Gramine-based structure optimization to enhance anti-gastric cancer activity

Zhang, Xinhui; Guo, Qin; Wang, Heng-Ying; Li, Yi-Han; Khamis, Mussa Yussuf; Ma, Liying; Wang, Bo; Liu, Hong‐Min

doi:10.1016/j.bioorg.2020.104549

Cited by 15 publications

(14 citation statements)

References 36 publications

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“…The induction of apoptosis was mediated by enhancing the expression of Bax, Cyt-C, Apaf-1, caspase-9/3, and PARP [ 82 ]. More recently, the group adopted a pharmacophore fusion strategy to introduce nitrogen-containing heterocyclic pharmacophores and the terminal alkyne into gramine to enhance the ability to inhibit the gastric cancer cell MGC803 proliferation [ 83 ]. The results show that compound 16 h-treated could activate mitochondria-associated apoptotic pathway to induce apoptosis and suppress the proliferation of MGC803 cells in a dose-dependent manner, which can be proved by the increase in Bax and cleaved caspase-3/7/9 as well as the decrease in Bcl-2 [ 83 ].…”

Section: Targeting Apoptotic Signaling Pathways With Indole Alkaloids...mentioning

confidence: 99%

“…More recently, the group adopted a pharmacophore fusion strategy to introduce nitrogen-containing heterocyclic pharmacophores and the terminal alkyne into gramine to enhance the ability to inhibit the gastric cancer cell MGC803 proliferation [ 83 ]. The results show that compound 16 h-treated could activate mitochondria-associated apoptotic pathway to induce apoptosis and suppress the proliferation of MGC803 cells in a dose-dependent manner, which can be proved by the increase in Bax and cleaved caspase-3/7/9 as well as the decrease in Bcl-2 [ 83 ]. Another simple indole alkaloid, indole-3-carbinol (I3C), a naturally occurring compound derived from multiple cruciferous vegetables, including cabbage, cauliflower, and radishes, contributes to inducing cancer cell growth arrest and exerts an anti-proliferative effect [ 84 ].…”

Section: Targeting Apoptotic Signaling Pathways With Indole Alkaloids...mentioning

confidence: 99%

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Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets

et al. 2022

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Regulated cell death (RCD) is a critical and active process that is controlled by specific signal transduction pathways and can be regulated by genetic signals or drug interventions. Meanwhile, RCD is closely related to the occurrence and therapy of multiple human cancers. Generally, RCD subroutines are the key signals of tumorigenesis, which are contributed to our better understanding of cancer pathogenesis and therapeutics. Indole alkaloids derived from natural sources are well defined for their outstanding biological and pharmacological properties, like vincristine, vinblastine, staurosporine, indirubin, and 3,3′-diindolylmethane, which are currently used in the clinic or under clinical assessment. Moreover, such compounds play a significant role in discovering novel anticancer agents. Thus, here we systemically summarized recent advances in indole alkaloids as anticancer agents by targeting different RCD subroutines, including the classical apoptosis and autophagic cell death signaling pathways as well as the crucial signaling pathways of other RCD subroutines, such as ferroptosis, mitotic catastrophe, necroptosis, and anoikis, in cancer. Moreover, we further discussed the cross talk between different RCD subroutines mediated by indole alkaloids and the combined strategies of multiple agents (e.g., 3,10-dibromofascaplysin combined with olaparib) to exhibit therapeutic potential against various cancers by regulating RCD subroutines. In short, the information provided in this review on the regulation of cell death by indole alkaloids against different targets is expected to be beneficial for the design of novel molecules with greater targeting and biological properties, thereby facilitating the development of new strategies for cancer therapy. Graphic abstract

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Section: Targeting Apoptotic Signaling Pathways With Indole Alkaloids...mentioning

confidence: 99%

Section: Targeting Apoptotic Signaling Pathways With Indole Alkaloids...mentioning

confidence: 99%

Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets

et al. 2022

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“…Compound 79c exhibited good activity against MGC803 human gastric cancer cells (IC 50 = 3.74 µM). A study of its mechanism revealed that compound 79c could cause cell cycle arrest, induce mitochondria-mediated apoptosis, and inhibit metastasis [60]. In 2023, gramine-loaded, polyvinyl-alcohol-coated iron oxide nanoparticles were prepared by Alnaim et al and exhibited a good anti-proliferation activity against HCT-116 human colon cancer cells, with an IC 50 value of 25 µg/mL.…”

Section: Antitumor Activitymentioning

confidence: 99%

Recent Developments of Gramine: Chemistry and Biological Activity

Zhang

Jia

et al. 2023

Molecules

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The natural alkaloid gramine has attracted significant attention in both academic and industrial circles because of its potential and diverse biological activities, including antiviral, antibacterial, antifungal, anti-inflammatory and antitumor activities; application in therapy for Alzheimer’s disease; serotonin-receptor-related activity; insecticidal activity; and application as an algicide. In this review, we focus on the research advances that have been made for gramine-based molecules since their discovery, providing key information on their extraction and separation, chemical synthesis and diverse biological activities. Data regarding their mechanisms of action are also presented. This comprehensive and critical review will serve as a guide for developing more drug candidates based on gramine skeletons.

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“…Gramine (GRM), an indole alkaloid occurring in Gramineae plants, also exhibits various pharmacological effects such as anti-inflammatory, antibacterial, antitumor, vasodilator, and bronchial smooth muscle modulator. − Its derivatives have a great potential to be developed to varieties of pharmaceutical agents. − In particular, GRM is a new biopesticide used to prevent brown planthoppers . Although the biopesticide has less impact on crop production than conventional pesticides, its environmental distribution has drawn public attention, due to potential environmental safety issues concerned .…”

Section: Introductionmentioning

confidence: 99%

Metabolic Activation and Cytotoxicity of Gramine Mediated by CYP3A in Rats

Gao,

Hu,

Wang

et al. 2024

J. Agric. Food Chem.

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Gramine (GRM), which occurs in Gramineae plants, has been developed to be a biological insecticide. Exposure to GRM was reported to induce elevations of serum ALT and AST in rats, but the mechanisms of the observed hepatotoxicity have not been elucidated. The present study aimed to identify reactive metabolites that potentially participate in the toxicity. In rat liver microsomal incubations fortified with glutathione or N-acetylcysteine, one oxidative metabolite (M1), one glutathione conjugate (M2), and one N-acetylcysteine conjugate (M3) were detected after exposure to GRM. The corresponding conjugates were detected in the bile and urine of rats after GRM administration. CYP3A was the main enzyme mediating the metabolic activation of GRM. The detected GSH and NAC conjugates suggest that GRM was metabolized to a quinone imine intermediate. Both GRM and M1 showed significant toxicity to rat primary hepatocytes.

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Gramine-based structure optimization to enhance anti-gastric cancer activity

Cited by 15 publications

References 36 publications

Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets

Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: from molecular mechanisms to potential therapeutic targets

Recent Developments of Gramine: Chemistry and Biological Activity

Metabolic Activation and Cytotoxicity of Gramine Mediated by CYP3A in Rats

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