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Terpenes and Terpenoids As Therapeutic Drugs: Molecular Pharmacology and Toxicology

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

Deadline for manuscript submissions: closed (24 February 2023) | Viewed by 14342

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Special Issue Editors

Prof. Dr. Olga Yarovaya

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Guest Editor

Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Interests: medicinal chemistry; chemistry of natural compounds; terpenes; virology; analytical chemistry in preclinical research; natural product chemistry; synthesis of heterocycles
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Irina Sorokina

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Guest Editor

Doctor of Biological Sciences, Leading Researcher of the Laboratory of Pharmacological Researches of the N.N. Department of Medicinal Chemistry, Vorozhtsov Novosibirsk Institute of Organic Chemistry of Siberian, Branch of Russian Academy of Science, Novosibirsk, Russia
Interests: plant metabolites; triterpenoids; betulonic acid; signaling pathways; molecular targets; malignant tumors; polychemotherapy; inflammation; immunomodulators; chemoprevention; hepatotoxisity; antioxidant; neurodegeneration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Terpenes and their metabolites are the largest class of organic compounds, widely distributed in plants as members of the defense system. Since the 1990s, when some lupane and oleanane triterpenoids were found to have selective antitumor and antiviral activity, extensive studies have been undertaken on the molecular mechanisms of these natural compounds and their synthetic derivatives. It was found that terpenes interact with key proteins of different signaling networks that regulate the activity of transcription factors and, following gene expression, manage cell adaptation in normal and pathological conditions. Depending upon the dose administered, triterpenoids induce anti-inflammatory, cytoprotective, tumor-differentiating, proliferation-arresting, and apoptotic effects. The inhibition of multiple targets by triterpenoids is mediated by the reversible Michael addition of these compounds to exposed nucleophilic groups (such as accessible cysteine sulfides) of various susceptible signaling proteins. The Nrf2 and NFκB pathways are the main pathways through which terpenoid molecules can modulate redox status, cell differentiation, mitochondrial function, drug metabolism, inflammation, and tissue regeneration. Recently, antispasmodic, analgesic, antiparkinsonian, hypolipidemic, antidiabetic agents were found in this class of compounds. Owing to these studies, terpenes and terpenoids are now recognized as prospective natural scaffolds for the development of poly-target modulators for chemoprevention and the therapy of various diseases. Particular attention should be paid to the synthesis of derivatives with antiviral activity, especially during current COVID-19 pandemic.

We welcome submissions that cover, but are not limited to, the following topics concerning medical applications of terpenes, terpenoids and their derivatives:

increasing the efficiency and reducing the side effects of conventional anticancer drugs;
mechanisms of cancer chemoprevention;
tumor immunotherapy;
antiviral, antiparasitic and antibacterial infections;
chronic and autoimmune inflammation;
neurological disorders, neurodegeneration;
metabolic disorders (hyperlipidemia, glucose tolerance, fibrosis, ischemia);
preclinical studies of derivatives of terpenoids.

Prof. Dr. Olga Yarovaya
Prof. Dr. Irina Sorokina
Guest Editors

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

terpenes
terpenoids
molecular targets
cancer
neurodegeneration
viral infection
immunomodulation
chemoprevention

Published Papers (5 papers)

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Research

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20 pages, 15393 KiB

Open AccessArticle

Discovery of N-Containing (-)-Borneol Esters as Respiratory Syncytial Virus Fusion Inhibitors

by Anastasiya S. Sokolova, Olga I. Yarovaya, Lana V. Kuzminykh, Anna A. Shtro, Artem M. Klabukov, Anastasia V. Galochkina, Yulia V. Nikolaeva, Galina D. Petukhova, Sophia S. Borisevich, Edward M. Khamitov and Nariman F. Salakhutdinov

Pharmaceuticals 2022, 15(11), 1390; https://doi.org/10.3390/ph15111390 - 11 Nov 2022

