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Secondary Metabolites of Plants and its Synthetic Derivatives in Cellular...
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Secondary Metabolites of Plants and its Synthetic Derivatives in Cellular and Molecular Pharmacology

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

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 23040

Special Issue Editor

Prof. Dr. Eduardo Fuentes Quinteros

E-Mail Website
Guest Editor
Thrombosis Research Center, Medical Technology School, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Universidad de Talca, Talca 3460000, Chile
Interests: synthesis; secondary metabolites; molecular pharmacology; molecular signaling; mechanism of drug action; medicinal chemistry

Special Issue Information

Dear Colleagues,

The therapeutic properties of plants have been recognized since time immemorial. Many pathological conditions have been treated using plant-derived medicines. Plant secondary metabolites are an extremely diverse and important group of natural products that have been a rich source for successful drugs and offer a nearly innumerable library of potential scaffolds for new drug precursors, drug prototypes, and pharmacological probes. Thus, natural products can be employed as very good starting materials for analog design and synthesis as semisynthetic derivatives exhibit selective and improved biological activities in several cases. These natural-product-based synthetic derivatives possess the characteristics of high chemical diversity and pharmacological properties that create them favorably as lead structures for new drug discovery and continue to motivate novel inventions in medicinal and pharmaceutical chemistry.

Natural products and their structural analogs have historically made a major contribution to pharmacotherapy. Natural products often have selective biological actions due to binding affinities for specific proteins relevant for their biological functions. Natural compounds in particular have been extensively explored for new drug discoveries with antioxidant, anti-inflammatory, anticancer, antiplatelet, antimicrobial, antihelminthic, anticoagulant, antidiabetic, and lipid-lowering properties, among others.

The natural products and their analogs have been present in molecular pharmacology from small molecule drug development, molecular biology of drug action, cell signaling, and drug delivery. One of the most significant hurdles in molecular pharmacology is understanding and the provision of a specific mechanism of action by which natural-product-based drug discovery exhibits bioactivity. In this way, detailed knowledge of the interaction of a natural product with its molecular target is very advantageous for the drug development process because it allows property optimization by medicinal chemistry approaches and, on some occasions, a more appropriate clinical trial design.

The main goal of this Special Issue is the elucidation and understanding of the cellular and molecular pharmacology of natural products and their analogs.

Prof. Dr. Eduardo Fuentes Quinteros
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • natural products
  • synthesis
  • derivatives
  • drug discovery
  • cellular pharmacology
  • molecular pharmacology
  • medicinal chemistry

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Published Papers (7 papers)

