Discovery of dihydrooxazolo[2,3-<i>a</i>]isoquinoliniums as highly specific inhibitors of hCE2

Ding, Lixia; Wang, Lu; Zou, Kun; Li, Bo; Song, Yun-Qing; Zhang, Qihua; Zhao, Yitian; Xu, Zhijian; Ge, Guangbo; Zhao, Bo; Zhu, Weiliang

doi:10.1039/c9ra07457k

Cited by 7 publications

(2 citation statements)

References 38 publications

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“…2-(Cyanomethyl)benzoic esters, an essential group of building blocks in synthetic chemistry, hold significant value in the production of therapeutic candidates. These compounds are essential in the synthesis of bioactive drugs, such as DCZ0359 and CWJ-a-5, which contain key components like 2-(cyanomethyl)benzoic esters. − Conventionally, these esters were produced through the S N 2 reaction of benzyl halides using toxic metal cyanides. In 2011, Lei discovered a more efficient and safer method to synthesize such esters by employing a nickel catalyst to couple arylboronic esters with α-bromonitriles .…”

Section: Cleavage Of Carbon–carbon Single Bondmentioning

confidence: 99%

Carbon–Carbon Bond Cleavage for Late-Stage Functionalization

Liang,

Bilal,

Tang

et al. 2023

Chem. Rev.

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Late-stage functionalization (LSF) introduces functional group or structural modification at the final stage of the synthesis of natural products, drugs, and complex compounds. It is anticipated that late-stage functionalization would improve drug discovery’s effectiveness and efficiency and hasten the creation of various chemical libraries. Consequently, late-stage functionalization of natural products is a productive technique to produce natural product derivatives, which significantly impacts chemical biology and drug development. Carbon–carbon bonds make up the fundamental framework of organic molecules. Compared with the carbon–carbon bond construction, the carbon–carbon bond activation can directly enable molecular editing (deletion, insertion, or modification of atoms or groups of atoms) and provide a more efficient and accurate synthetic strategy. However, the efficient and selective activation of unstrained carbon–carbon bonds is still one of the most challenging projects in organic synthesis. This review encompasses the strategies employed in recent years for carbon–carbon bond cleavage by explicitly focusing on their applicability in late-stage functionalization. This review expands the current discourse on carbon–carbon bond cleavage in late-stage functionalization reactions by providing a comprehensive overview of the selective cleavage of various types of carbon–carbon bonds. This includes C–C(sp), C–C(sp2), and C–C(sp3) single bonds; carbon–carbon double bonds; and carbon–carbon triple bonds, with a focus on catalysis by transition metals or organocatalysts. Additionally, specific topics, such as ring-opening processes involving carbon–carbon bond cleavage in three-, four-, five-, and six-membered rings, are discussed, and exemplar applications of these techniques are showcased in the context of complex bioactive molecules or drug discovery. This review aims to shed light on recent advancements in the field and propose potential avenues for future research in the realm of late-stage carbon–carbon bond functionalization.

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Section: Cleavage Of Carbon–carbon Single Bondmentioning

confidence: 99%

Carbon–Carbon Bond Cleavage for Late-Stage Functionalization

Liang,

Bilal,

Tang

et al. 2023

Chem. Rev.

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“…In this study, hCES2A inhibition assay was conducted using FD as a specific fluorescent probe substrate for hCES2A [17b,21] . Briefly, the incubation mixture (200 μL) contained each tested compound, HLM (2 μg/mL), and PBS (pH 7.4).…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Structure‐Activity Relationships of 3‐Arylisoquinolone Analogues as Highly Specific hCES2A Inhibitors

et al. 2020

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Mammalian carboxylesterases (CES) are key enzymes that participate in the hydrolytic metabolism of various endogenous and exogenous substrates. Human carboxylesterase 2A (hCES2A), mainly distributed in the small intestine and colon, plays a significant role in the hydrolysis of many drugs. In this study, 3‐arylisoquinolones 3 h [3‐(4‐(benzyloxy)‐3‐methoxyphenyl)‐7,8‐dimethoxyisoquinolin‐1(2H)‐one] and 4 a [3‐(4‐(benzyloxy)‐3‐methoxyphenyl)‐4‐bromo‐7,8‐dimethoxyisoquinolin‐1(2H)‐one] were found to have potent inhibitory effects on hCES2A (IC50=0.68 μΜ, Ki=0.36 μΜ) and excellent specificity (more than 147.05‐fold over hCES1 A). Moreover, 4 a exhibited threefold improved inhibition on intracellular hCES2A in living HepG2 cells relative to 3 h, with an IC50 value of 0.41 μΜ. Results of inhibition kinetics studies and molecular docking simulations demonstrate that both 3 h and 4 a can bind to multiple sites on hCES2A, functioning as mixed inhibitors. Structure−activity relationship analysis revealed that the lactam moiety on the B ring is crucial for specificity towards hCES2A, while a benzyloxy group is optimal for hCES2A inhibitory potency; the introduction of a bromine atom may enhance cell permeability, thereby increasing the intracellular hCES2A inhibitory activity.

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