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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 60353

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Prof. Dr. Eduardo Sobarzo-Sánchez

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1. Instituto de Investigación y Postgrado, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago 8370292, Chile
2. Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15705 Santiago de Compostela, Spain
Interests: drug delivery systems; medicinal chemistry; natural products
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Special Issue Information

Dear Colleagues,

In antiquity, diverse natural compounds were used to treat several ailments and chronic diseases and were recognized for their therapeutic properties in folklore medicine. These compounds have heterogeneous chemical structure and varied pharmacological activity, being useful in the treatment of diseases of high complexity such as Parkinson’s disease, Alzheimer's disease, and others. Notwithstanding, at the present time, commercial drugs are in many cases aspecific and present side effects that increase pain or malaise in patients. It has been observed that some chemical structures, such as quinone, are present in many compounds and are associated with successful medical treatment. Thus, extended carbon systems with planar moieties that favor their intercalation among aminoacid residues and specific receptors of certain pathogens seem to be key to generating effective drugs. Many researchers are studying how to incorporate quinone moieties in complex chemical structures by large-scale organic synthesis; at the same time, they are interested in discovering new natural products with effective medical applications. The interest in these drugs is especially related to the treatment of the so-called chronic diseases, which include allergies, neurodegenerative disorders like Alzheimer's disease, asthma, cancer, diabetes, epilepsy, heart disease, etc..

Therefore, the aim of this Special Issue, is to collect diverse research articles and reviews describing the possible and future therapeutic applications of compounds or commercial medicines, as well as their synthesis and isolation (if natural products); of interest are also theoretical studies of structure–activity relationships of heterocycle and hydrocarbon compounds that incorporate active fragments/moieties of natural products and are being tested for their possible application in the treatment of chronic diseases. The critical and objective perspective offered by these contributions will help us to appreciate and emphasize the latest advances in the field of organic and medicinal chemistry.

Prof. Dr. Eduardo Sobarzo-Sánchez
Guest Editor

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Keywords

Chronic disease
Natural products
Neurodegenerative diseases
Antinociceptive drug
Drug delivery system

Published Papers (11 papers)

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Research

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21 pages, 2154 KiB

Open AccessArticle

Chemical Fingerprinting and Biological Evaluation of the Endemic Chilean Fruit Greigia sphacelata (Ruiz and Pav.) Regel (Bromeliaceae) by UHPLC-PDA-Orbitrap-Mass Spectrometry

by Ruth E. Barrientos, Shakeel Ahmed, Carmen Cortés, Carlos Fernández-Galleguillos, Javier Romero-Parra, Mario J. Simirgiotis and Javier Echeverría

Molecules 2020, 25(16), 3750; https://doi.org/10.3390/molecules25163750 - 17 Aug 2020

Cited by 16 | Viewed by 3118

Abstract

Greigia sphacelata (Ruiz and Pav.) Regel (Bromeliaceae) is a Chilean endemic plant popularly known as “quiscal” and produces an edible fruit consumed by the local Mapuche communities named as “chupón”. In this study, several metabolites including phenolic acids, organic acids, sugar derivatives, catechins, proanthocyanidins, fatty acids, iridoids, coumarins, benzophenone, flavonoids, and terpenes were identified in G. sphacelata fruits using ultrahigh performance liquid chromatography-photodiode array detection coupled with a Orbitrap mass spectrometry (UHPLC-PDA-Orbitrap-MS) analysis for the first time. The fruits showed moderate antioxidant capacities (i.e., 487.11 ± 26.22 μmol TE/g dry weight) in the stable radical DPPH assay, 169.08 ± 9.81 TE/g dry weight in the ferric reducing power assay, 190.32 ± 6.23 TE/g dry weight in the ABTS assay, and 76.46 ± 3.18% inhibition in the superoxide anion scavenging assay. The cholinesterase inhibitory potential was evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). From the findings, promising results were observed for pulp and seeds. Our findings suggest that G. sphacelata fruits are a rich source of diverse secondary metabolites with antioxidant capacities. In addition, the inhibitory effects against AChE and BChE suggest that natural products or food supplements derived from G. sphacelata fruits are of interest for their neuroprotective potential. Full article

(This article belongs to the Special Issue Natural Products for Neurodegenerative Diseases)

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10 pages, 1936 KiB

Open AccessArticle

Sedative Effects of Latexes Obtained from Some Lactuca L. Species Growing in Turkey

by Selen Ilgün, Esra Küpeli Akkol, Mert Ilhan, Derya Çiçek Polat, Ayse Baldemir Kılıç, Maksut Coşkun and Eduardo Sobarzo-Sánchez

