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Pharmaceuticals
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Biological and Pharmacological Research on Indole-3-Carbinol (I3C) and Its Derivatives
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Biological and Pharmacological Research on Indole-3-Carbinol (I3C) and Its Derivatives

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (20 June 2025) | Viewed by 3667

Special Issue Editor

Dr. Federica Centofanti

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Guest Editor
Department of Biomedicine and Prevention—Medical Genetic Section, Tor Vergata University of Rome, 00133 Rome, Italy
Interests: genetics; natural compounds; antiviral activity

Special Issue Information

Dear Colleagues,

Indole-3-carbinol (I3C) is a natural compound found in vegetables from the Brassicaceae family. It has been extensively studied for its biological and pharmacological properties, including it ability to suppress cell cycle progression, block cancer cell migration, promote apoptosis, and inhibit tumor growth and Sars-CoV-2 viral egression. In addition, it has demonstrated cardioprotective, antioxidant, anti-inflammatory, antiangiogenetic, and antimicrobial properties. Although it interacts with different pathways, it has been proposed that I3C and its synthetic derivatives may influence human cells by directly inhibiting them with specific enzymatic target proteins. Since I3C affects various cellular mechanisms, it is not surprising to researchers proposing its use for treating or preventing different cancer types and other diseases. On the other hand, I3C is a metabolically unstable compound and decomposes under gastric pH conditions when it is orally administered. Therefore, one of the main focuses for researchers is to make changes to I3C’s chemical structure characteristics to improve its stability. Different design strategies were applied to enhance the possibility of performing lead optimization and obtaining derivatives with a better pharmacodynamic and pharmacokinetic profile than I3C.This Special Issue aims to invite both reviews and original articles that shed light on the biosynthetic processes and synthetic procedures for obtaining I3C and its main derivatives. This Special Issue’s objective is also to explore the characteristics, mechanism of action, and therapeutic potential of I3C and/or its derivatives both in health and in preventing and treating various diseases.

Dr. Federica Centofanti
Guest Editor

Manuscript Submission Information

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Keywords

  • indole-3-carbinol
  • natural and synthetic derivatives of I3C
  • synthetic procedures
  • biosynthetic processes
  • in vitro, in vivo and clinical studies
  • mechanism of action
  • biological properties
  • pharmacological properties
  • potential therapeutic applications in health and disease

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Published Papers (3 papers)

