Benzoin oximes in sulfuric acid. Cyclization and fragmentation

Hill, John H.; Gilbert, David P.; Feldsott, Arthur H.

doi:10.1021/jo00913a025

Cited by 6 publications

(2 citation statements)

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“…This method was adapted from a previously reported study. 32 Benzoin oxime (254 mg, 1.12 mmol) was dissolved in concentrated sulfuric acid (5 mL), and the reaction mixture was stirred at room temperature until the reaction mixture turned dark red after approximately 2 h. The crude product was precipitated after quenching on ice and then filtered to give a paleyellow powder. Recrystallization from 2-isopropanol gave the desired product as a yellow crystalline solid (213 mg, 1.02 mmol, 91%).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Mannich Base PIP-199 Is a Chemically Unstable Pan-Assay Interference Compound

Sudhakar

Alcock

et al. 2023

J. Med. Chem.

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Mannich base PIP-199 is the only reported smallmolecule inhibitor of the Fanconi anemia complementation group M-RecQ-mediated genome instability protein (FANCM-RMI), a protein−protein interaction that governs genome instability in the genetic disorders Fanconi anemia and Bloom's syndrome. PIP-199 and analogues with the same indole-derived Mannich base scaffold have been used as tool compounds in diverse biological studies. We report the first published synthesis of PIP-199 and its analogues, demonstrating that PIP-199 immediately decomposes in common aqueous buffers and some organic solvents. Neither PIP-199 nor its more hydrolytically stable analogues show any observable activity in binding and competitive biophysical assays for FANCM-RMI. We conclude that PIP-199 is not an effective tool compound for biological studies and that apparent cellular activity likely arises from the nonspecific toxicity of breakdown products. More generally, apparent inhibitors that share this Mannich scaffold potentially represent a new family of pan-assay interference compounds (PAINS) that should be thoroughly assessed for aqueous stability prior to use in biological studies.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Mannich Base PIP-199 Is a Chemically Unstable Pan-Assay Interference Compound

Sudhakar

Alcock

et al. 2023

J. Med. Chem.

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show abstract

“…This method was adapted from previously reported literature. 31 Benzoin oxime (254 mg, 1.12 mmol) was dissolved in concentrated sulfuric acid (5 mL) and the reaction mixture was stirred at room temperature until the reaction mixture turned dark red after approximately 2 h. The crude product was precipitated after quenching on ice and filtered to give a pale-yellow powder. Recrystallization from 2-isopropanol gave the desired product as a yellow crystalline solid (213 mg, 1.02 mmol, 91%).…”

Section: -Phenyl-1h-indol-1-ol (12)mentioning

confidence: 99%

Mannich base PIP-199 is a chemically unstable pan-assay interference compound

Sudhakar

Alcock

et al. 2023

Preprint

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PIP-199 is the only reported small molecule inhibitor of FANCM-RMI, a key protein-protein interaction that governs genome instability in the genetic disorders Fanconi Anemia and Bloom’s Syndrome. PIP-199 and close analogues that share the same indole-derived Mannich base core scaffold have been used as commercially available tool compounds for studying a wide range of therapeutically relevant biological pathways and targets, including the Alternative Lengthening of Telomeres (ALT), G-quadruplexes, pro-apoptotic proteins, and quorum sensing. Herein, we report the first published synthesis of PIP-199 and related analogues, demonstrating that the parent compound immediately decomposes in common aqueous buffers and some organic solvents. We characterize the breakdown products and show that PIP-199 and its more hydrolytically stable analogues show no observable activity in binding and competitive biophysical assays for FANCM-RMI. We conclude that PIP-199 is not an effective tool compound for biological studies, and that apparent activity in cellular studies likely arises from non-specific toxicity of mixed breakdown products. More generally, apparent inhibitors that share this indole-derived Mannich scaffold potentially represent a new family of pan-assay interference compounds (PAINS) that should be thoroughly assessed for aqueous stability prior to use in biological studies.

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