Molecules 2020, 25(7), 1587; https://doi.org/10.3390/molecules25071587 - 30 Mar 2020

Cited by 10 | Viewed by 4166

Abstract

Lactuca L. species belong to the Asteraceae family and these plants are traditionally used for therapeutic purposes around the world. The dried milky latex of L. serriola is known as “lettuce oil” and is used as a sedative in Turkey. This study aimed to evaluate the sedative effects and analyze the chemical compositions of latexes obtained from some Lactuca species growing in Turkey. The sedative effects were evaluated through various behavioral tests on mice. For this purpose, latexes were obtained from L. glareosa Boiss., L. viminea (L.) J. Presl and C. P, L. mulgedioides (Vis and Panćić) Boiss. and Kotschy ex. Boiss., L. saligna L., and L. serriola L. The latex from L. saligna showed the highest sedative effects, whilst L. serriola and L. viminea latexes also displayed significant sedative effects compared to the control group at a dose of 100 mg/kg. However, the latexes from L. glareosa and L. mulqedioides did not exhibit any sedative effects on mice. Characteristic sesquiterpene lactones (lactucin, lactucopicrin, 11,13β-dihydrolactucin, and 11,13β-dihydrolactucopicrin) were determined qualitatively and quantitatively by high-performance liquid chromatography (HPLC). Lactucin was identified as the main component. Full article

(This article belongs to the Special Issue Natural Products for Neurodegenerative Diseases)

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11 pages, 437 KiB

Open AccessFeature PaperArticle

Antidepressant Potential of Lotus corniculatus L. subsp. corniculatus: An Ethnobotany Based Approach

by Fatma Tuğçe Gürağaç Dereli, Haroon Khan, Eduardo Sobarzo-Sánchez and Esra Küpeli Akkol

Molecules 2020, 25(6), 1299; https://doi.org/10.3390/molecules25061299 - 12 Mar 2020

Cited by 6 | Viewed by 3012

Abstract

As a Turkish traditional medicinal plant, aerial parts of Lotus corniculatus L. subsp. corniculatus (Fabaceae) are used as a painkiller, antihemoroidal, diuretic and sedative. In this study, the antidepressant potential of the plant has been attempted to clarify. Extracts with water, n-Hexane, ethyl acetate, and methanol were prepared respectively from the aerial parts. Antidepressant activity of the extracts were researched by using three different in vivo test models namely a tail suspension test, antagonism of tetrabenazine-induced hypothermia, ptosis, and suppression of locomotor activity and forced swimming test on male BALB/c mice and in vitro monoamine oxidase (MAO)-A and B inhibition assays. The results were evaluated through comparing with control and reference groups, and then active compounds of the active extract have been determined. Bioassay-guided fractionation of active fraction led to the isolation of three compounds and structures of the compounds were elucidated by spectroscopic methods. The data of this study demonstrate that the MeOH extract of the aerial parts of the plant showed remarkable in vivo antidepressant effect and the isolated compounds medicarpin-3-O-glucoside, gossypetin-3-O-glucoside and naringenin-7-O-glucoside (prunin) from the active sub-fractions could be responsible for the activity. Further mechanistic and toxicity studies are planned to develop new antidepressant-acting drugs. Full article

(This article belongs to the Special Issue Natural Products for Neurodegenerative Diseases)

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17 pages, 5263 KiB

Open AccessArticle

Vitamin B Complex Treatment Attenuates Local Inflammation after Peripheral Nerve Injury

by Adil Ehmedah, Predrag Nedeljkovic, Sanja Dacic, Jelena Repac, Biljana Draskovic Pavlovic, Dragana Vucevic, Sanja Pekovic and Biljana Bozic Nedeljkovic

Molecules 2019, 24(24), 4615; https://doi.org/10.3390/molecules24244615 - 17 Dec 2019

