Synthesis of aza and carbocyclic β-carbolines for the treatment of alcohol abuse. Regiospecific solution to the problem of 3,6-disubstituted β- and aza-β-carboline specificity

Tiruveedhula, V. V. N. Phani Babu; Methuku, Kashi Reddy; Deschamps, Jeffrey R.; Cook, James M.

doi:10.1039/c5ob01572c

Cited by 13 publications

(6 citation statements)

References 49 publications

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“…β-Carboline alkaloids are widely spread in nature and have been isolated from plants, marine tunicates, fungi and actinomycetes. − They are considered to be important molecules in drug discovery and development due to a wide variety of biological and pharmacological activities including antiviral, antibacterial, fungicidal, insecticidal, antimalarial and antileishmanial activities. − Reduction in alcohol self-administration, antiallergic effects, anti-inflammatory and antitumoral activities have also been described for these compounds. − …”

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confidence: 99%

Manipulation of the Precursor Supply in Yeast Significantly Enhances the Accumulation of Prenylated β-Carbolines

et al. 2017

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The tryptophan derivative 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (MTCA) is present in many plants and foods including fermentation products of the baker's yeast Saccharomyces cerevisiae. MTCA is formed from tryptophan and acetaldehyde via a Pictet-Spengler reaction. In this study, up to 9 mg/L of MTCA were detected as a mixture of (1S,3S) and (1R,3S) isomers in a ratio of 2.2:1 in Saccharomyces cerevisiae cultures. To the best of our knowledge, this is the first report on the presence of MTCA in laboratory baker's yeast cultures. Expression of three fungal tryptophan prenyltransferase genes, fgaPT2, 5-dmats, and 7-dmats in S. cerevisiae resulted in the formation of MTCA derivatives with prenyl moieties at different positions of the indole ring. Expression of these genes in dimethylallyl diphosphate and tryptophan overproducing strains led to generation of up to 400 mg/L of prenylated MTCAs as mixtures of (1S,3S) and (1R,3S) diastereomers in ratios similar to that of unprenylated MTCA. The structures of the described substances including their stereochemistry were unequivocally elucidated by mass spectrometry as well as one- and two-dimensional NMR spectroscopy. The results of this study provide a convenient system for the production of high amounts of designed prenylated MTCAs in S. cerevisiae. Furthermore, our work can be considered as an excellent example for the construction of more complex molecules by introducing just one key gene.

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Manipulation of the Precursor Supply in Yeast Significantly Enhances the Accumulation of Prenylated β-Carbolines

et al. 2017

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“…Taking into account the limitations of the method, especially the lack of regioselectivity, the same authors developed a novel disconnection approach in 2015 (Scheme 16B). [64] By switching the chlorine atom to the pyridine ring 66, high yields and high selectivity were obtained, without the presence of side-products. Ultimately, 3-ISOPBC ( 67) was synthetized via an intramolecular CÀ H arylation in a 20 g scale, in 92 % yield after column chromatography.…”

Section: Palladiummentioning

confidence: 99%

“…Ultimately, under inert conditions, a 10 g scale C−H arylation of 63 afforded βCCt ( 64 a ) in 56 % yield, and in a 20 g scale C−H activation step, 3‐PCB ( 64 b ) was obtained in 58 % yield. Taking into account the limitations of the method, especially the lack of regioselectivity, the same authors developed a novel disconnection approach in 2015 (Scheme 16B) [64] . By switching the chlorine atom to the pyridine ring 66 , high yields and high selectivity were obtained, without the presence of side‐products.…”

Section: Preparative Scale Applications Of C−h Activation In Medicina...mentioning

confidence: 99%

Preparative Scale Applications of C−H Activation in Medicinal Chemistry

2023

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C−H activation is an attractive methodology to increase molecular complexity without requiring substrate prefunctionalization. In contrast to well‐established cross‐coupling methods, C−H activation is less explored on large scales and its use in the production of pharmaceuticals faces substantial hurdles. However, the inherent advantages, such as shorter synthetic routes and simpler starting materials, motivate medicinal chemists and process chemists to overcome these challenges, and exploit C−H activation steps for the synthesis of pharmaceutically relevant compounds. In this review, we will cover examples of drugs/drug candidates where C−H activation has been implemented on a preparative synthetic scale (range between 355 mg and 130 kg). The optimization processes will be described, and each example will be examined in terms of its advantages and disadvantages, providing the reader with an in‐depth understanding of the challenges and potential of C−H activation methodologies in the production of pharmaceuticals.

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“…Unter inerten Bedingungen führte schließlich eine C−H‐Arylierung von 63 im 10 g‐Maßstab in 56 % Ausbeute zu βCCt ( 64 a ) und in einem C−H‐Aktivierungsschritt im 20 g‐Maßstab wurde 3‐PCB ( 64 b ) in 58 % Ausbeute erhalten. Die Limitierungen der Methode, insbesondere der mangelnden Regioselektivität, führten 2015 zur Entwickelung eines anderen Ansatzes durch die gleichen Autoren (Schema 16B) [64] . Durch den Wechsel des Chloratoms zum Pyridinring 66 wurden hohe Ausbeuten und eine hohe Selektivität erzielt, ohne dass Nebenprodukte auftraten.…”

Section: C−h‐aktivierung Im Präparativen Maßstab In Der Medizinischen...unclassified

Anwendungen der C−H‐Aktivierung im präparativen Maßstab in der medizinischen Chemie

2023

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Die C−H‐Aktivierung ist eine attraktive Methode zur Steigerung der molekularen Komplexität, ohne Vorfunktionalisierung des Substrats. Im Gegensatz zu den etablierten Kreuzkupplungsmethoden ist die C−H‐Aktivierung in großem Maßstab weniger erforscht und ihre Anwendung bei der Herstellung von Arzneimitteln ist mit erheblichen Hürden verbunden. Die inhärenten Vorteile, wie kürzere Synthesewege und einfachere Ausgangsmaterialien, motivieren Medizinal‐ und Prozesschemiker jedoch dazu, diese Herausforderungen zu überwinden und C−H‐Aktivierungsschritte für die Synthese pharmazeutisch relevanter Verbindungen zu nutzen. In diesem Aufsatz werden wir Beispiele von Arzneimitteln/Wirkstoffkandidaten behandeln, bei denen die C−H‐Aktivierung in einem präparativen Synthesemaßstab (zwischen 355 mg und 130 kg) durchgeführt wurden. Die Optimierungsprozesse werden beschrieben und jedes Beispiel wird im Hinblick auf seine Vor‐ und Nachteile untersucht, um dem Leser ein umfassendes Verständnis der Herausforderungen und des Potenzials von C−H‐Aktivierungsmethoden für die Herstellung von Arzneimitteln zu vermitteln.

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Synthesis of aza and carbocyclic β-carbolines for the treatment of alcohol abuse. Regiospecific solution to the problem of 3,6-disubstituted β- and aza-β-carboline specificity

Cited by 13 publications

References 49 publications

Manipulation of the Precursor Supply in Yeast Significantly Enhances the Accumulation of Prenylated β-Carbolines

Manipulation of the Precursor Supply in Yeast Significantly Enhances the Accumulation of Prenylated β-Carbolines

Preparative Scale Applications of C−H Activation in Medicinal Chemistry

Anwendungen der C−H‐Aktivierung im präparativen Maßstab in der medizinischen Chemie

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