Cited by 10 | Viewed by 1560

Abstract

Respiratory syncytial virus (RSV) causes acute respiratory infections, thus, posing a serious threat to the health of infants, children, and elderly people. In this study, we have discovered a series of potent RSV entry inhibitors with the (-)-borneol scaffold. The active compounds 3b, 5a, 5c, 7b, 9c, 10b, 10c, and 14b were found to exhibit activity against RSV A strain A2 in HEp-2 cells. The most active substances, 3b (IC₅₀ = 8.9 μM, SI = 111) and 5a (IC₅₀ = 5.0 μM, SI = 83), displayed more potency than the known antiviral agent Ribavirin (IC₅₀ = 80.0 μM, SI = 50). Time-of-addition assay and temperature shift studies demonstrated that compounds 3b, 5a, and 6b inhibited RSV entry, probably by interacting with the viral F protein that mediated membrane fusion, while they neither bound to G protein nor inhibited RSV attachment to the target cells. Appling procedures of molecular modeling and molecular dynamics, the binding mode of compounds 3b and 5a was proposed. Taken together, the results of this study suggest (-)-borneol esters to be promising lead compounds for developing new anti-RSV agents. Full article

(This article belongs to the Special Issue Terpenes and Terpenoids As Therapeutic Drugs: Molecular Pharmacology and Toxicology)

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22 pages, 20288 KiB

Open AccessArticle

The Anti-Melanoma Effect of Betulinic Acid Functionalized Gold Nanoparticles: A Mechanistic In Vitro Approach

by Roxana Ghiulai, Alexandra Mioc, Roxana Racoviceanu, Marius Mioc, Andreea Milan, Alexandra Prodea, Alexandra Semenescu, Cristina Dehelean, Lucian Barbu Tudoran, Ștefana Avram, Cristina Trandafirescu and Codruța Șoica

Pharmaceuticals 2022, 15(11), 1362; https://doi.org/10.3390/ph15111362 - 5 Nov 2022

Cited by 4 | Viewed by 2150

Abstract

Implementing metallic nanoparticles as research instruments for the transport of therapeutically active compounds remains a fundamentally vital work direction that can still potentially generate novelties in the field of drug formulation development. Gold nanoparticles (GNP) are easily tunable carriers for active phytocompounds like pentacyclic triterpenes. These formulations can boost the bioavailability of a lipophilic structure and, in some instances, can also enhance its therapeutic efficacy. In our work, we proposed a biological in vitro assessment of betulinic acid (BA)-functionalized GNP. BA-GNP were obtained by grafting BA onto previously synthesized citrate-capped GNP through the use of cysteamine as a linker. The nanoformulation was tested in HaCaT human keratinocytes and RPMI-7951 human melanoma cells, revealing selective cytotoxic properties and stronger antiproliferative effects compared to free BA. Further examinations revealed a pro-apoptotic effect, as evidenced by morphological changes in melanoma cells and supported by western blot data showing the downregulation of anti-apoptotic Bcl-2 expression coupled with the upregulation of pro-apoptotic Bax. GNP also significantly inhibited mitochondrial respiration, confirming its mitochondrial-targeted activity. Full article

(This article belongs to the Special Issue Terpenes and Terpenoids As Therapeutic Drugs: Molecular Pharmacology and Toxicology)

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20 pages, 82590 KiB

Open AccessArticle

Asperuloside Prevents Peri-Implantitis via Suppression of NF-κB and ERK1/2 on Rats

by Xinge Wang, Xutao Chen, Zhaoxin Zhang, Ji Chen, Zeyang Ge, Shitou Huang, Hongbo Wei and Dehua Li

Pharmaceuticals 2022, 15(8), 1027; https://doi.org/10.3390/ph15081027 - 20 Aug 2022

