Counterion Control of<i>t</i>‐BuO‐Mediated Single Electron Transfer to Nitrostilbenes to Construct<i>N</i>‐Hydroxyindoles or Oxindoles

Zhao, Yingwei; Zhu, Huajian; Sung, Soonchang; Wink, Donald J.; Zadrozny, Joseph M.; Driver, Tom G.

doi:10.1002/ange.202104319

Cited by 2 publications

(1 citation statement)

References 123 publications

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“…NMR spectra match those previously reported in the literature. 32 General procedure for the Mannich reaction. To 1 equivalent of corresponding aldehyde (1.00 mmol) was added 1 equivalent of acetic acid and 1.1 equivalents of secondary amine.…”

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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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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Denitrative Hydroxylation of Unactivated Nitroarenes**

Duff

Meakin

Richardson

et al. 2023

Chemistry A European J

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A one-step method for the conversion of nitroarenes into phenols under operationally simple, transitionmetal-free conditions is described. This denitrative functionalization protocol provides a concise and economical alterna-tive to conventional three-step synthetic sequences. Experimental and computational studies suggest that nitroarenes may be substituted by an electron-catalysed radical-nucleophilic substitution (S RN 1) chain mechanism.Nitroarenes are easily prepared, abundant chemical feedstocks, and privileged synthetic intermediates in organic chemistry. [1,2] The nitro group can be converted into a large variety of functional groups through a well-established three-step sequence consisting of (1) reduction, (2) diazotization and (3) substitution through Sandmeyer-type reactions (Scheme 1a). [3] Whilst generally reliable, this approach requires multiple synthetic steps, typically involving harsh reaction conditions and the handling of hazardous intermediates. The development of more efficient, single-step denitrative functionalization reactions is therefore an area of significant synthetic value and interest. [4,5] In this regard, direct nucleophilic substitution is an attractive synthetic approach due to its low cost and operational simplicity. [6] However, these methods are typically limited to electron-deficient (activated) nitroarenes bearing strong electron-withdrawing groups in the ortho or para positions. [7] Methods which can overcome this limitation are known, but are rare and of limited scope. For example, Snyder and co-workers reported that unactivated nitroarene 1 could be substituted with oxime anion 2 to form phenol 3 in 20 % yield (Scheme 1b). [8] This denitrative hydroxylation reaction was proposed to proceed via a stepwise addition-elimination nucleophilic aromatic substitution (S N Ar) mechanism (followed by the elimination of an O-aryl oxime intermediate to form phenol 3). However, the mechanism of this reaction -along with many such denitrative substitution reactions -has long [a

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Counterion Control oft‐BuO‐Mediated Single Electron Transfer to Nitrostilbenes to ConstructN‐Hydroxyindoles or Oxindoles

Cited by 2 publications

References 123 publications

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

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

Denitrative Hydroxylation of Unactivated Nitroarenes**

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