Magic Methyl Research Articles

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

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.

Radical Cascade Cyclization of N-(o-Cyanobiaryl)acrylamides with Sulfonium Salts via Synergetic Photoredox and Copper Catalysis.

As the magic methyl effect is well acknowledged in pharmaceutical molecules, the development of simple and efficient methods for the installment of methyl groups on complex molecules is highly coveted. Hence, we provide a general strategy for radical cascade cyclization of N-(o-cyanobiaryl)acrylamides by utilizing sulfonium salts as the sources of methyl radical and merging photoredox and copper catalysis. This novel protocol can access a wide variety of methylation or remote thioether-substituted benzo-fused N-heterocycle derivatives, which can be easily transformed into diverse highly valuable sulfone and sulfoximine compounds via late-stage diversification. Moreover, to further demonstrate the synthetic utility of this conversion, the methyl(phenyl)sulfide, which serves as both raw material and byproduct, can be recovered and reused in this transformation. The scale-up experiment for the one-pot two-step process directly offers the target product in good yield under the standard conditions.

Molecular Motors' Magic Methyl and Its Pivotal Influence on Rotation.

Molecular motors have found a wide range of applications, powering a transition from molecules to dynamic molecular systems for which their motion must be precisely tuned. To achieve this adjustment, strategies involving laborious changes in their design are often used. Herein, we show that control over a single methyl group allows a drastic change in rotational properties. In this regard, we present the straightforward asymmetric synthesis of β-methylated first-generation overcrowded-alkene-based molecular motors. Both enantiomers of the new motors were prepared in good yields and high enantiopurities, and these motors were thoroughly studied by variable-temperature nuclear magnetic resonance (VT-NMR), ultraviolet-visible (UV-vis), and circular dichroism (CD) spectroscopy, showing a crucial influence of the methylation pattern on the rotational behavior of the motors. Starting from a common chiral precursor, we demonstrate that subsequent methylation can drastically reduce the speed of the motor and reverse the direction of the rotation. We show for the first time that complete unidirectionality can be achieved even when the energy difference between the stable and metastable states is small, resulting in the coexistence of both states under ambient conditions without hampering the energy ratcheting process. This discovery opens the way for the design of more advanced first-generation motors.

‘Magic methyl effect’ in 2-benzylpyridine-based H2 storage materials: Enhanced H2 storage/release performances

The molecular structures of organic hydrogen storage materials profoundly impact their physical and thermodynamic properties. However, the influence of molecular modifications, especially via methyl groups, on the hydrogen storage and release reactions remains unclear. Herein, the effects of introducing methyl groups onto the two rings in the 2-benzylpyridine structure were evaluated. Specifically, four materials with different methyl substitution positions were synthesized, their hydrogen storage and release reactivities were compared, and their reaction intermediates were analyzed. The presence of a methyl group on the heterocycle notably increased the rates of hydrogen storage and release by 206% and 49.4%, respectively, and its rate-accelerating impact was highly effective in the Pt-catalyzed reaction by 40.5% compared to the Pd-catalyzed reaction. However, the presence of a methyl group on the homocycle decelerated both reactions and hindered intermediate formation. Adsorption experiments revealed that the methyl group on the heterocycle regulates the adsorption strength, promoting the desorption of the heterocycle after its reactions from the catalyst surface. These discoveries emphasize the pivotal role of methyl groups that not only can improve the material properties but also can enhance the reaction performances. We anticipate this work to be a cornerstone for the development and optimization of diverse high-performance organic hydrogen storage materials based on this ‘magic methyl effect.’

Demystifying the recent photochemical and electrochemical strategies in installing the magic methyl group: a comprehensive overview

The strategic installation of the “magic methyl” group has become highly desirable for drug discovery. This review summarized the recent photochemical and electrochemical strategies in installing the methyl group.

The Magic Methyl and Its Tricks in Drug Discovery and Development.

One of the key scientific aspects of small-molecule drug discovery and development is the analysis of the relationship between its chemical structure and biological activity. Understanding the effects that lead to significant changes in biological activity is of paramount importance for the rational design and optimization of bioactive molecules. The "methylation effect", or the "magic methyl" effect, is a factor that stands out due to the number of examples that demonstrate profound changes in either pharmacodynamic or pharmacokinetic properties. In many cases, this has been carried out rationally, but in others it has been the product of serendipitous observations. This paper summarizes recent examples that provide an overview of the current state of the art and contribute to a better understanding of the methylation effect in bioactive small-molecule drug candidates.

