Recent advances of the site-specific direct methylation on aromatic rings

Mao, Nian-Dong; Yang, Yong; Zhuo, Xiao‐Tao; Ye, Xiang‐Yang; Xie, Tian

doi:10.1016/j.tet.2021.132402

Cited by 8 publications

(3 citation statements)

References 59 publications

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“…The pyridine heterocycle is the second most common ring in approved drugs, presumably a reflection of its topographical similarities with benzene while offering the advantage of increased polarity. Aromatic chemistry and the manipulation of phenyl and pyridine ring substitution patterns has its origin at the inception of organic chemistry as a scientific discipline and the development and application of synthetic methodologies in this arena remains a vigorous contemporary pursuit . Against this backdrop, the reliance of medicinal chemists on the benzene ring as a component of drugs, drug candidates, and experimental molecules is perhaps not surprising.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

2021

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The benzene moiety is the most prevalent ring system in marketed drugs, underscoring its historic popularity in drug design either as a pharmacophore or as a scaffold that projects pharmacophoric elements. However, introspective analyses of medicinal chemistry practices at the beginning of the 21st century highlighted the indiscriminate deployment of phenyl rings as an important contributor to the poor physicochemical properties of advanced molecules, which limited their prospects of being developed into effective drugs. This Perspective deliberates on the design and applications of bioisosteric replacements for a phenyl ring that have provided practical solutions to a range of developability problems frequently encountered in lead optimization campaigns. While the effect of phenyl ring replacements on compound properties is contextual in nature, bioisosteric substitution can lead to enhanced potency, solubility, and metabolic stability while reducing lipophilicity, plasma protein binding, phospholipidosis potential, and inhibition of cytochrome P450 enzymes and the hERG channel.

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Section: Conclusion and Perspectivementioning

confidence: 99%

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

2021

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“…Although studies on Cmethylation have increased over the past decade, some challenges remain in organic synthesis, such as high catalyst loading, low regiospecific selectivity, and complex reaction conditions. 13 Therefore, effectively introducing a methyl group into aromatic systems has been a research hot spot in organic synthesis and drug discovery for a long time. 14 C-Methyltransferase is a potential approach to address these issues.…”

mentioning

confidence: 99%

QM/MM Study of the Catalytic Mechanism and Substrate Specificity of the Aromatic Substrate C-Methyltransferase Fur6

Zhao,

Moriwaki,

Noguchi

et al. 2024

Biochemistry

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In the field of medical chemistry and other organic chemistry, introducing a methyl group into a designed position has been difficult to achieve. However, owing to the vigorous developments in the field of enzymology, methyltransferases are considered potential tools for addressing this problem. Within the methyltransferase family, Fur6 catalyzes the methylation of C3 of 1,2,4,5,7-pentahydroxynaphthalene (PHN) using Sadenosyl-L-methionine (SAM) as the methyl donor. Here, we report the catalytic mechanism and substrate specificity of Fur6 based on computational studies. Our molecular dynamics (MD) simulation studies reveal the reactive form of PHN and its interactions with the enzyme. Our hybrid quantum mechanics/molecular mechanics (QM/MM) calculations suggest the reaction pathway of the methyl transfer step in which the energy barrier is 8.6 kcal mol −1 . Our free-energy calculations with a polarizable continuum model (PCM) indicate that the final deprotonation step of the methylated intermediate occurs after it is ejected into the water solvent from the active center pocket of Fur6. Additionally, our studies on the protonation states, the highest occupied molecular orbital (HOMOs), and the energy barriers of the methylation reaction for the analogs of PHN demonstrate the mechanism of the specificity to PHN. Our study provides valuable insights into Fur6 chemistry, contributing to a deeper understanding of molecular mechanisms and offering an opportunity to engineer the enzyme to achieve high yields of the desired product(s).

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“…Thus, we observed a unique case of regioselective alkylation (directed ortho methylation and ethylation) requiring no additional coordination with metal centres, ligands, and catalysts. 17 The optimal balance of N -nucleophilicity and mesomeric activation of the aromatic π-system in diamine 15 leads to a smooth course of the whole multistep and atom-economy process without or with minor by-products. Why do salts 14 and 16 behave differently?…”

mentioning

confidence: 99%

Dialkylamino and trialkylammonium groups in close proximity: intra- and intermolecular ways of formation, structural consequences, and properties. A case of metal-free directed ortho alkylation

Kolupaeva

Ozeryanskii

2022

New J. Chem.

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Recent advances of the site-specific direct methylation on aromatic rings

Cited by 8 publications

References 59 publications

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design

QM/MM Study of the Catalytic Mechanism and Substrate Specificity of the Aromatic Substrate C-Methyltransferase Fur6

Dialkylamino and trialkylammonium groups in close proximity: intra- and intermolecular ways of formation, structural consequences, and properties. A case of metal-free directed ortho alkylation

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