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15 pages, 2143 KiB  
Article
Indole-3-Acetic Acid: Promising Protective Agent Against Methotrexate-Induced Liver Injury via Modulation of TLR4/NF-κB/Caspase-3 Pathway
by Sumayya A. Alturaif, Ahlam Alhusaini, Wedad Sarawi, Iman Hasan, Juman Alsaab, Rehab Ali, Raeesa Mohammed, Sahar S. Alotaibi, Faris Almutairi, Shaikha Alsaif, Ebtesam Alsultan, Ebtesam Aljasas and Sary Alsanea
Pharmaceuticals 2025, 18(6), 828; https://doi.org/10.3390/ph18060828 - 1 Jun 2025
Viewed by 420
Abstract
Background and Purpose: Methotrexate (MTX) is a widely used therapeutic agent for inflammatory and malignant diseases; however, its prolonged use is associated with hepatotoxicity through mechanisms that remain inadequately understood. This study aims to elucidate these mechanisms and assess the hepatoprotective potential of [...] Read more.
Background and Purpose: Methotrexate (MTX) is a widely used therapeutic agent for inflammatory and malignant diseases; however, its prolonged use is associated with hepatotoxicity through mechanisms that remain inadequately understood. This study aims to elucidate these mechanisms and assess the hepatoprotective potential of indole-3-acetic acid (IAA). Methods: Rats were allocated into five groups: control (group 1), IAA-treated (group 2), MTX-treated (group 3), quercetin (QUR) + MTX (group 4), and IAA + MTX (group 5). Hepatic function was assessed through the evaluation of serum liver enzymes, oxidative stress, and inflammatory and apoptotic markers using biochemical, molecular, histopathological, and immunohistochemical analyses. Results: The MTX-treated group demonstrated a significant increase in hepatic oxidative stress, inflammation, and apoptotic markers. Co-administration of IAA or QUR with MTX markedly reduced malondialdehyde (MDA) levels, while enhancing glutathione (GSH) levels and superoxide dismutase (SOD) activity. Moreover, hepatic inflammatory markers, including TNF-α, IL-6, and IL-1β, were significantly decreased in the IAA- and QUR-treated groups. Immunohistochemical analysis further revealed a reduced expression of NF-κB, TLR4, and caspase-3 in hepatic tissues following QUR-MTX or IAA-MTX treatments. Conclusions: IAA exhibited hepatoprotective effects against MTX-induced liver injury, comparable to QUR, by modulating the TLR4/NF-κB/caspase-3 pathway. These findings highlight its potential clinical application in reducing MTX-associated hepatic complications. Full article
(This article belongs to the Special Issue Biological and Pharmacological Research on Indole-3-Carbinol (I3C) and Its Derivatives)
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24 pages, 2886 KiB  
Article
Theoretical–Cheminformatic Study of Four Indolylphytoquinones, Prospective Anticancer Candidates
by Edgar Daniel Moyers-Montoya, María Jazmín Castañeda-Muñoz, Daniel Márquez-Olivas, René Miranda-Ruvalcaba, Carlos Alberto Martínez-Pérez, Perla E. García-Casillas, Wilber Montejo-López, María Inés Nicolás-Vázquez and René Gerardo Escobedo-González
Pharmaceuticals 2024, 17(12), 1595; https://doi.org/10.3390/ph17121595 - 26 Nov 2024
Viewed by 1059
Abstract
Background/Objectives: Breast cancer is a disease with a high mortality rate worldwide; consequently, urgent achievements are required to design new greener drugs, leaving natural products and their derivatives as good options. A constant antineoplastic effect has been observed when the phytoproduct contains an [...] Read more.
Background/Objectives: Breast cancer is a disease with a high mortality rate worldwide; consequently, urgent achievements are required to design new greener drugs, leaving natural products and their derivatives as good options. A constant antineoplastic effect has been observed when the phytoproduct contains an indole fragment. Methods: Therefore, the objective of this work was to carry out a thoughtful computational study to perform an appropriate evaluation of four novel molecules of the class of the 3-indolylquinones as phytodrug candidates for antineoplastic activity: thymoquinone (TQ), 2,6-dimethoxy-1,4-benzoquinone (DMQ), 2,3-dimethoxy-5-methyl-1,4-benzoquinone (DMMQ), and 2,5-dihydroxy-1,4-benzoquinone (DHQ). It is important to highlight that the obtained computational results of the target compounds were compared-correlated with the theoretical and experimental literature data previously reported of several indolylquinones: indolylperezone, indolylisoperezone, indolylmenadione, and indolylplumbagin (IE-IH, respectively). Results: The results revealed that the studied structures possibly presented antineoplastic activity, in addition to the fact that the reactivity parameters showed that two of the evaluated compounds have the option to present IC50 values lower than or similar to 25 mg/mL, activity like that of indolylisoperezone; moreover, they show molecular coupling to PARP-1. Finally, the prediction of the calculated physicochemical parameters coincides with the Lipinski and Veber rules, indicating that the adsorption, metabolism, and toxicity parameters are acceptable for the studied compounds, obtaining high drug score values. Conclusions: Finally, a comparison between the proposed molecules and others previously synthesized was appropriately performed, establishing that the synthesis of the studied compounds and the determination of their pharmacological properties in an experimental manner are of interest. Full article
(This article belongs to the Special Issue Biological and Pharmacological Research on Indole-3-Carbinol (I3C) and Its Derivatives)
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16 pages, 5977 KiB  
Article
Novel Deep Sea Isoindole Alkaloid FGFC1 Exhibits Its Fibrinolytic Effects by Inhibiting Thrombin-Activatable Fibrinolysis Inhibitor
by Haixing Zhang, Xiaozhen Diao, Tingting Jiang, Mingjun Wei, Yue Su, Jingjing Shen, Chunlin Bao and Wenhui Wu
Pharmaceuticals 2024, 17(10), 1401; https://doi.org/10.3390/ph17101401 - 20 Oct 2024
Viewed by 1231
Abstract
Background: The thrombin-activatable fibrinolysis inhibitor (TAFI) is an important regulator in the balance between blood clot formation (coagulation) and dissolution (fibrinolysis), which is mainly activated by thrombin bonded with thrombomodulin (TM). Methods: In this study, the investigation focused on the unique target TAFI [...] Read more.
Background: The thrombin-activatable fibrinolysis inhibitor (TAFI) is an important regulator in the balance between blood clot formation (coagulation) and dissolution (fibrinolysis), which is mainly activated by thrombin bonded with thrombomodulin (TM). Methods: In this study, the investigation focused on the unique target TAFI of fungi fibrinolytic compound 1 (FGFC1), a novel fibrinolytic compound sourced from the deep sea. In this sense, the regulation of TAFI by FGFC1, in comparison to established TAFI inhibitors such as DS-1040 and PCTI in hPPP, was investigated, which was validated through the molecular docking of FGFC1 to TAFI. The inhibitory effect of FGFC1 on TAFI-mediating coagulation (ex vivo and in vitro) and its fibrinolytic effect (ex vivo) were investigated in hPPP and hCMEC/D3 cells, respectively, followed by SEM. Results: FGFC1 solutions ranging from 0.023 to 0.736 mM effectively inhibited TAFI activation. Notably, the 0.023 mM concentration demonstrated significant suppression, comparable to DS-1040 and PCTI. These inhibitory effects of FGFC1 (0.023–0.368 mM) were further validated through the enhancement in TAFI (TAFIa) activation by fibrins in the coagulum prior to proteolysis, resulting in the cleavage of TAFIa from 33 kDa to 28 kDa. Furthermore, these regulatory effects of FGFC1 on TAFI were demonstrated to have minimal association with TM-mediated control, as confirmed through a molecular docking analysis. FGFC1 (0.023–0.092 mM) was suggested to have obstructive effects on TAFI-mediated coagulation in the hPPP, which was demonstrated by the inhibition of clot aggregation, protein crystallization, and platelet anchoring, as observed through SEM. Simultaneously, FGFC1 (0.023 to 0.368 mM) significantly enhanced TAFI-mediated fibrinolysis, which was also supported by increased levels of t-PA, u-PA, and plasmin. Conclusions: From the above findings, FGFC1 is identified as a novel dual-target bioactive compound participating in blood formation/dissolution that demonstrates anti-coagulation and fibrinolytic effects by regulating TAFI activation, inhibiting TAFIa–fibrin combination, and initiating proteolysis. It also provided convincing evidence that TAFI plays a critical role in thrombolysis as a molecular link between coagulation and fibrinolysis. Furthermore, the application of FGFC1 was indicated as a potential therapeutic strategy in thromboembolic and hemorrhagic diseases. Full article
(This article belongs to the Special Issue Biological and Pharmacological Research on Indole-3-Carbinol (I3C) and Its Derivatives)
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