Browse
Submit Data
Databases
API
Help

Dataset Information

25 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Biocatalytic asymmetric formation of tetrahydro-?-carbolines.

ABSTRACT: Strictosidine synthase triggers the formation of strictosidine from tryptamine and secologanin, thereby generating a carbon-carbon bond and a new stereogenic center. Strictosidine contains a tetrahydro-?-carboline moiety - an important N-heterocyclic framework found in a range of natural products and synthetic pharmaceuticals. Stereoselective methods to produce tetrahydro-?-carboline enantiomers are greatly valued. We report that strictosidine synthase from Ophiorrhiza pumila utilizes a range of simple achiral aldehydes and substituted tryptamines to form highly enantioenriched (ee >98%) tetrahydro-?-carbolines via a Pictet-Spengler reaction. This is the first example of aldehyde substrate promiscuity in the strictosidine synthase family of enzymes and represents a first step towards developing a general biocatalytic strategy to access chiral tetrahydro-?-carbolines.

SUBMITTER: Bernhardt P

PROVIDER: S-EPMC2913883 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Biocatalytic asymmetric formation of tetrahydro-β-carbolines.

Bernhardt Peter P Usera Aimee R AR O'Connor Sarah E SE

Tetrahedron letters 20100801 33

Strictosidine synthase triggers the formation of strictosidine from tryptamine and secologanin, thereby generating a carbon-carbon bond and a new stereogenic center. Strictosidine contains a tetrahydro-β-carboline moiety - an important N-heterocyclic framework found in a range of natural products and synthetic pharmaceuticals. Stereoselective methods to produce tetrahydro-β-carboline enantiomers are greatly valued. We report that strictosidine synthase from Ophiorrhiza pumila utilizes a range of ...[more]

PMID: 20689670

Similar Datasets

Stereodivergent assembly of tetrahydro-γ-carbolines via synergistic catalytic asymmetric cascade reaction.

Project description:Enantiomerically enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry. As one of the most attractive subtypes of indole alkaloids, highly substituted tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. However, the syntheses of tetrahydro-γ-carbolines with high functionalities from readily available reagents are significant challenging. In particular, the stereodivergent syntheses of tetrahydro-γ-carbolines containing multi-stereogenic centers remain quite difficult. Herein, we report an expedient and stereodivergent assembly of tetrahydro-γ-carbolines with remarkably high levels of stereoselective control in an efficient cascade process from aldimine esters and indolyl allylic carbonates via a synergistic Cu/Ir catalyst system. Control experiments-guided optimization of synergistic catalysts and mechanistic investigations reveal that a stereodivergent allylation reaction and a subsequent highly stereoselective iso-Pictet-Spengler cyclization are the key elements to success.

| S-EPMC6895234 | biostudies-literature

Asymmetric Biocatalytic Synthesis of 1-Aryltetrahydro-?-carbolines Enabled by "Substrate Walking".

Project description:Stereoselective catalysts for the Pictet-Spengler reaction of tryptamines and aldehydes may allow a simple and fast approach to chiral 1-substituted tetrahydro-?-carbolines. Although biocatalysts have previously been employed for the Pictet-Spengler reaction, not a single one accepts benzaldehyde and its substituted derivatives. To address this challenge, a combination of substrate walking and transfer of beneficial mutations between different wild-type backbones was used to develop a strictosidine synthase from Rauvolfia serpentina (RsSTR) into a suitable enzyme for the asymmetric Pictet-Spengler condensation of tryptamine and benzaldehyde derivatives. The double variant RsSTR V176L/V208A accepted various ortho-, meta- and para-substituted benzaldehydes and produced the corresponding chiral 1-aryl-tetrahydro-?-carbolines with up to 99?% enantiomeric excess.

| S-EPMC7756766 | biostudies-literature

Synthesis, Molecular Docking and Antiplasmodial Activities of New Tetrahydro-β-Carbolines.

Project description:Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-β-carbolines were designed, synthesized by the Pictet-Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N-(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide (7) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1S,3R)-7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.

| S-EPMC8707145 | biostudies-literature

Asymmetric Synthesis of (R)-1-Alkyl-Substituted Tetrahydro-ß-carbolines Catalyzed by Strictosidine Synthases.

Project description:Stereoselective methods for the synthesis of tetrahydro-ß-carbolines are of significant interest due to the broad spectrum of biological activity of the target molecules. In the plant kingdom, strictosidine synthases catalyze the C-C coupling through a Pictet-Spengler reaction of tryptamine and secologanin to exclusively form the (S)-configured tetrahydro-ß-carboline (S)-strictosidine. Investigating the biocatalytic Pictet-Spengler reaction of tryptamine with small-molecular-weight aliphatic aldehydes revealed that the strictosidine synthases give unexpectedly access to the (R)-configured product. Developing an efficient expression method for the enzyme allowed the preparative transformation of various aldehydes, giving the products with up to >98?% ee. With this tool in hand, a chemoenzymatic two-step synthesis of (R)-harmicine was achieved, giving (R)-harmicine in 67?% overall yield in optically pure form.

| S-EPMC6146909 | biostudies-other

Synthesis of tetrahydro-β-carbolines from 2-indolylmethyl azides and propargylic alcohols.

