Synthesis and in vitro/in vivo anticancer evaluation of pentacyclic triterpenoid derivatives linked with  -phenylalanine or  -proline

Yin, Yudong; Sheng, Lixin; Zhang, Juzheng; Zhang, Liqiong; Liu, Jingjing; Wen, Xiaoan; Liu, Yanghan; Shen, Yang; Cheng, Keguang

doi:10.1016/j.bioorg.2022.105865

Cited by 11 publications

(3 citation statements)

References 50 publications

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“…These results clearly showed that seven PTAs from Styrax could be exposed to the intestinal tract (especially in jejunum, ileum and colon) at relatively high levels in rats after single oral dose of Styrax (100 mg/kg), but these PTAs were hardly exposed to the liver. The extremely low exposure of these PTAs from Styrax to mammal liver could be attributed to the poor oral bioavailability and the first-pass metabolism of PTAs ( Zhang et al, 2019 ; Yin et al, 2022 ) . The high local exposure of PTAs in the intestinal tract indicated that intestinal CYP3A could be significantly inhibited by these natural compounds in Styrax, while the extremely low exposure of PTAs to mammal liver well-explained why Styrax hardly modulated the in vivo pharmacokinetic behaviors of the CYP3A-substrate drugs administrated by intravenous injection.…”

Section: Discussionmentioning

confidence: 99%

“…Frontiers in Pharmacology frontiersin.org mammal liver could be attributed to the poor oral bioavailability and the first-pass metabolism of PTAs (Zhang et al, 2019;Yin et al, 2022). The high local exposure of PTAs in the intestinal tract indicated that intestinal CYP3A could be significantly inhibited by these natural compounds in Styrax, while the extremely low exposure of PTAs to mammal liver wellexplained why Styrax hardly modulated the in vivo pharmacokinetic behaviors of the CYP3A-substrate drugs administrated by intravenous injection.…”

Section: Figurementioning

confidence: 99%

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The Chinese herb Styrax triggers pharmacokinetic herb-drug interactions via inhibiting intestinal CYP3A

Zhang

Gong

et al. 2022

Front. Pharmacol.

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Human cytochrome P450 3A4 (hCYP3A4) is a predominant enzyme to trigger clinically relevant drug/herb-drug interactions (DDIs or HDIs). Although a number of herbal medicines have been found with strong anti-hCYP3A4 effects in vitro, the in vivo modulatory effects of herbal medicines on hCYP3A4 and their potential risks to trigger HDIs are rarely investigated. Herein, we demonstrate a case study to efficiently find the herbal medicine(s) with potent hCYP3A4 inhibition in vitro and to accurately assess the potential HDIs risk in vivo. Following screening over 100 herbal medicines, the Chinese herb Styrax was found with the most potent hCYP3A4 inhibition in HLMs. In vitro assays demonstrated that Styrax could potently inhibit mammalian CYP3A in liver and intestinal microsomes from both humans and rats. In vivo pharmacokinetic assays showed that Styrax (i.g., 100 mg/kg) significantly elevated the plasma exposure of two CYP3A-substrate drugs (midazolam and felodipine) when midazolam or felodipine was administered orally. By contrast, the plasma exposure of either midazolam or felodipine was hardly affected by Styrax (i.g.) when the victim drug was administered intravenously. Further investigations demonstrated that seven pentacyclic triterpenoid acids (PTAs) in Styrax were key substances responsible for CYP3A inhibition, while these PTAs could be exposed to intestinal tract at relatively high exposure levels but their exposure levels in rat plasma and liver were extremely low. These findings well explained why Styrax (i.g.) could elevate the plasma exposure of victim drugs only when these agents were orally administrated. Collectively, our findings demonstrate that Styrax can modulate the pharmacokinetic behavior of CYP3A-substrate drugs via inhibiting intestinal CYP3A, which is very helpful for the clinical pharmacologists to better assess the HDIs triggered by Styrax or Styrax-related herbal products.

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

The Chinese herb Styrax triggers pharmacokinetic herb-drug interactions via inhibiting intestinal CYP3A

Zhang

Gong

et al. 2022

Front. Pharmacol.

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“…The introduction of a heterocycle into the pentacyclic triterpene molecule or the oxidation of the pentacyclic triterpene rings can significantly enhance biological activity. A recent study [ 74 ] described the synthesis of 37 derivatives of OA, UA, and glycyrrhetinic acid linked with L-phenylalanine or L-proline. The structural modification, especially for two glycyrrhetinic acid derivatives, induced significant antitumor activities in vitro (against SK-OV-3, MGC-803, T24, HeLa, and A549 tumor cell lines and normal human hepatocytes HL-7702) via apoptosis (decrease of mitochondrial membrane potential, activation of caspase-3/8/9, and inhibition of proteasome activity).…”

Section: Biological and Pharmacological Activitymentioning

confidence: 99%

Pentacyclic Triterpenoid Phytochemicals with Anticancer Activity: Updated Studies on Mechanisms and Targeted Delivery

Nistor,

Rugina,

Diaconeasa

et al. 2023

IJMS

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Pentacyclic triterpenoids (TTs) represent a unique family of phytochemicals with interesting properties and pharmacological effects, with some representatives, such as betulinic acid (BA) and betulin (B), being mainly investigated as potential anticancer molecules. Considering the recent scientific and preclinical investigations, a review of their anticancer mechanisms, structure-related activity, and efficiency improved by their insertion in nanolipid vehicles for targeted delivery is presented. A systematic literature study about their effects on tumor cells in vitro and in vivo, as free molecules or encapsulated in liposomes or nanolipids, is discussed. A special approach is given to liposome-TTs and nanolipid-TTs complexes to be linked to microbubbles, known as contrast agents in ultrasonography. The production of such supramolecular conjugates to deliver the drugs to target cells via sonoporation represents a new scientific and applicative direction to improve TT efficiency, considering that they have limited availability as lipophilic molecules. Relevant and recent examples of in vitro and in vivo studies, as well as the challenges for the next steps towards the application of these complex delivery systems to tumor cells, are discussed, as are the challenges for the next steps towards the application of targeted delivery to tumor cells, opening new directions for innovative nanotechnological solutions.

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Pentacyclic triterpenes, potential novel therapeutic approaches for cardiovascular diseases

Peng,

Wang,

Shi

et al. 2024

Arch. Pharm. Res.

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Synthesis and in vitro/in vivo anticancer evaluation of pentacyclic triterpenoid derivatives linked with -phenylalanine or -proline

Cited by 11 publications

References 50 publications

The Chinese herb Styrax triggers pharmacokinetic herb-drug interactions via inhibiting intestinal CYP3A

The Chinese herb Styrax triggers pharmacokinetic herb-drug interactions via inhibiting intestinal CYP3A

Pentacyclic Triterpenoid Phytochemicals with Anticancer Activity: Updated Studies on Mechanisms and Targeted Delivery

Pentacyclic triterpenes, potential novel therapeutic approaches for cardiovascular diseases

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