Cited by 28 | Viewed by 6452

Abstract

Peripheral nerve injury (PNI) leads to a series of cellular and molecular events necessary for axon regeneration and reinnervation of target tissues, among which inflammation is crucial for the orchestration of all these processes. Macrophage activation underlies the pathogenesis of PNI and is characterized by morphological/phenotype transformation from proinflammatory (M1) to an anti-inflammatory (M2) type with different functions in the inflammatory and reparative process. The aim of this study was to evaluate influence of the vitamin B (B1, B2, B3, B5, B6, and B12) complex on the process of neuroinflammation that is in part regulated by l-type Ca_V1.2 calcium channels. A controlled transection of the motor branch of the femoral peripheral nerve was used as an experimental model. Animals were sacrificed after 1, 3, 7, and 14 injections of vitamin B complex. Isolated nerves were used for immunofluorescence analysis. Treatment with vitamin B complex decreased expression of proinflammatory and increased expression of anti-inflammatory cytokines, thus contributing to the resolution of neuroinflammation. In parallel, B vitamins decreased the number of M1 macrophages that expressed the Ca_V1.2 channel, and increased the number of M2 macrophages that expressed this channel, suggesting their role in M1/M2 transition after PNI. In conclusion, B vitamins had the potential for treatment of neuroinflammation and neuroregeneration and thereby might be an effective therapy for PNI in humans. Full article

(This article belongs to the Special Issue Natural Products for Neurodegenerative Diseases)

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16 pages, 2668 KiB

Open AccessArticle

Ginsenoside Re Inhibits ROS/ASK-1 Dependent Mitochondrial Apoptosis Pathway and Activation of Nrf2-Antioxidant Response in Beta-Amyloid-Challenged SH-SY5Y Cells

by Meichen Liu, Xueyuan Bai, Shiting Yu, Wenxue Zhao, Juhui Qiao, Ying Liu, Daqing Zhao, Jiawen Wang and Siming Wang

Molecules 2019, 24(15), 2687; https://doi.org/10.3390/molecules24152687 - 24 Jul 2019

Cited by 65 | Viewed by 7780

Abstract

Accumulation of amyloid-β (Aβ), which results in the formation of senile plaques that cause oxidative damage and neuronal cell death, has been accepted as the major pathological mechanism of Alzheimer’s disease (AD). Hence, inhibition of Aβ-induced oxidative damage and neuronal cell apoptosis represents the effective strategies in combating AD. Ginsenoside Re (Re) has pharmacological effects against Aβ-induced neurotoxicity. However, its molecular mechanism remains elusive. The present study evaluated the effect of Re against Aβ-induced cytotoxicity and apoptosis in SH-SY5Y cells, and investigated the underlying mechanism. We demonstrate that Re inhibits the Aβ-triggered mitochondrial apoptotic pathway, as indicated by maintenance of mitochondrial functional, elevated Bcl-2/Bax ratio, reduced cytochrome c release, and inactivation of caspase-3/9. Re attenuated Aβ-evoked reactive oxygen species (ROS) production, apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, and JNK activation. ROS-scavenging abrogated the ability of Re to alter ASK-1 activation. Simultaneously, inhibition of JNK abolished Re-induced Bax downregulation in Aβ-challenged SH-SY5Y cells. In addition, Re enhanced activation of the nuclear factor-E2-related factor 2 (Nrf2) in Aβ-induced SH-SY5Y cells. Knockdown of Nrf2 by small interfering RNA targeting Nrf2 abolished the protective effect of Re. Our findings indicate that Re could be a potential therapeutic approach for the treatment of AD. Full article

(This article belongs to the Special Issue Natural Products for Neurodegenerative Diseases)

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20 pages, 13879 KiB

Open AccessArticle

Lycopodium Attenuates Loss of Dopaminergic Neurons by Suppressing Oxidative Stress and Neuroinflammation in a Rat Model of Parkinson’s Disease

by Richard L. Jayaraj, Rami Beiram, Sheikh Azimullah, Mohamed Fizur Nagoor Meeran, Shreesh K. Ojha, Abdu Adem and Fakhreya Yousuf Jalal

Molecules 2019, 24(11), 2182; https://doi.org/10.3390/molecules24112182 - 10 Jun 2019

Cited by 29 | Viewed by 7829

Abstract

Parkinson’s disease, a chronic, age related neurodegenerative disorder, is characterized by a progressive loss of nigrostriatal dopaminergic neurons. Several studies have proven that the activation of glial cells, presence of alpha-synuclein aggregates, and oxidative stress, fuels neurodegeneration, and currently there is no definitive treatment for PD. In this study, a rotenone-induced rat model of PD was used to understand the neuroprotective potential of Lycopodium (Lyc), a commonly-used potent herbal medicine. Immunohistochemcial data showed that rotenone injections significantly increased the loss of dopaminergic neurons in the substantia nigra, and decreased the striatal expression of tyrosine hydroxylase. Further, rotenone administration activated microglia and astroglia, which in turn upregulated the expression of α-synuclein, pro-inflammatory, and oxidative stress factors, resulting in PD pathology. However, rotenone-injected rats that were orally treated with lycopodium (50 mg/kg) were protected against dopaminergic neuronal loss by diminishing the expression of matrix metalloproteinase-3 (MMP-3) and MMP-9, as well as reduced activation of microglia and astrocytes. This neuroprotective mechanism not only involves reduction in pro-inflammatory response and α-synuclein expression, but also synergistically enhanced antioxidant defense system by virtue of the drug’s multimodal action. These findings suggest that Lyc has the potential to be further developed as a therapeutic candidate for PD. Full article

