Ring-Fused Cyclic Aminals from Tetrahydro-β-carboline-Based Dipeptide Compounds

Bertamino, Alessia; Lauro, Gianluigi; Ostacolo, Carmine; Sarno, Veronica Di; Musella, Simona; Ciaglia, Tania; Campiglia, Pietro; Bifulco, Giuseppe; Gómez-Monterrey, Isabel

doi:10.1021/acs.joc.7b01656

Cited by 7 publications

(4 citation statements)

References 79 publications

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“…Compound 24b was synthesized in 29% yield starting from intermediate 14b and N -Boc- L -Phe-OH following the general procedure B. FC in ethyl acetate/ n -hexane 1/2, R f = 0.65. Spectral data were in accordance with literature …”

Section: Methodssupporting

confidence: 61%

“…1 mmol of l -tryptophan methyl ester or ( S )-2-amino- N -(4-fluorobenzyl)-3-(1 H -indol-3-yl)propanamide ( 8 ) was dissolved in methanol and added with the proper aldehyde (1.5 equiv) and trifluoroacetic acid (1.5 equiv). The mixture was subjected to a microwave assisted closed vessel reaction for 45 min at 110 °C . The mixture was then evaporated in vacuo , and the residue was dissolved in dichloromethane and was washed three times with water.…”

Section: Methodsmentioning

confidence: 99%

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Exploration of TRPM8 Binding Sites by β-Carboline-Based Antagonists and Their In Vitro Characterization and In Vivo Analgesic Activities

et al. 2020

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Transient receptor potential melastatin 8 (TRPM8) ion channel represents a valuable pharmacological option for several therapeutic areas. Here, a series of conformationally restricted derivatives of the previously described TRPM8 antagonist N , N ′-dibenzyl tryptophan 4 were prepared and characterized in vitro by Ca 2+ -imaging and patch-clamp electrophysiology assays. Molecular modeling studies led to identification of a broad and well-defined interaction network of these derivatives inside the TRPM8 binding site, underlying their antagonist activity. The (5 R ,11a S )-5-(4-chlorophenyl)-2-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1 H -imidazo[1′,5′:1,6]pyrido[3,4- b ]indole-1,3(2 H )-dione ( 31a ) emerged as a potent (IC 50 = 4.10 ± 1.2 nM), selective, and metabolically stable TRPM8 antagonist. In vivo, 31a showed significant target coverage in an icilin-induced WDS (at 11.5 mg/kg ip), an oxaliplatin-induced cold allodynia (at 10–30 μg sc), and CCI-induced thermal hyperalgesia (at 11.5 mg/kg ip) mice models. These results confirm the tryptophan moiety as a solid pharmacophore template for the design of highly potent modulators of TRPM8-mediated activities.

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Section: Methodssupporting

confidence: 61%

Section: Methodsmentioning

confidence: 99%

Exploration of TRPM8 Binding Sites by β-Carboline-Based Antagonists and Their In Vitro Characterization and In Vivo Analgesic Activities

et al. 2020

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“…In 2017, Bifulco, Gomez‐Monterrey, and co‐authors designed a series of tetrahydro‐ β ‐carboline‐based amino acids and developed an acid‐ and oxidant‐promoted intramolecular cyclization of these tetrahydro‐ β ‐carboline derivatives affording new tetrahydro‐ β ‐carboline‐containing aminoacetals (Scheme 74). [107] In this approach, several amino acids, such as Gly, Ala, Pro, Phe, and Leu, were attached to the pyridinyl nitrogen atom, which could deliver the corresponding fused tetracyclic compounds in 24–79% yields in the presence of perbenzoic acid, TFA, and triethylsilane. The diastereoselectivity of this cyclization reaction was examined by using 1‐aryl tetrahydro‐ β ‐carboline substrate, and the results showed that almost no diastereoselectivity was observed.…”

Section: Tetrahydro‐β‐carbolines As Substrates For Synthesis Of Other...mentioning

confidence: 99%

Recent Advances on the Synthesis and Application of Tetrahydro‐β‐Carbolines

Du,

Semghouli,

Mei

et al. 2024

Adv Synth Catal

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Abstract. Tetrahydro‐β‐carbolines (THβCs) also known as tryptolines serve as important structural elements in natural products and pharmaceutical compounds, and they are also utilized in drug discovery. They display diverse bioactivities, including anticancer, antifungal, antiparasitic, anti‐ischemic, anti‐inflammatory, and other activities. Besides their pharmacological and biological significance, these structural motifs are also extensively used in the production of other bioactive compounds. This review is intended to summarize recent advancements in the chemistry of this compound class, including the synthesis and the applications as organic synthetic intermediates and bioactive molecules.

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“…The QM/NMR integrated approach, successfully applied by different research groups and us, − is based on the assumption that the possible theoretical stereoisomers show different NMR features (e.g., 1 H/ 13 C chemical shifts and J coupling constants). Once both the experimental and predicted data are collected, their comparison may be quantified using different factors, such as by the mean absolute error (MAE), the corrected MAE, the root-mean-square deviation (RMSD), and the correlation coefficient R and, as reported in recent studies, by more challenging statistical parameters, such as the DP4 parameter by Goodman and the optimized DP4+ by Sarotti …”

Section: Introductionmentioning

confidence: 99%

DFT/NMR Approach for the Configuration Assignment of Groups of Stereoisomers by the Combination and Comparison of Experimental and Predicted Sets of Data

et al. 2020

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Quantum mechanical/nuclear magnetic resonance (NMR) approaches are widely used for the configuration assignment of organic compounds generally comparing one cluster of experimentally determined data (e.g., 13 C NMR chemical shifts) with those predicted for all possible theoretical stereoisomers. More than one set of experimental data, each related to a specific stereoisomer, may occur in some cases, and the accurate stereoassignments can be obtained by combining the experimental and computed data. We introduce here a straightforward methodology based on the simultaneous analysis, combination, and comparison of all sets of experimental/calculated 13 C chemical shifts for aiding the correct configuration assignment of groups of stereoisomers. The comparison of the differences between the calculated/experimental chemical shifts instead of the shifts themselves led to the advantage of avoiding errors arising from calibration procedures, reducing systematic errors, and highlighting the most diagnostic differences between calculated and experimental data. This methodology was applied on a tetrad of synthesized cladosporin stereoisomers (cladologs) and further corroborated on a tetrad of pochonicine stereoisomers, obtaining the correct correspondences between experimental and calculated sets of data. The new MAE ΔΔδ parameter, useful for indicating the best fit between sets of experimental and calculated data, is here introduced for facilitating the stereochemical assignment of groups of stereoisomers.

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Ring-Fused Cyclic Aminals from Tetrahydro-β-carboline-Based Dipeptide Compounds

Cited by 7 publications

References 79 publications

Exploration of TRPM8 Binding Sites by β-Carboline-Based Antagonists and Their In Vitro Characterization and In Vivo Analgesic Activities

Exploration of TRPM8 Binding Sites by β-Carboline-Based Antagonists and Their In Vitro Characterization and In Vivo Analgesic Activities

Recent Advances on the Synthesis and Application of Tetrahydro‐β‐Carbolines

DFT/NMR Approach for the Configuration Assignment of Groups of Stereoisomers by the Combination and Comparison of Experimental and Predicted Sets of Data

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