Project description:A facile and efficient route to tetrahydro-β-carbolines from 2-indolylmethyl azides and propargylic alcohols via acid-catalyzed dehydrative annulation reactions is described. This reaction proceeds through a cascade sequence of Friedel-Crafts-type alkylation followed by intramolecular "Click" reaction, involving the formation of multiple chemical bonds in a single operation with excellent atom-economy and broad functional group tolerance.

| S-EPMC9033608 | biostudies-literature

Mechanistic studies on the cis to trans epimerization of trisubstituted 1,2,3,4-tetrahydro-beta-carbolines.

Project description:It is well-known that N(b)-benzyltryptophan alkyl esters undergo the Pictet-Spengler reaction with aldehydes to furnish both cis- and trans-1,2,3,4-tetrahydro-beta-carbolines, with the trans isomer predominating. Epimerization at C-1 took place under acidic conditions to produce, exclusively, the thermodynamically more stable trans diastereomer via internal asymmetric induction. Recent kinetic experiments provided insight into the cis to trans epimerization mechanism involved in the Pictet-Spengler reaction of 1,2,3-trisubstituted tetrahydro-beta-carbolines. Since the epimerization reaction had been shown to be sensitive to electronic effects at C-1, the rate data for a series of 1-phenyl-substituted 1,2,3,4-tetrahydro-beta-carbolines was investigated via a Hammett study. Analysis of the data supported the presence of a positively charged intermediate with a rho value of -1.4, although the existence of an iminium ion intermediate or a carbocationic intermediate could not be determined from this data alone. Analysis of the rate of epimerization demonstrated first-order kinetics with respect to TFA following the initial protonation of the substrate. This observation was consistent with the formation of a doubly protonated intermediate as the rate-determining step in the carbocation-mediated cis to trans epimerization process. In addition, the observed first-order rate dependence was inconsistent with the retro-Pictet-Spengler mechanism since protonation at the indole-2 position was not rate determining as demonstrated by kinetic isotope effects. Based on this kinetic data, the retro-Pictet-Spengler pathway was ruled out for the cis to trans epimerization of 1,2,3-trisubstituted 1,2,3,4-tetrahydro-beta-carbolines, while the olefinic mechanism had been ruled out by experiments carried out in TFA-d.

| S-EPMC2911483 | biostudies-literature

Design, Synthesis, Antiproliferative Evaluation, and Molecular Docking Studies of <i>N</i>-(3-Hydroxyindole)-Appended β-Carbolines/Tetrahydro-β-Carbolines Targeting Triple-Negative and Non-Triple-Negative Breast Cancer.

Project description:The present manuscript pertains to the design and synthesis of a series of 3-hydroxyindole-substituted β-carbolines/tetrahydro-β-carbolines with an aim to explore their antiproliferative structure-activity relationship against breast cancer. The conjugate with an optimum combination of a flexible tetrahydro-β-carboline core, a tertiary alcoholic group along with a chloro substituent on the indole ring, proved to be the most active compound. It displayed IC50 values of 13.61 and 22.76 μM against MCF-7 (ER+) and MDA-MB-231 (ER-) cells, respectively. The docking studies were found to be consistent with experimental results owing to the stronger binding affinity of the synthesized conjugates via hydrophobic and H-bonding interactions.

| S-EPMC7675558 | biostudies-literature

Tricyclic Imidazolidin-4-ones by Witkop Oxidation of Tetrahydro-?-carbolines.

Project description:1-Substituted and 1,1-disubstituted tetrahydro-?-carbolines undergo sodium periodate oxidative ring expansion in the presence of formaldehyde and other aldehydes to form 5,6-dihydro-7H-1,4-methanobenzo[e][1,4]diazonine-2,7(3H)-diones in 30-81% yield. In most cases, the reaction to form this new 6/8/5-tricyclic ring system proceeds with high diastereoselectivity. These benzannulated medium-ring keto imidazolidin-4-ones expand the menu of tetrahydro-?-carboline oxidation products.

| S-EPMC7092372 | biostudies-literature

A facile and efficient method for the synthesis of crystalline tetrahydro-β-carbolines via the Pictet-Spengler reaction in water.

Project description:A facile and efficient synthesis of tetrahydro-β-carbolines (tryptolines) in one step from tryptamine and aldehydes, in an environmentally friendly water solvent, has been investigated. This convenient and clean synthesis of various tryptolines was facilitated by L-tartaric acid, a natural compound, to obtain the desired products as clear crystals. Among the four crystalline products, the most substituted tryptoline 2 showed the best inhibitory activity against EJ cells and the least cytotoxicity, with an LC50 value of 1.49 mg/mL, against brine shrimp larvae.

| S-EPMC6978303 | biostudies-literature

TCCA-mediated oxidative rearrangement of tetrahydro-β-carbolines: facile access to spirooxindoles and the total synthesis of (±)-coerulescine and (±)-horsfiline.

Project description: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.

| S-EPMC9031260 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data