(This article belongs to the Special Issue Natural Products for Neurodegenerative Diseases)

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13 pages, 659 KiB

Open AccessArticle

Assessment of Antidepressant Effect of the Aerial Parts of Micromeria myrtifolia Boiss. & Hohen on Mice

by Esra Küpeli Akkol, Fatma Tuğçe Gürağaç Dereli and Mert Ilhan

Molecules 2019, 24(10), 1869; https://doi.org/10.3390/molecules24101869 - 15 May 2019

Cited by 15 | Viewed by 3397

Abstract

The currently available antidepressant agents necessitate the development of newer alternatives because of their serious adverse effects and costs. Traditional medicinal knowledge is likely the key that opens the door to discover new medicines. In Turkish folk medicine, the infusion prepared from aerial parts of Micromeria myrtifolia Boiss. & Hohen is used as pleasure and medicinal tea for its relaxing action. The present research was conceived to confirm the antidepressant’s potential of this traditional medicinal plant. In this process, first of all, the collected and shade-dried aerial parts of M. myrtifolia were powdered and then, extracted using solvents with different polarity as follows; n-hexane, ethyl acetate (EtOAc), and methanol (MeOH). The antidepressant activity of the extracts was evaluated by using several in vivo and in vitro experimental models of depression. When the data obtained from the control and experimental groups were compared, it was determined that the MeOH extract was the most active. The active components of this extract were isolated and identified utilizing various chromatographic separation techniques. The MeOH extract was applied to reversed phase (RP-18) column chromatography to obtain five main fractions and they were tested on antidepressant activity models. The isolated compounds from the obtained fractions were elucidated as rosmarinic acid (1), myricetin (2), apigenin (3), and naringenin (4) which were assumed to be responsible for the antidepressant activity of the aerial parts. According to the results, rosmarinic acid, myricetin, apigenin, and naringenin showed statistically significant activity on forced swimming test and tetrabenazine-induced ptosis models, whereas only rosmarinic acid showed statistically significant activity on the tail suspension test. Apigenin displayed the highest inhibitory activity on MAO A and B enzymes. Studies in the future should be performed to investigate the antidepressant activity mechanism of these natural compounds. The current research could be an important step in the development of the new agents that can be used in the treatment of depression. Full article

(This article belongs to the Special Issue Natural Products for Neurodegenerative Diseases)

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15 pages, 6565 KiB

Open AccessArticle

Systems Pharmacological Approach to Investigate the Mechanism of Ohwia caudata for Application to Alzheimer’s Disease

by Yi-wei Sun, Yue Wang, Zi-feng Guo, Kai-cheng Du and Da-li Meng

Molecules 2019, 24(8), 1499; https://doi.org/10.3390/molecules24081499 - 17 Apr 2019

Cited by 12 | Viewed by 4079

Abstract

Ohwia caudata (OC)—a traditional Chinese medicine (TCM)—has been reported to have large numbers of flavonoids, alkaloids, and triterpenoids. The previous studies on OC for treating Alzheimer’s disease (AD) only focused on single targets and its mechanisms, while no report had shown about the synergistic mechanism of the constituents from OC related to their potential treatment on dementia in any database. This study aimed to predict the bioactive targets constituents and find potential compounds from OC with better oral bioavailability and blood–brain barrier permeability against AD, by using a system network level-based in silico approach. The results revealed that two new flavonoids, and another 26 compounds isolated from OC in our lab, were highly connected to AD-related signaling pathways and biological processes, which were confirmed by compound–target network, Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, respectively. Predicted by the virtual screening and various network pharmacology methods, we found the multiple mechanisms of OC, which are effective for alleviating AD symptoms through multiple targets in a synergetic way. Full article

(This article belongs to the Special Issue Natural Products for Neurodegenerative Diseases)

