Design, synthesis, and discovery of ocotillol-type amide derivatives as orally available modulators of P-glycoprotein-mediated multidrug resistance

Ren, Qianwen; Yang, Gangqiang; Guo, Mengye; Guo, Jingwen; Yang, Li; Lü, Jing; Yang, Qing; Tang, Hanhan; Li, Yi; Fang, Xiaojuan; Sun, Yixiao; Qi, Jia; Tian, Jingwei; Wang, Hongbo

doi:10.1016/j.ejmech.2018.10.038

Cited by 30 publications

(24 citation statements)

References 25 publications

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“…Compound 135 showed the strongest P-gp modulating properties by significantly reducing 28-fold the IC 50 of paclitaxel in KBV cells ( Table 15 ). The oral administration of 135 (15 mg/kg) significantly increased the antitumor activity of paclitaxel on a nude mouse bearing KBV xenografts, confirming in vivo its ability to reverse P-gp-related multidrug resistance [ 148 ].…”

Section: Terpenesmentioning

confidence: 99%

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

2020

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Multidrug resistance (MDR) in cancer is one of the main limitations for chemotherapy success. Numerous mechanisms are behind the MDR phenomenon wherein the overexpression of the ATP-binding cassette (ABC) transporter proteins P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MRP1) is highlighted as a prime factor. Natural product-derived compounds are being addressed as promising ABC transporter modulators to tackle MDR. Flavonoids and terpenoids have been extensively explored in this field as mono or dual modulators of these efflux pumps. Nitrogen-bearing moieties on these scaffolds were proved to influence the modulation of ABC transporters efflux function. This review highlights the potential of semisynthetic nitrogen-containing flavonoid and terpenoid derivatives as candidates for the design of effective MDR reversers. A brief introduction concerning the major role of efflux pumps in multidrug resistance, the potential of natural product-derived compounds in MDR reversal, namely natural flavonoid and terpenoids, and the effect of the introduction of nitrogen-containing groups are provided. The main modifications that have been performed during last few years to generate flavonoid and terpenoid derivatives, bearing nitrogen moieties, such as aliphatic, aromatic and heterocycle amine, amide, and related functional groups, as well as their P-gp, MRP1 and BCRP inhibitory activities are reviewed and discussed.

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Section: Terpenesmentioning

confidence: 99%

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

2020

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“…For the A549 cell line, compound 69 (IC 50 , 7.63 μM) showed the strongest activity, which was 5.6 times stronger than PD (43.13 μM). Ocotillol enantiopure and its derivatives showed good antibacterial activity anti-gram-positive bacteria (Bi et al, 2015 ; Ren et al, 2019 ), and they can be obtained by the oxidation of PPD with m -CPBA. Wang et al ( 2018 ) introduced free amino groups at the C-3 position to confirm whether the group can enhance the antibacterial activity.…”

Section: Application Of Amino Acids In the Structural Modification Of Natural Productsmentioning

confidence: 99%

Application of Amino Acids in the Structural Modification of Natural Products: A Review

Deng

et al. 2021

Front. Chem.

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Natural products and their derivatives are important sources for drug discovery; however, they usually have poor solubility and low activity and require structural modification. Amino acids are highly soluble in water and have a wide range of activities. The introduction of amino acids into natural products is expected to improve the performance of these products and minimize their adverse effects. Therefore, this review summarizes the application of amino acids in the structural modification of natural products and provides a theoretical basis for the structural modification of natural products in the future. The articles were divided into six types based on the backbone structures of the natural products, and the related applications of amino acids in the structural modification of natural products were discussed in detail.

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“…Many efforts and progress had been made in modifying 3-OH of ocotillol-type sapogenins. The substitution at C-3 hydroxy such as the oxidation products [54], aromatic carboxylate derivatives [55], alkylation products [56], nitrate derivatives [20], amino acid derivatives [28], bromoalkanoates derivatives [20], oxime derivatives [53] and N-substituted amide derivatives [57] could all significantly enhance the biological activity of ocotillol-type sapogenins. Therefore, 3-OH was selected for further modification [19] in our study.…”

Section: Designmentioning

confidence: 99%

Synthesis and Anti-Hepatocarcinoma Effect of Amino Acid Derivatives of Pyxinol and Ocotillol

Zhang

et al. 2021

Molecules

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Aiming at seeking an effective anti-hepatocarcinoma drug with low toxicity, a total of 24 amino acid derivatives (20 new along with 4 known derivatives) of two active ocotillol-type sapogenins (pyxinol and ocotillol) were synthesized. Both in vitro and in vivo anti-hepatocarcinoma effects of derivatives were evaluated. At first, the HepG2 human cancer cell was employed to evaluate the anti-cancer activity. Most of the derivatives showed obvious enhanced activity compared with pyxinol or ocotillol. Among them, compound 2e displayed the most excellent activity with an IC50 value of 11.26 ± 0.43 µM. Next, H22 hepatoma-bearing mice were used to further evaluate the anti-liver cancer activity of compound 2e. It was revealed that the growth of H22 transplanted tumor was significantly inhibited when treated with compound 2e or compound 2e combined with cyclophosphamide (CTX) (p < 0.05, p < 0.01), and the inhibition rates of tumor growth were 35.32% and 55.30%, respectively. More importantly, compound 2e caused limited damage to liver and kidney in contrast with CTX causing significant toxicity. Finally, the latent mechanism of compound 2e was explored by serum and liver metabolomics based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) technology. A total of 21 potential metabolites involved in 8 pathways were identified. These results suggest that compound 2e is a promising agent for anti-hepato-carcinoma, and that it also could be used in combination with CTX to increase efficiency and to reduce toxicity.

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Design, synthesis, and discovery of ocotillol-type amide derivatives as orally available modulators of P-glycoprotein-mediated multidrug resistance

Cited by 30 publications

References 25 publications

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

Application of Amino Acids in the Structural Modification of Natural Products: A Review

Synthesis and Anti-Hepatocarcinoma Effect of Amino Acid Derivatives of Pyxinol and Ocotillol

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