Easily accessible and tunable porous organic polymer anode from azo coupling for sustainable lithium-organic batteries

Porous organic polymers (POPs) are promising sustainable electrodes for energy storage applications. Although a handful of POPs with facile synthesis and structural tunability have been developed, they are limited to specific classes of precursors and transition metal-based catalysts. In this work, three tunable porous organic polymers were successfully synthesized and characterized using the simple azo coupling reaction of readily available precursors, phloroglucinol, and diarylamines. The α-hydrazoketone was unambiguously assigned based on X-ray photoelectron spectroscopy (XPS). The POPs with a redox-active functional group deliver impressive reversible capacity. The effects of POP precursors, surface area, and pore size on the electrochemical properties and battery performances were systematically investigated. According to the results, a high content of α-hydrazoketone and a large surface area are critical factors in designing efficient organic electrodes for high-performance energy storage. Interestingly, POP-1 derived from o-tolidine precursor exhibited a high specific capacity with greater rate capability as well as superior cycling stability over 1,000 cycles due to the importance of the magic methyl effect, optimal surface area (294 m2 g−1), and porosity. Furthermore, ex-situ FT-IR, Raman, and XPS studies also implicate the reversible redox reaction of α-hydrazoketone. Cyclic voltammetry and electrochemical impedance spectroscopy revealed kinetic behavior influencing the lithium-ion storage mechanism. This research provides empirical evidence that this tunable family of porous organic polymers is the first to exhibit promising organic electrode characteristics for the next generation of sustainable lithium-organic batteries.

Installation of the Magic Methyl Group onto Heterocycles by Dual Decatungstate Photo-/Nickel Catalysis

Key words late-stage functionalization - C(sp3)–H methylation - magic methyl - nickel catalysis - photocatalysis - tungsten catalysis

Discovery of 5‐alkyl‐2‐pyrazol‐oxazolidin‐4‐one derivatives as novel hepatitis B virus capsid assembly modulators

The "magic methyl effect" strategy was used to design a series of 5-alkyl-2-pyrazol-oxazolidin-4-one derivatives as novel hepatitis B virus (HBV) capsid assembly modulators. Most of these compounds exhibited potent HBV inhibitory activities with low cytotoxicities in HepG2.2.15 cells. The most promising compounds 9d and 10b had single-digit nanomolar IC50 values with a high selectivity index. Compared with the lead compound (3.0%), they caused 15% and 18% decreases in HBe antigen secretion at 1.0 μM, respectively. In addition, compounds 9d and 10b possessed good pharmacokinetic profiles with oral bioavailability values of 56.1% and 48.9%, respectively. These results indicated that the two compounds were potential therapeutic agents for HBV infection.

"Magic Chloro": Profound Effects of the Chlorine Atom in Drug Discovery.

Chlorine is one of the most common atoms present in small-molecule drugs beyond carbon, hydrogen, nitrogen, and oxygen. There are currently more than 250 FDA-approved chlorine-containing drugs, yet the beneficial effect of the chloro substituent has not yet been reviewed. The seemingly simple substitution of a hydrogen atom (R = H) with a chlorine atom (R = Cl) can result in remarkable improvements in potency of up to 100,000-fold and can lead to profound effects on pharmacokinetic parameters including clearance, half-life, and drug exposure in vivo. Following the literature terminology of the "magic methyl effect" in drugs, the term "magic chloro effect" has been coined herein. Although reports of 500-fold or 1000-fold potency improvements are often serendipitous discoveries that can be considered "magical" rather than planned, hypotheses made to explain the magic chloro effect can lead to lessons that accelerate the cycle of drug discovery.

