Enzymatic hydrolysis of ∆8-THC-O, ∆9-THC-O, 11-α-HHC-O, and 11-β-HHC-O by pooled human liver microsomes to generate ∆8-THC, ∆9-THC, 11-α-HHC, and 11-β-HHC

Article

作者: Li, Ren-Shi ; Kikura-Hanajiri, Ruri ; Demizu, Yosuke ; Zhao, Shuangli ; Pineda García, Jorge Carlos ; Tanaka, Yoshitaka ; Ishii, Yuji

PURPOSE:

In recent years, analogues of ∆⁹-tetrahydrocannabinol (∆⁹-THC) have been widely distributed in Japan via the internet. Hexahydrocannabinol (HHC), synthesized by reducing THC, was controlled as a designated substance under the Pharmaceutical and Medical Device Act in Japan in 2022. However, other semi-synthetic cannabinoids, such as acetyl derivatives of THC and HHC, appeared soon. Herein, we examined whether the enzymatic hydrolysis of acetylated forms of ∆⁹-THC, ∆⁸-THC 11-α-HHC, and 11-β-HHC by human liver microsomes (HLM) occurs.

METHODS:

The hydrolysis reaction was accomplished with HLM. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine products. Recombinant enzymes carboxylesterase 1C (CES1c), carboxylesterase 2 (CES2), and carboxylesterase inhibitor bis-(4-nitrophenyl) phosphate (BNPP) were used to clarify the principal hydrolysis enzymes for acetylated cannabinoids.

RESULTS:

The acetylated form underwent hydrolysis with HLM time-dependently, with almost no acetylated product remaining after 60 min. Furthermore, results from LC-MS showed that only the deacetylated form was present after hydrolysis. Although hydrolysis did not occur when HLM was pre-incubated with the carboxylesterase inhibitor BNPP, it was observed when CES1c or CES2 was used for in vitro experiments.

CONCLUSION:

This is the first time that it is elucidated that ∆⁹-THC-O, ∆⁸-THC-O, 11-α-HHC-O, and 11-β-HHC-O are enzymatically hydrolyzed with HLM to produce ∆⁹-THC, ∆⁸-THC, 11-α-HHC, and 11-β-HHC, respectively. Our results also support that CES1c and CES2 were the main enzymes involved in the hydrolysis of the acetylated cannabinoids. This study provides scientific support for the metabolism of newly regulated acetylated cannabinoids to cause the parent compound in vivo.

2025-05-16·JOURNAL OF ORGANIC CHEMISTRY

Iodine-Catalyzed Room-Temperature Aerobic Oxidation of C(sp³)–H Bonds and Its Application in the Synthesis of Quinoxaline Derivatives

Article

作者: Yu, Wenquan ; Xiong, Hanyu ; Wang, Longxing ; Chang, Junbiao ; Li, Jiajun ; Mu, Yuanyang

An iodine-catalyzed aerobic oxidation reaction of C(sp³)-H bonds was established at room temperature. In this transformation, iodine acts as a Lewis acid catalyst, and the pyridine moiety in the substrate plays a crucial role. Under the optimum reaction conditions, picolyl ketone substrates were smoothly transformed into the corresponding 1,2-dicarbonyl compounds, and the subsequent introduction of 1,2-diaminobenzenes into the reaction mixture led to the formation of various quinoxaline derivatives. This synthetic process does not use transition metals and also features mild reaction conditions, operational simplicity, and gram-scale synthesis.

2025-03-04·ADVANCED SYNTHESIS & CATALYSIS

Visible‐Light‐Promoted Photocatalyst‐Free Unsymmetrical Synthesis of Diaryl 1, 2‐Diketones from Terminal Alkynes/ Alkenes and Aryl Halides Under the Formate‐Air‐DMSO Condition

作者: Liu, Yingtian ; Li, Jiahong ; Chen, Xueqin ; Tan, Rui ; Wen, Xiaoqing ; Fu, Yang

Abstract:

A method has been developed for the synthesis of symmetrical and unsymmetrical aryl 1, 2‐diketones at room temperature, without the need for transition metals or photocatalysts. This protocol employs aromatic terminal alkynes or alkenes to react with aryl iodides under conditions involving formate, air, and DMSO. Mechanistic studies indicate that formate, air, and DMSO are all necessary conditions, and that the highly reactive carbon dioxide radical anion (CO2⋅−) generated under these conditions plays a key role in the reaction.

100 项与 Carboxylesterase Inhibitors(Takeda Oncology) 相关的药物交易

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