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Research

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14 pages, 1466 KiB  
Article
The Use of Triphenyl Phosphonium Cation Enhances the Mitochondrial Antiplatelet Effect of the Compound Magnolol
by Francisca Tellería, Santiago Mansilla, Diego Méndez, Magdalena Sepúlveda, Ramiro Araya-Maturana, Laura Castro, Andrés Trostchansky and Eduardo Fuentes
Pharmaceuticals 2023, 16(2), 210; https://doi.org/10.3390/ph16020210 - 30 Jan 2023
Cited by 5 | Viewed by 1881
Abstract
Although platelets are anucleated cells, they have fully functional mitochondria, and currently, it is known that several processes that occur in the platelet require the action of mitochondria. There are plenty of mitochondrial-targeted compounds described in the literature related to cancer, however, only [...] Read more.
Although platelets are anucleated cells, they have fully functional mitochondria, and currently, it is known that several processes that occur in the platelet require the action of mitochondria. There are plenty of mitochondrial-targeted compounds described in the literature related to cancer, however, only a small number of studies have approached their interaction with platelet mitochondria and/or their effects on platelet activity. Recent studies have shown that magnolia extract and mitochondria-targeted magnolol can inhibit mitochondrial respiration and cell proliferation in melanoma and oral cancer cells, respectively, and they can also induce ROS and mitophagy. In this study, the effect of triphenylphosphonium cation, linked by alkyl chains of different lengths, to the organic compound magnolol on human-washed platelets was evaluated. We demonstrated that the addition of triphenylphosphonium by a four-carbon linker to magnolol (MGN4) considerably enhanced the Magnolol antiplatelet effect by a 3-fold decrease in the IC50. Additionally, platelets exposed to MGN4 5 µM showed several differences from the control including increased basal respiration, collagen-induced respiration, ATP-independent respiration, and reduced ATP-dependent respiration and non-mitochondrial respiration. Full article
(This article belongs to the Special Issue Secondary Metabolites of Plants and its Synthetic Derivatives in Cellular and Molecular Pharmacology)
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20 pages, 3537 KiB  
Article
Xanthium spinosum L. Extracts Inhibit Breast Cancer in Mice by Apoptosis Induction and Immune System Modulation
by Lina T. Al Kury, Zainab Taha, Asma Ismail Mahmod and Wamidh H. Talib
Pharmaceuticals 2022, 15(12), 1504; https://doi.org/10.3390/ph15121504 - 2 Dec 2022
Cited by 5 | Viewed by 2383
Abstract
Plants have been considered for many years as an important source of medicine to treat different diseases. Xanthium spinosum L. (Asteraceae, Compositae) is known for its diuretic, anti-inflammatory, and sedative effects. It is also used in the treatment of several ailments, such as [...] Read more.
Plants have been considered for many years as an important source of medicine to treat different diseases. Xanthium spinosum L. (Asteraceae, Compositae) is known for its diuretic, anti-inflammatory, and sedative effects. It is also used in the treatment of several ailments, such as cancer. In order to evaluate the anticancer and immunomodulatory activities, crude ethanol extract was prepared from the aerial part of X. spinosum and then fractionated using solvents with different polarities. As well, the chemical composition of X. spinosum extract and fractions were identified using LC-MS analysis. The antitumor effect of X. spinosum was assessed in both in vitro and in vivo models. Apoptosis induction was measured in vitro using a caspase-3 activity kit. Lymphocyte proliferation and phagocytosis and pinocytosis induction were used to quantify the effect of the plant extract and fractions on acquired and innate immunity, respectively. The effect of X. spinosum extract, and fractions on the levels of cytokines (IFN-γ, IL-2, IL-4, and IL-10) in murine lymphocytes was determined using a mouse-uncoated TH1/TH2 ELISA kit. Results showed that ethanol extract had the highest antiproliferative activity (IC₅₀ = 2.5 mg mL−1) against EMT6/P cell lines, while the aqueous and chloroform fractions had the highest apoptotic activity with 2.2 and 1.7 folds, respectively. On the other hand, the n-hexane fraction was the most effective in stimulating lymphocyte proliferation, whereas ethanol extract, aq. Methanol and aqueous fractions exhibited the highest phagocytic activity. As well, X. spinosum extract and fractions were able to modulate the expression of IL-2, IL-4, and IFN-γ. A remarkable decrease in tumor size was accomplished following the treatment of tumor-bearing mice with X. spinosum extract and fractions. Both aq. Methanol and chloroform fractions showed the highest percentage change in tumor size with -58 and -55%, respectively. As well, tumor-bearing mice treated with chloroform fraction demonstrated a high curable percentage with a value of 57.1%. Anyway, X. spinosum extract and fractions exhibited no toxic impact on the liver or kidney functions of the mice-treated groups. These findings may confirm that X. spinosum has favorable anticancer and immunomodulatory effects. However, additional studies are required to fully understand the mechanisms of action of this plant and the signaling pathways involved in its effects. Moreover, more testing is needed to have better insight into the apoptotic pathway and to know the exact concentration of active compounds. Full article
(This article belongs to the Special Issue Secondary Metabolites of Plants and its Synthetic Derivatives in Cellular and Molecular Pharmacology)
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18 pages, 1348 KiB  