Cited by 3 | Viewed by 2000

Abstract

Peri-implantitis is characterized by inflammatory cell infiltration and hyperactivation of the osteoclasts surrounding dental implants which can result in bone resorption and ultimately implant failure. Therefore, coordinating the activity of inflammatory response and bone-resorbing osteoclasts is crucial for the prevention of peri-implantitis. Asperuloside (ASP), an iridoid glycoside, has significant anti-inflammatory activities, suggesting the great potential in attenuating peri-implantitis bone resorption. A ligature-induced peri-implantitis model in the maxilla of rats was established, and the effects of ASP on preventing peri-implantitis were evaluated after four weeks of ligation using micro-CT and histological staining. RT-PCR, western blotting, tartrate-resistant acid phosphatase (TRAP), and immunofluorescent staining were conducted on osteoclasts to confirm the mechanisms of ASP on osteoclastogenesis. The results show that ASP could lead to attenuation of alveolar bone resorption in peri-implantitis by inhibiting osteoclast formation and decreasing pro-inflammatory cytokine levels in vivo. Furthermore, ASP could inhibit osteoclastogenesis by downregulating expression levels of transcription factors nuclear factor of activated T-cell (NFATc1) via restraining the activations of nuclear factor kappa beta (NF-κB) and the phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2). In conclusion, ASP could significantly attenuate bone resorption in peri-implantitis via inhibition of osteoclastogenesis by suppressing NF-κB and ERK1/2 signaling pathways activations. Full article

(This article belongs to the Special Issue Terpenes and Terpenoids As Therapeutic Drugs: Molecular Pharmacology and Toxicology)

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34 pages, 7875 KiB

Open AccessArticle

Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo

by Andrey V. Markov, Anna A. Ilyina, Oksana V. Salomatina, Aleksandra V. Sen’kova, Alina A. Okhina, Artem D. Rogachev, Nariman F. Salakhutdinov and Marina A. Zenkova

Pharmaceuticals 2022, 15(5), 603; https://doi.org/10.3390/ph15050603 - 14 May 2022

Cited by 4 | Viewed by 2616

Abstract

The modification of natural or semisynthetic triterpenoids with amines can be explored as a promising strategy for improving their pharmacological properties. Here, we report the design and synthesis of 11 novel amide derivatives of soloxolone methyl (SM), a cyano enone-bearing derivative of 18βH-glycyrrhetinic acid. Analysis of their bioactivities in vitro and in silico revealed their high toxicity against a panel of tumor cells (average IC₅₀^(24h) = 3.7 µM) and showed that the formation of amide moieties at the C-30 position of soloxolone did not enhance the cytotoxicity of derivatives toward tumor cells compared to SM, though it can impart an ability to pass across the blood–brain barrier. Further HPLC–MS/MS and mechanistic studies verified significant brain accumulation of hit compound 12 (soloxolone tryptamide) in a murine model and showed its high anti-glioblastoma potential. It was found that 12 induced ROS-dependent and autophagy-independent death of U87 and U118 glioblastoma cells via mitochondrial apoptosis and effectively blocked their clonogenicity, motility and capacity to form vessel-like structures. Further in vivo study demonstrated that intraperitoneal injection of 12 at a dosage of 20 mg/kg effectively inhibited the growth of U87 glioblastoma in a mouse xenograft model, reducing the proliferative potential of the tumor and leading to a depletion of collagen content and normalization of blood vessels in tumor tissue. The obtained results clearly demonstrate that 12 can be considered as a promising leading compound for drug development in glioblastoma treatment. Full article

(This article belongs to the Special Issue Terpenes and Terpenoids As Therapeutic Drugs: Molecular Pharmacology and Toxicology)

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Review

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96 pages, 28601 KiB

Open AccessReview

Total Synthesis of Terpenes and Their Biological Significance: A Critical Review

by Aqsa Kanwal, Muhammad Bilal, Nasir Rasool, Muhammad Zubair, Syed Adnan Ali Shah and Zainul Amiruddin Zakaria

Pharmaceuticals 2022, 15(11), 1392; https://doi.org/10.3390/ph15111392 - 11 Nov 2022

Cited by 2 | Viewed by 4823

Abstract

Terpenes are a group of natural products made up of molecules with the formula (C₅H₈)_n that are typically found in plants. They are widely employed in the medicinal, flavor, and fragrance industries. The total synthesis of terpenes as [...] Read more.

(This article belongs to the Special Issue Terpenes and Terpenoids As Therapeutic Drugs: Molecular Pharmacology and Toxicology)

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