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH3, CH2D, CD2H, CD3and13CH3Groups onto (Hetero)Arenes

Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH₃, CH₂D, CD₂H, CD₃and¹³CH₃Groups onto (Hetero)Arenes

Introducing the Magic Methyl: Enantioselective Hydro­methylation of Olefins under Copper Hydride Catalysis

Introducing the Magic Methyl: Enantioselective Hydro­methylation of Olefins under Copper Hydride Catalysis

Two-enzyme cascade catalyzed trideuteromethylative modification of natural products

Site-selective incorporation of the trideuterated “magic methyl” group may provide profound pharmacological benefits, which has been considered as an important tool for drug optimization and development in medicinal chemistry. S-adenosyl-L-methionine (SAM) usually acts as the methyl donor under the catalysis of SAM-dependent methyltransferases (MTs), which transfer a methyl group from SAM to substrates, and are widely reported for methylation in natural product biosynthesis. However, it is difficult to introduce other high-value functional groups to substrates in this way since SAM analogs are not easy to obtain in biological methods. Herein we report that trideuterated SAM can be obtained from S-adenosylhomocysterine (SAH) and trideuterated methyl iodide (CD3I) under the participation of halide methyltransferase (HMT). Subsequent one-pot cascades with different MTs achieved the regioselective trideuteromethylation of three natural products, which indicated that trideuterated SAM can be accepted as a co-substrate by C-, N-, O-specific MTs for enzyme-catalyzed trideuteromethylation of natural products.

Improved flotation separation of sulfide minerals by synthesized surfactant based on para-position methyl effect

Flotation, as one of the greatest technologies in the 21st century, enables humans to utilize the mineral resources on a large scale. The key to a successful flotation separation is the surfactants with unique selectivity towards different minerals. A flotation surfactant has both chelating side and hydrophobic side. In the past decades, the selectivity of the flotation surfactants has been always attributed to the chelating side. Inspired by an interesting ‘magic methyl effect’ in the field of pharmaceutical chemistry that introducing a methyl group on the hydrophobic side can significantly improve the medicine’s selectivity. In this work, based on an archetype collector sodium benzenesulfinate (SBS) which bears inconspicuous selectivity towards galena and pyrite, a methyl group was introduced to synthesize a novel collector sodium p-toluenesulfinate (SPTS). The flotation tests confirmed that SPTS has much better selectivity than SBS and ethyl xanthate (EX), a commonly used collector for galena flotation against pyrite, which was supported by the results of FTIR, XPS, adsorption capacity and contact angle measurements. DFT calculations revealed that the selectivity of SPTS stems from its desolvation effect and the difference in hydration layers of galena and pyrite. The SPTS can destroy the S···H hydrogen-bonded water molecules via desolvation effect and adsorb on galena surface to make it hydrophobic, but cannot repel the FeO chemically bonded water molecules on pyrite surface. However, the SBS or EX can realize co-adsorption with the water molecules on both minerals with no selectivity. This study provided a new strategy for designing the selective surfactants for successful sulfide minerals flotation.

The quest for magic: recent advances in C(sp3)–H methylation

Abstract Frequently referred to as the “magic methyl” effect, the introduction of a methyl group into a biologically active molecule has the potential to drastically alter its physical and biological properties and significantly increase potency. This effect is most pronounced when the methyl group is added at the α-position of an aliphatic heterocycle or ortho to a large rotatable group on an aromatic ring. Although seminal developments in C–H activation strategies offered solutions to the latter, until recent years there had been no selective and functional-group-tolerant method for C(sp3)–H methylation at late stages of synthesis. For many years, the lack of a generally applicable methylation strategy necessitated arduous de novo synthesis approaches to access methylated drug candidates, and discouraged further investigation and understandings of the magic methyl effect. This review will provide a summary of the most recent advances that enabled non-directed late-stage C(sp3)–H methylation, including through hydride transfer, chemical or anodic oxidation, and photocatalytic hydrogen atom transfer.

Modifications of the Triaminoaryl Metabophore of Flupirtine and Retigabine Aimed at Avoiding Quinone Diimine Formation.

The potassium channel opening drugs flupirtine and retigabine have been withdrawn from the market due to occasional drug-induced liver injury (DILI) and tissue discoloration, respectively. While the mechanism underlying DILI after prolonged flupirtine use is not entirely understood, evidence indicates that both drugs are metabolized in an initial step to reactive ortho- and/or para-azaquinone diimines or ortho- and/or para-quinone diimines, respectively. Aiming to develop safer alternatives for the treatment of pain and epilepsy, we have attempted to separate activity from toxicity by employing a drug design strategy of avoiding the detrimental oxidation of the central aromatic ring by shifting oxidation toward the formation of benign metabolites. In the present investigation, an alternative retrometabolic design strategy was followed. The nitrogen atom, which could be involved in the formation of both ortho- or para-quinone diimines of the lead structures, was shifted away from the central ring, yielding a substitution pattern with nitrogen substituents in the meta position only. Evaluation of KV7.2/3 opening activity of the 11 new specially designed derivatives revealed surprisingly steep structure–activity relationship data with inactive compounds and an activity cliff that led to the identification of an apparent “magic methyl” effect in the case of N-(4-fluorobenzyl)-6-[(4-fluorobenzyl)amino]-2-methoxy-4-methylnicotinamide. This flupirtine analogue showed potent KV7.2/3 opening activity, being six times as active as flupirtine itself, and by design is devoid of the potential for azaquinone diimine formation.

