Methyl Effect on the Metabolism, Chemical Stability, and Permeability Profile of Bioactive <i>N</i>-Sulfonylhydrazones

Guedes, Jéssica de Siqueira; Carneiro, Teiliane Rodrigues; Pinheiro, Pedro de Sena Murteira; Fraga, Carlos A.M.; Sant’Anna, Carlos Maurício R.; Barreiro, Eliezer J.; Lima, Lı́dia Moreira

doi:10.1021/acsomega.2c04368

Cited by 3 publications

(1 citation statement)

References 48 publications

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“…In the case of compound 2 , methylation of PHGs in NDGA resulted in a promising product that is currently being studied in clinical trials. However, the phenol ether could be metabolized to the free phenol by cytochrome P450 (CYP) as shown previously although no such study has been conducted for 2 . Future PK studies are necessary to test this possibility.…”

Section: Medicinal Chemistry Of Small Molecule Survivin Inhibitorsmentioning

confidence: 99%

Small Molecule Inhibitors Targeting the “Undruggable” Survivin: The Past, Present, and Future from a Medicinal Chemist’s Perspective

Cui,

Huang,

Liu

et al. 2023

J. Med. Chem.

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Section: Medicinal Chemistry Of Small Molecule Survivin Inhibitorsmentioning

confidence: 99%

Small Molecule Inhibitors Targeting the “Undruggable” Survivin: The Past, Present, and Future from a Medicinal Chemist’s Perspective

Cui,

Huang,

Liu

et al. 2023

J. Med. Chem.

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Design, Synthesis and Evaluation of Photophysical and Biological Properties of Tetrafluoroacridine

Kumar,

Yadav,

Indari

et al. 2024

ChemistrySelect

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Abstract1,4,5,8‐Tetrafluoroacridine was successfully synthesized from 1,4,5,8‐tetrafluoroacridone through transfer hydrogenation using an in‐house ruthenium pincer catalyst followed by in situ dehydration. The synthetic protocol involves the copper‐catalyzed coupling of 2‐amino‐3,6‐difluorobenzoic acid 1 and 1,4‐difluoro‐2‐iodobenzene 2 to obtain 3 followed by cyclization using polyphosphoric acid to get the 1,4,5,8‐tetrafluoroacridone 4. Common synthetic strategies for converting 4 to the 1,4,5,8‐tetrafluoroacridine 5 were unsuccessful and the transfer hydrogenation approach proved to be most fruitful. 1,4,5,8‐Tetrafluoroacridone 4 can be N‐methylated to give 9. The investigation into the photophysical properties of 4, 5, and 9 revealed that the average photoluminescence (PL) lifetime of the acridine derivatives was longer in the aqueous medium than in ethanol and methanol, indicating the influence of the solvent environment on the excited‐state dynamics. To assess their potential therapeutic applications, the cytotoxic activity of these compounds was evaluated against AGS and IMR‐32 cells, and compound 9 showed significant activity. The addition of methyl group to the acridone was found helpful in enhancing the solubility and biological activity.

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Catalytic undirected methylation of unactivated C(sp3)−H bonds suitable for complex molecules

Tan,

Kang,

Hartwig

2024

Nat Commun

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In pharmaceutical discovery, the “magic methyl” effect describes a substantial improvement in the pharmacological properties of a drug candidate with the incorporation of methyl groups. Therefore, to expedite the synthesis of methylated drug analogs, late-stage, undirected methylations of C(sp3)−H bonds in complex molecules would be valuable. However, current methods for site-selective methylations are limited to activated C(sp3)−H bonds. Here we describe a site-selective, undirected methylation of unactivated C(sp3)−H bonds, enabled by photochemically activated peroxides and a nickel(II) complex whose turnover is enhanced by an ancillary ligand. The methodology displays compatibility with a wide range of functional groups and a high selectivity for tertiary C−H bonds, making it suitable for the late-stage methylation of complex organic compounds that contain multiple alkyl C−H bonds, such as terpene natural products, peptides, and active pharmaceutical ingredients. Overall, this method provides a synthetic tool to explore the “magic methyl” effect in drug discovery.

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Methyl Effect on the Metabolism, Chemical Stability, and Permeability Profile of Bioactive N-Sulfonylhydrazones

Cited by 3 publications

References 48 publications

Small Molecule Inhibitors Targeting the “Undruggable” Survivin: The Past, Present, and Future from a Medicinal Chemist’s Perspective

Small Molecule Inhibitors Targeting the “Undruggable” Survivin: The Past, Present, and Future from a Medicinal Chemist’s Perspective

Design, Synthesis and Evaluation of Photophysical and Biological Properties of Tetrafluoroacridine

Catalytic undirected methylation of unactivated C(sp3)−H bonds suitable for complex molecules

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