yan, Yuhui,Zhao, Yifan
, (2020/04/22)
Alzheimer's disease (AD) is a complex neurodegenerative disease with multiple pathological features. Multifunctional compounds able to simultaneously interact with several pathological components have been considered as a solution to treat the complex pathologies of neurodegenerative diseases. β-carboline and cinnamic acid have been extensively studied for their widespread biological effects in treatment of AD, further application is limited due to its poor solubility and high toxicity. Herein, a series of carboline-cinnamic acid hybrids was designed and synthesized to obtain new multifunctional molecules with low toxicity and good physicochemical properties. In particular, e3 and e12 exhibited significant inhibition of Aβ aggregation (inhibitory rate at 25 μM: 65% and 72% respectively), moderate BuChE inhibition, excellent neuroprotective effects and low neurotoxicity. Furthermore, in the AD mice model, e3 and e12 could restore learning and memory function to a comparable level to that of the control and did not exhibit any acute toxicity in vivo at a relatively high dose of 600 mg/kg. Thus, these new compounds can be further studied as multifunctional molecules for AD.
Crossing the Border: From Keto- to Imine Reduction in Short-Chain Dehydrogenases/Reductases
Roth, Sebastian,Stockinger, Peter,Steff, Jakob,Steimle, Simon,Sautner, Viktor,Tittmann, Kai,Pleiss, Jürgen,Müller, Michael
, p. 2615 - 2619 (2020/07/06)
The family of NAD(P)H-dependent short-chain dehydrogenases/reductases (SDRs) comprises numerous biocatalysts capable of C=O or C=C reduction. The highly homologous noroxomaritidine reductase (NR) from Narcissus sp. aff. pseudonarcissus and Zt_SDR from Zephyranthes treatiae, however, are SDRs with an extended imine substrate scope. Comparison with a similar SDR from Asparagus officinalis (Ao_SDR) exhibiting keto-reducing activity, yet negligible imine-reducing capability, and mining the Short-Chain Dehydrogenase/Reductase Engineering Database indicated that NR and Zt_SDR possess a unique active-site composition among SDRs. Adapting the active site of Ao_SDR accordingly improved its imine-reducing capability. By applying the same strategy, an unrelated SDR from Methylobacterium sp. 77 (M77_SDR) with distinct keto-reducing activity was engineered into a promiscuous enzyme with imine-reducing activity, thereby confirming that the ability to reduce imines can be rationally introduced into members of the “classical” SDR enzyme family. Thus, members of the SDR family could be a promising starting point for protein approaches to generate new imine-reducing enzymes.