Exploring Electrochemical C(sp3)-H Oxidation for the Late-Stage Methylation of Complex Molecules.

The "magic methyl" effect, a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group, provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp3)-H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C-C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the "magic methyl" effect. This synthesis strategy thus circumvents multistep de novo synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.

Magic Methyl Effects in Drug Design

Methyl group is one of the most commonly occurring substituents in drugs. More than 50% of drugs with high market value have methyl groups in their structures. Methyl group has a capacity to act as Electron Donating Group and modulating physicochemical and biological properties of drug molecules. These properties include effect on half-life on a drug, selectivity, potency and binding affinity. When introduction of methyl group results in profound increase biological activity of molecules, it is known as Magic Methyl Effect. These enhancements in biological activity are attributed to effect of methyl group on free energy of Desolvation. The present review explores the origin of this magic methyl effect along with some supporting case studies in drug design.

Base Metal‐Catalyzed C‐Methylation Reactions Using Methanol

AbstractC‐methylation is a vitally important reaction applicable in chemical synthesis and structure‐based drug design. Notably, the “magic methyl” effect has become decisive in medicinal chemistry and drug discovery for the modulation of bio‐active properties in life science molecules. In this regard, C‐methylation reaction is widely applied chemical modification in various biomolecules, pharmaceuticals, and natural products. In general, this reaction often relies on activated, hazardous and uneconomical methyl sources such as diazomethane, dimethyl sulfate, and methyl halides. To achieve methylation reactions in a sustainable and cost‐effective manner, the use of ‘ideal’ C1 source is crucial. In this regard, methanol constitutes an expedient −CH3 source because this simple alcohol is less‐hazardous, inexpensive, and abundantly available platform chemical as well as it produces only water as the by‐product in methylation processes. Regarding potential catalysts to perform C‐methylation using methanol by hydrogen borrowing methodology, non‐noble metal‐based catalysts are highly preferable due to their unique advantages such as more abundance, inexpensive and low‐toxicity. In recent years, chemists made significant contributions towards catalytic valorization of methanol as C1 source to insert methyl groups via C−H activation in a variety of compounds and life science molecules. Consequently, in this minireview we summarize the C‐methylation process using methanol by applying Fe‐, Mn‐, Co‐ and Ni‐based catalysts as well as metal free catalysts.magnified image

Discovery of "Molecular Switches" within a Series of mGlu5 Allosteric Ligands Driven by a "Magic Methyl" Effect Affording Both PAMs and NAMs with In Vivo Activity, Derived from an M1 PAM Chemotype.

In the course of optimizing an M1 PAM chemotype, introduction of an ether moiety unexpectedly abolished M1 PAM activity while engendering a "molecular switch" to afford a weak, pure mGlu5 PAM. Further optimization was able to deliver a potent (mGlu5 EC50 = 520 nM, 63% Glu Max), centrally penetrant (Kp = 0.83), MPEP-site binding mGlu5 PAM 17a (VU6036486) that reversed amphetamine-induced hyperlocomotion. A pronounced "magic methyl" effect was noted with a regioisomeric methyl congener, leading to a change in pharmacology to afford a potent (mGlu5 IC50 = 110 nM, 3% Glu Min), centrally penetrant (Kp = 0.94), MPEP-site binding NAM 28d (VU6044766) that displayed anxiolytic activity in a mouse marble burying assay. These data further support the growing body of literature concerning the existence of G protein-coupled receptor (GPCR) allosteric privileged structures, and the value and impact of subtle methyl group walks, as well as the highly productive fluorine walk, around allosteric ligand cores to stabilize unique GPCR conformations.