Design, synthesis and cytotoxic evaluation of a library of oxadiazole-containing hybrids

Camacho, Cristián M.; Pizzio, Marianela G.; Roces, David L.; Boggián, Dora B.; Mata, Ernesto G.; Bellizzi, Yanina; Barrionuevo, Elizabeth; Blank, Viviana C.; Roguin, Leonor P.

doi:10.1039/d1ra05602f

Cited by 7 publications

(5 citation statements)

References 48 publications

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“…We were able to reintroduce the cysteine reactive nitrile moiety via dehydration of the amides 9-11 with trifluoroacetic anhydride (TFAA) in pyridine in the presence of the free hydroxyl groups, to afford the luciferin precursors 12-14 in good yields. [21,22] We envisioned that the reaction of d-cysteine with nitriles 12-14 could be executed in situ prior to the enzymatic assay to afford the glycosyl luciferins. In our hands, the nitrile-bearing substrates appeared to be more stable compared to the corresponding luciferins, making storage and use of these compounds more practical.…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, we proceeded with the acetyl deprotection of 6 – 8 with sodium methoxide in methanol to afford the glycosides 9 – 11 . We were able to reintroduce the cysteine reactive nitrile moiety via dehydration of the amides 9 – 11 with trifluoroacetic anhydride (TFAA) in pyridine in the presence of the free hydroxyl groups, to afford the luciferin precursors 12 – 14 in good yields [21,22] …”

Section: Resultsmentioning

confidence: 99%

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Synthesis and Evaluation of Glycosyl Luciferins

Sondag,

de Kleijne,

Castermans

et al. 2023

Chemistry A European J

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Measuring glycosidase activity is important to monitor any aberrations in carbohydrate hydrolase activity, but also for the screening of potential glycosidase inhibitors. To this end, synthetic substrates are needed which provide an enzyme‐dependent read‐out upon hydrolysis by the glycosidase. Herein, we present two new routes for the synthesis of caged luminescent carbohydrates, which can be used for determining glycosidase activity with a luminescent reporter molecule. The substrates were validated with glycosidase and revealed a clear linear range and enzyme‐dependent signal upon in situ generation of the luciferin moiety from the corresponding nitrile precursors. Besides, we showed that these compounds could directly be synthesized from unprotected glycosyl‐α‐fluorides in a two‐step procedure with yields up to 75%. The intermediate methyl imidate appeared a key intermediate which also reacted with d‐cysteine to give the corresponding d‐luciferin substrate rendering this a highly attractive method for synthesizing glycosyl luciferins in good yields.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis and Evaluation of Glycosyl Luciferins

Sondag,

de Kleijne,

Castermans

et al. 2023

Chemistry A European J

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“…The ( S )-α-aminopropanenitrile was synthesized from N -Boc-L-alanine using methods reported in the literature 16 , 17 . Briefly, N -Boc- l -alanine served as the starting material and reacted with ethyl chloroacetate and aqueous ammonia to produce a primary amide intermediate, which was pure enough for use in the subsequent step without additional purification.…”

Section: Methodsmentioning

confidence: 99%

Discovery from Hypericum elatoides and synthesis of hyperelanitriles as α-aminopropionitrile-containing polycyclic polyprenylated acylphloroglucinols

Xie,

Li,

Yan

et al. 2024

Commun Chem

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The search for lead compounds with anti-neuroinflammatory activity from structurally ‘optimized’ natural products is a crucial and promising strategy in the quest to discover safe and efficacious agents for treating neurodegenerative diseases. A phytochemical investigation on the aerial portions of Hypericum elatoides led to the isolation of five nitrogenous polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperelanitriles A–D (1–4) and hyperelamine A (5). Their structures were determined by spectroscopic analysis, ECD and NMR calculations, and X-ray crystallography. To the best of our knowledge, compounds 1–4 represent the first examples of acylphloroglucinols featuring an α-aminonitrile moiety, while 5 is a rare enamine-containing PPAP. Further, the synthesis of these naturally occurring PPAP-based nitriles or amines was accomplished. Compound 5 exhibited inhibitory activity against LPS-activated NO production in BV-2 cells, potentially through the suppression of TLR-4/NF-κB signaling. Here we show the isolation, structural elucidation, synthesis, and bioactive evaluation of compounds 1–5.

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“…Then, the carboxylic acid group of the produced pyrazine carboxylic acid 9 either reacted with different benzohydrazides in the presence of triphenylphosphine and carbon tetrabromide to afford the 2-phenyl-1,3,4-oxadiazole derivative 10a, b or was coupled with aniline through a HATU-mediated coupling reaction to form the corresponding carboxamide derivative 11a [12,26]. The benzohydrazide derivative 7, which was required for the synthesis of the oxadiazole derivative 10b, was synthesized starting from the corresponding substituted methyl benzoate 5 by N-methylation with methyl iodide in the presence of sodium hydride, followed by reaction with hydrazine hydrate in methanol, affording the corresponding benzohydrazide derivative 7.…”

Section: Docking Studymentioning

confidence: 99%

Design, synthesis, and biological characterization of proteolysis targeting chimera (PROTACs) for the Ataxia telangiectasia and RAD3-related (ATR) kinase

Alfayomy,

Ashry,

Kansy

et al. 2024

Preprint

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The Ataxia telangiectasia and RAD3-related (ATR) kinase is a key regulator of DNA replication stress responses and DNA-damage checkpoints. Several potent and selective ATR inhibitors are reported and four of them are currently in clinical trials in combination with radio- or chemotherapy. Based on the idea of degrading target proteins rather than inhibiting them, we designed, synthesized and biologically characterized a library of ATR-targeted proteolysis targeting chimera (PROTACs). Among the synthesized compounds, the lenalidomide-based PROTAC 42i was the most promising. In pancreatic and cervix cancer cells cancer cells (MIA PaCa-2), it reduced ATR to 40% of the levels in untreated cells. 42i selectively degraded ATR through the proteasome, dependent on the E3 ubiquitin ligase component cereblon, and without affecting the associated kinases ATM and DNA-PKcs. 42i may be a promising candidate for further optimization and biological characterization in various cancer cells.

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Design, synthesis and cytotoxic evaluation of a library of oxadiazole-containing hybrids

Abstract: Synthesized hybrids of 1,2,4-oxadiazole and 1,3,4-oxadiazole connecting a penicillin and aliphatic amino acids displayed a high degree of cytotoxic selectivity.

Cited by 7 publications

References 48 publications

Synthesis and Evaluation of Glycosyl Luciferins

Synthesis and Evaluation of Glycosyl Luciferins

Discovery from Hypericum elatoides and synthesis of hyperelanitriles as α-aminopropionitrile-containing polycyclic polyprenylated acylphloroglucinols

Design, synthesis, and biological characterization of proteolysis targeting chimera (PROTACs) for the Ataxia telangiectasia and RAD3-related (ATR) kinase

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