Article
In Vitro Safety, Off-Target and Bioavailability Profile of the Antiviral Compound Silvestrol
by Susanne Schiffmann, Sandra Gunne, Thomas Ulshöfer, Marina Henke, Luise A. Roser, Ann-Kathrin Schneider, Jindrich Cinatl, Dominique Thomas, Yannick Schreiber, Pia Viktoria Wagner, Arnold Grünweller and Michael J. Parnham
Pharmaceuticals 2022, 15(9), 1086; https://doi.org/10.3390/ph15091086 - 31 Aug 2022
Cited by 8 | Viewed by 3074
Abstract
We characterized the in vitro safety and bioavailability profile of silvestrol, a compound effective against various viruses, such as corona- and Ebolaviruses, with an EC50 value of about 5 nM. The cytotoxic profile of silvestrol was assessed in various cancer cell lines, [...] Read more.
We characterized the in vitro safety and bioavailability profile of silvestrol, a compound effective against various viruses, such as corona- and Ebolaviruses, with an EC50 value of about 5 nM. The cytotoxic profile of silvestrol was assessed in various cancer cell lines, as well as the mutagenic and genotoxic potential with Ames and micronuclei tests, respectively. To identify off-target effects, we investigated whether silvestrol modulates G-protein coupled receptor (GPCR) signaling pathways. To predict the bioavailability of silvestrol, its stability, permeability and cellular uptake were determined. Silvestrol reduced viability in a cell-type-dependent manner, mediated no off-target effects via GPCRs, had no mutagenic potential and minor genotoxic effects at 50 nM. Silvestrol did not disturb cell barrier integrity, showed low membrane permeability, was stable in liver microsomes and exhibited good cellular uptake. Efficient cellular uptake and increased cytotoxicity were observed in cell lines with a low expression level of the transport protein P-glycoprotein, the known efflux transporter of silvestrol. In conclusion, silvestrol showed low permeability but good cellular uptake and high stability. Cell-type-dependent cytotoxicity seems to be caused by the accumulation of silvestrol in cells lacking the ability to expel silvestrol due to low P-glycoprotein levels. Full article
(This article belongs to the Special Issue Secondary Metabolites of Plants and its Synthetic Derivatives in Cellular and Molecular Pharmacology)
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22 pages, 4775 KiB  
Article
Orientin, a Bio-Flavonoid from Trigonella hamosa L., Regulates COX-2/PGE-2 in A549 Cell Lines via miR-26b and miR-146a
by Hany Ezzat Khalil, Hairul-Islam Mohamed Ibrahim, Emad A. Ahmed, Promise Madu Emeka and Ibrahim A. Alhaider
Pharmaceuticals 2022, 15(2), 154; https://doi.org/10.3390/ph15020154 - 27 Jan 2022
Cited by 19 | Viewed by 4250
Abstract
Cancer is a severe health condition and considered one of the major healthcare issues and is in need of innovative strategy for a cure. The current study aimed to investigate the chemical profile of Trigonella hamosa L. and a potential molecular approach to [...] Read more.
Cancer is a severe health condition and considered one of the major healthcare issues and is in need of innovative strategy for a cure. The current study aimed to investigate the chemical profile of Trigonella hamosa L. and a potential molecular approach to explain its regulation in cancer progression through an inflammatory mediator (COX-2) in A549 non-small lung cancer cell lines via in silico, mechanistic and molecular aspects. T. hamosa was extracted and then subjected to a CCK-8 cell viability assay in different cancer cell lines including MDA-MB-231, A549 and HCT-116. Total extract was subjected to several chromatographic techniques to yield orientin (OT); the structure was elucidated by inspection of NMR spectroscopic data. To achieve anticancer effects of OT, a cell viability assay using a CCK-8 kit, immunoprecipitation by Western blot, cell migration using a wound healing assay, cell invasion using a Matrigel-Transwell assay, apoptosis by AO/EB dual staining, flow cytometric analysis and DAPI staining, a silenced COX-2 model to determine PGE-2 production and real-time PCR and Western blot of BCL-2, CYP-1A1, iNOS and COX-2 markers were carried out. The results demonstrated that OT decreased the cell proliferation and controlled cell migration and invasive properties. OT destabilized the COX-2 mRNA and downregulated its expression in A549 cell lines. Virtual binding showed interaction (binding energy −10.43) between OT and COX-2 protein compared to the selective COX-2 inhibitor celecoxib (CLX) (binding energy −9.4). The OT-CLX combination showed a superior anticancer effect. The synergistic effect of OT-CLX combination was noticed in controlling the migration and invasion of A549 cell lines. OT-CLX downregulated the expression of BCL-2, iNOS and COX-2 and activated the proapoptotic gene CYP-1A1. OT mitigated the COX-2 expression via upregulation of miR-26b and miR-146a. Interestingly, COX-2-silenced transfected A549 cells exhibited reduced expression of miR-26b and miR-146a. The findings confirmed the direct interaction of OT with COX-2 protein. PGE-2 expression was quantified in both naïve and COX-2-silenced A549 cells. OT downregulated the release of PGE-2 in both tested conditions. These results confirmed the regulatory effect of OT on A549 cell growth in a COX-2-dependent manner. OT activated apoptosis via activation of CYP-1A1 expression in an independent manner. These results revealed that the OT-CLX combination could serve as a potential synergistic treatment for effective inflammatory-mediated anticancer strategies. Full article
(This article belongs to the Special Issue Secondary Metabolites of Plants and its Synthetic Derivatives in Cellular and Molecular Pharmacology)
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Review