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Review

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30 pages, 3252 KiB

Open AccessReview

Oxoisoaporphines and Aporphines: Versatile Molecules with Anticancer Effects

by Esteban Rodríguez-Arce, Patricio Cancino, Manuel Arias-Calderón, Paul Silva-Matus and Marianela Saldías

Molecules 2020, 25(1), 108; https://doi.org/10.3390/molecules25010108 - 27 Dec 2019

Cited by 12 | Viewed by 4772

Abstract

Cancer is a disease that involves impaired genome stability with a high mortality index globally. Since its discovery, many have searched for effective treatment, assessing different molecules for their anticancer activity. One of the most studied sources for anticancer therapy is natural compounds and their derivates, like alkaloids, which are organic molecules containing nitrogen atoms in their structure. Among them, oxoisoaporphine and sampangine compounds are receiving increased attention due to their potential anticancer effects. Boldine has also been tested as an anticancer molecule. Boldine is the primary alkaloid extract from boldo, an endemic tree in Chile. These compounds and their derivatives have unique structural properties that potentially have an anticancer mechanism. Different studies showed that this molecule can target cancer cells through several mechanisms, including reactive oxygen species generation, DNA binding, and telomerase enzyme inhibition. In this review, we summarize the state-of-art research related to oxoisoaporphine, sampangine, and boldine, with emphasis on their structural characteristics and the relationship between structure, activity, methods of extraction or synthesis, and anticancer mechanism. With an effective cancer therapy still lacking, these three compounds are good candidates for new anticancer research. Full article

(This article belongs to the Special Issue Natural Products for Neurodegenerative Diseases)

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23 pages, 1417 KiB

Open AccessReview

Glycan Mimetics from Natural Products: New Therapeutic Opportunities for Neurodegenerative Disease

by Wenyue Wang, Sandeep Gopal, Roger Pocock and Zhicheng Xiao

Molecules 2019, 24(24), 4604; https://doi.org/10.3390/molecules24244604 - 16 Dec 2019

Cited by 21 | Viewed by 4645

Abstract

Neurodegenerative diseases (NDs) affect millions of people worldwide. Characterized by the functional loss and death of neurons, NDs lead to symptoms (dementia and seizures) that affect the daily lives of patients. In spite of extensive research into NDs, the number of approved drugs for their treatment remains limited. There is therefore an urgent need to develop new approaches for the prevention and treatment of NDs. Glycans (carbohydrate chains) are ubiquitous, abundant, and structural complex natural biopolymers. Glycans often covalently attach to proteins and lipids to regulate cellular recognition, adhesion, and signaling. The importance of glycans in both the developing and mature nervous system is well characterized. Moreover, glycan dysregulation has been observed in NDs such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Therefore, glycans are promising but underexploited therapeutic targets. In this review, we summarize the current understanding of glycans in NDs. We also discuss a number of natural products that functionally mimic glycans to protect neurons, which therefore represent promising new therapeutic approaches for patients with NDs. Full article

(This article belongs to the Special Issue Natural Products for Neurodegenerative Diseases)

19 pages, 1744 KiB

Open AccessReview

The Neuroprotective Effects of Astaxanthin: Therapeutic Targets and Clinical Perspective

by Sajad Fakhri, Ina Yosifova Aneva, Mohammad Hosein Farzaei and Eduardo Sobarzo-Sánchez

Molecules 2019, 24(14), 2640; https://doi.org/10.3390/molecules24142640 - 20 Jul 2019

Cited by 94 | Viewed by 9812

Abstract

As the leading causes of human disability and mortality, neurological diseases affect millions of people worldwide and are on the rise. Although the general roles of several signaling pathways in the pathogenesis of neurodegenerative disorders have so far been identified, the exact pathophysiology of neuronal disorders and their effective treatments have not yet been precisely elucidated. This requires multi-target treatments, which should simultaneously attenuate neuronal inflammation, oxidative stress, and apoptosis. In this regard, astaxanthin (AST) has gained growing interest as a multi-target pharmacological agent against neurological disorders including Parkinson’s disease (PD), Alzheimer’s disease (AD), brain and spinal cord injuries, neuropathic pain (NP), aging, depression, and autism. The present review highlights the neuroprotective effects of AST mainly based on its anti-inflammatory, antioxidative, and anti-apoptotic properties that underlies its pharmacological mechanisms of action to tackle neurodegeneration. The need to develop novel AST delivery systems, including nanoformulations, targeted therapy, and beyond, is also considered. Full article

(This article belongs to the Special Issue Natural Products for Neurodegenerative Diseases)

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