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53 pages, 3722 KiB  
Review
Modulation of Cytoskeleton, Protein Trafficking, and Signaling Pathways by Metabolites from Cucurbitaceae, Ericaceae, and Rosaceae Plant Families
by Ankit Patel, Aliyah Rasheed, Isiah Reilly, Zil Pareek, Mattia Hansen, Zayn Haque, Daniela Simon-Fajardo, Chloe Davies, Akash Tummala, Karlyn Reinhardt, Alexandria Bustabad, Maxwell Shaw, Jasmine Robins, Karolaent Vera Gomez, Thitisuda Suphakorn, Mariana Camacho Gemelgo, Ashley Law, Kristina Lin, Elizabeth Hospedales, Harrison Haley, Jean Pierre Perez Martinez, Saifullah Khan, Jessica DeCanio, Malcolm Padgett, Artem Abramov and Meera Nanjundanadd Show full author list remove Hide full author list
Pharmaceuticals 2022, 15(11), 1380; https://doi.org/10.3390/ph15111380 - 10 Nov 2022
Cited by 3 | Viewed by 3882
Abstract
One promising frontier within the field of Medical Botany is the study of the bioactivity of plant metabolites on human health. Although plant metabolites are metabolic byproducts that commonly regulate ecological interactions and biochemical processes in plant species, such metabolites also elicit profound [...] Read more.
One promising frontier within the field of Medical Botany is the study of the bioactivity of plant metabolites on human health. Although plant metabolites are metabolic byproducts that commonly regulate ecological interactions and biochemical processes in plant species, such metabolites also elicit profound effects on the cellular processes of human and other mammalian cells. In this regard, due to their potential as therapeutic agents for a variety of human diseases and induction of toxic cellular responses, further research advances are direly needed to fully understand the molecular mechanisms induced by these agents. Herein, we focus our investigation on metabolites from the Cucurbitaceae, Ericaceae, and Rosaceae plant families, for which several plant species are found within the state of Florida in Hillsborough County. Specifically, we compare the molecular mechanisms by which metabolites and/or plant extracts from these plant families modulate the cytoskeleton, protein trafficking, and cell signaling to mediate functional outcomes, as well as a discussion of current gaps in knowledge. Our efforts to lay the molecular groundwork in this broad manner hold promise in supporting future research efforts in pharmacology and drug discovery. Full article
(This article belongs to the Special Issue Secondary Metabolites of Plants and its Synthetic Derivatives in Cellular and Molecular Pharmacology)
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12 pages, 3302 KiB  
Review
Binding of Natural Inhibitors to Respiratory Complex I
by Jonathan Schiller and Volker Zickermann
Pharmaceuticals 2022, 15(9), 1088; https://doi.org/10.3390/ph15091088 - 31 Aug 2022
Cited by 8 | Viewed by 3069
Abstract
NADH:ubiquinone oxidoreductase (respiratory complex I) is a redox-driven proton pump with a central role in mitochondrial oxidative phosphorylation. The ubiquinone reduction site of complex I is located in the matrix arm of this large protein complex and connected to the membrane via a [...] Read more.
NADH:ubiquinone oxidoreductase (respiratory complex I) is a redox-driven proton pump with a central role in mitochondrial oxidative phosphorylation. The ubiquinone reduction site of complex I is located in the matrix arm of this large protein complex and connected to the membrane via a tunnel. A variety of chemically diverse compounds are known to inhibit ubiquinone reduction by complex I. Rotenone, piericidin A, and annonaceous acetogenins are representatives of complex I inhibitors from biological sources. The structure of complex I is determined at high resolution, and inhibitor binding sites are described in detail. In this review, we summarize the state of knowledge of how natural inhibitors bind in the Q reduction site and the Q access pathway and how their inhibitory mechanisms compare with that of a synthetic anti-cancer agent. Full article
(This article belongs to the Special Issue Secondary Metabolites of Plants and its Synthetic Derivatives in Cellular and Molecular Pharmacology)
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18 pages, 5064 KiB  
Review
Structural Modifications and Biological Activities of Natural α- and β-Cembrenediol: A Comprehensive Review
by Kuo Xu, Xinying Du, Xia Ren, XiuXue Li, Hui Li, Xianjun Fu and Xiaoyi Wei
Pharmaceuticals 2022, 15(5), 601; https://doi.org/10.3390/ph15050601 - 13 May 2022
Cited by 4 | Viewed by 3552
Abstract
As one of the most characteristic ingredients of glandular trichome secretions from Nicotiana tabacum L. (tobacco), natural cembrenediols, namely, (1S,2E,4S,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (α-cembrenediol/α-CBD) and its C-4 epimer (β-cembrenediol/β-CBD), have attracted considerable attention for [...] Read more.
As one of the most characteristic ingredients of glandular trichome secretions from Nicotiana tabacum L. (tobacco), natural cembrenediols, namely, (1S,2E,4S,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (α-cembrenediol/α-CBD) and its C-4 epimer (β-cembrenediol/β-CBD), have attracted considerable attention for their potent antitumor, neuroprotective, antimicrobial, and other activities. Many researchers are committed to exploring the possibility of utilizing these two cembrenediols and their derivatives both in human medicine and in agricultural fungicides. To the best of our knowledge, this review is the first to provide a comprehensive summary of the chemical modifications and bioactivities of α- and β-CBD from their discovery to the present day; the review highlights their potential medicinal value for humans. The extensive references from 1962 to 2022 provided herein were systematically gathered from the SciFinder, Web of Science, and Google Scholar databases. We expect this review to assist in providing practical ideas for future drug development based on α- and β-CBD and in further facilitating the utilization of the tobacco cembrenediols. Full article
(This article belongs to the Special Issue Secondary Metabolites of Plants and its Synthetic Derivatives in Cellular and Molecular Pharmacology)
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