Research

13 pages, 1614 KiB

Open AccessArticle

A New Oxadiazole-Based Topsentin Derivative Modulates Cyclin-Dependent Kinase 1 Expression and Exerts Cytotoxic Effects on Pancreatic Cancer Cells

by Camilla Pecoraro, Barbara Parrino, Stella Cascioferro, Adrian Puerta, Amir Avan, Godefridus J. Peters, Patrizia Diana, Elisa Giovannetti and Daniela Carbone

Molecules 2022, 27(1), 19; https://doi.org/10.3390/molecules27010019 - 21 Dec 2021

Cited by 28 | Viewed by 3072

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal form of cancer characterized by drug resistance, urging new therapeutic strategies. In recent years, protein kinases have emerged as promising pharmacological targets for the treatment of several solid and hematological tumors. Interestingly, cyclin-dependent kinase 1 [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal form of cancer characterized by drug resistance, urging new therapeutic strategies. In recent years, protein kinases have emerged as promising pharmacological targets for the treatment of several solid and hematological tumors. Interestingly, cyclin-dependent kinase 1 (CDK1) is overexpressed in PDAC tissues and has been correlated to the aggressive nature of these tumors because of its key role in cell cycle progression and resistance to the induction of apoptosis. For these reasons, CDK1 is one of the main causes of chemoresistance, representing a promising pharmacological target. In this study, we report the synthesis of new 1,2,4-oxadiazole compounds and evaluate their ability to inhibit the cell growth of PATU-T, Hs766T, and HPAF-II cell lines and a primary PDAC cell culture (PDAC3). Compound 6b was the most active compound, with IC₅₀ values ranging from 5.7 to 10.7 µM. Molecular docking of 6b into the active site of CDK1 showed the ability of the compound to interact effectively with the adenosine triphosphate binding pocket. Therefore, we assessed its ability to induce apoptosis (which increased 1.5- and 2-fold in PATU-T and PDAC3 cells, respectively) and to inhibit CDK1 expression, which was reduced to 45% in Hs766T. Lastly, compound 6b passed the ADME prediction, showing good pharmacokinetic parameters. These data demonstrate that 6b displays cytotoxic activity, induces apoptosis, and targets CDK1, supporting further studies for the development of similar compounds against PDAC. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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Review

Jump to: Research, Other

111 pages, 50769 KiB

Open AccessReview

Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

by János Marton, Anikó Fekete, Paul Cumming, Sándor Hosztafi, Pál Mikecz and Gjermund Henriksen

Molecules 2022, 27(9), 2863; https://doi.org/10.3390/molecules27092863 - 30 Apr 2022

Cited by 5 | Viewed by 3007

Abstract

6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ligands in which the 6,14-etheno bridged structural motif [...] Read more.

6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ligands in which the 6,14-etheno bridged structural motif originates from a [4 + 2] cycloaddition of morphinan-6,8-dienes with dienophiles. Certain 6,14-ethenomorphinans having extremely high affinity for opioid receptors are often non-selective for opioid receptor subtypes, but this view is now undergoing some revision. The agonist 20R-etorphine and 20R-dihydroetorphine are several thousand times more potent analgesics than morphine, whereas diprenorphine is a high-affinity non-selective antagonist. The partial agonist buprenorphine is used as an analgesic in the management of post-operative pain or in substitution therapy for opiate addiction, sometimes in combination with the non-selective antagonist naloxone. In the context of the current opioid crisis, we communicated a summary of several decades of work toward generating opioid analgesics with lesser side effects or abuse potential. Our summary placed a focus on Diels–Alder reactions of morphinan-6,8-dienes and subsequent transformations of the cycloadducts. We also summarized the pharmacological aspects of radiolabeled 6,14-ethenomorphinans used in molecular imaging of opioid receptors. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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38 pages, 7434 KiB

Open AccessReview

Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development, Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance

by Carlota Leonardo-Sousa, Andreia Neves Carvalho, Romina A. Guedes, Pedro M. P. Fernandes, Natália Aniceto, Jorge A. R. Salvador, Maria João Gama and Rita C. Guedes

Molecules 2022, 27(7), 2201; https://doi.org/10.3390/molecules27072201 - 28 Mar 2022

Cited by 12 | Viewed by 4389

Abstract

Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge [...] Read more.

Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literature. In this review, we discuss the development of proteasome inhibitors and the mechanisms of innate and acquired resistance to their activity—a major challenge in preclinical and clinical therapeutics. An improved understanding of these mechanisms is crucial to guiding the design of new and more effective drugs to tackle these devastating diseases. In addition, we provide a comprehensive overview of proteasome inhibitors used in combination with other chemotherapeutic agents, as this is a key strategy to combat resistance. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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15 pages, 2256 KiB

Open AccessReview

Technetium-99m Radiopharmaceuticals for Ideal Myocardial Perfusion Imaging: Lost and Found Opportunities

by Alessandra Boschi, Licia Uccelli, Lorenza Marvelli, Corrado Cittanti, Melchiore Giganti and Petra Martini

Molecules 2022, 27(4), 1188; https://doi.org/10.3390/molecules27041188 - 10 Feb 2022

Cited by 15 | Viewed by 3515

Abstract

The favorable nuclear properties in combination with the rich coordination chemistry make technetium-99m the radioisotope of choice for the development of myocardial perfusion tracers. In the early 1980s, [^99mTc]Tc-Sestamibi, [^99mTc]Tc-Tetrofosmin, and [^99mTc]Tc-Teboroxime were approved as commercial radiopharmaceuticals [...] Read more.

The favorable nuclear properties in combination with the rich coordination chemistry make technetium-99m the radioisotope of choice for the development of myocardial perfusion tracers. In the early 1980s, [^99mTc]Tc-Sestamibi, [^99mTc]Tc-Tetrofosmin, and [^99mTc]Tc-Teboroxime were approved as commercial radiopharmaceuticals for myocardial perfusion imaging in nuclear cardiology. Despite its peculiar properties, the clinical use of [^99mTc]Tc-Teboroxime was quickly abandoned due to its rapid myocardial washout. Despite their widespread clinical applications, both [^99mTc]Tc-Sestamibi and [^99mTc]Tc-Tetrofosmin do not meet the requirements of an ideal perfusion imaging agent due to their relatively low first-pass extraction fraction and high liver absorption. An ideal radiotracer for myocardial perfusion imaging should have a high myocardial uptake; a high and stable target-to-background ratio with low uptake in the lungs, liver, stomach during the image acquisition period; a high first-pass myocardial extraction fraction and very rapid blood clearance; and a linear relationship between radiotracer myocardial uptake and coronary blood flow. Although it is difficult to reconcile all these properties in a single tracer, scientific research in the field has always channeled its efforts in the development of molecules that are able to meet the characteristics of ideality as much as possible. This short review summarizes the developments in ^99mTc myocardial perfusion tracers, which are able to fulfill hitherto unmet medical needs and serve a large population of patients with heart disease, and underlines their strengths and weaknesses, the lost and found opportunities thanks to the developments of the new ultrafast SPECT technologies. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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24 pages, 2021 KiB

Open AccessReview

Alpha B-Crystallin in Muscle Disease Prevention: The Role of Physical Activity

by Ivan Dimauro and Daniela Caporossi

Molecules 2022, 27(3), 1147; https://doi.org/10.3390/molecules27031147 - 08 Feb 2022

Cited by 8 | Viewed by 3145

Abstract

HSPB5 or alpha B-crystallin (CRYAB), originally identified as lens protein, is one of the most widespread and represented of the human small heat shock proteins (sHSPs). It is greatly expressed in tissue with high rates of oxidative metabolism, such as skeletal and cardiac [...] Read more.

HSPB5 or alpha B-crystallin (CRYAB), originally identified as lens protein, is one of the most widespread and represented of the human small heat shock proteins (sHSPs). It is greatly expressed in tissue with high rates of oxidative metabolism, such as skeletal and cardiac muscles, where HSPB5 dysfunction is associated with a plethora of human diseases. Since HSPB5 has a major role in protecting muscle tissues from the alterations of protein stability (i.e., microfilaments, microtubules, and intermediate filament components), it is not surprising that this sHSP is specifically modulated by exercise. Considering the robust content and the protective function of HSPB5 in striated muscle tissues, as well as its specific response to muscle contraction, it is then realistic to predict a specific role for exercise-induced modulation of HSPB5 in the prevention of muscle diseases caused by protein misfolding. After offering an overview of the current knowledge on HSPB5 structure and function in muscle, this review aims to introduce the reader to the capacity that different exercise modalities have to induce and/or activate HSPB5 to levels sufficient to confer protection, with the potential to prevent or delay skeletal and cardiac muscle disorders. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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22 pages, 2477 KiB

Open AccessReview

Anti-Inflammatory and Immunoregulatory Action of Sesquiterpene Lactones

by Ana Paço, Teresa Brás, Jacqueline O. Santos, Paula Sampaio, Andreia C. Gomes and Maria F. Duarte

Molecules 2022, 27(3), 1142; https://doi.org/10.3390/molecules27031142 - 08 Feb 2022

Cited by 34 | Viewed by 4052

Abstract

Sesquiterpene lactones (SL), characterized by their high prevalence in the Asteraceae family, are one of the major groups of secondary metabolites found in plants. Researchers from distinct research fields, including pharmacology, medicine, and agriculture, are interested in their biological potential. With new SL [...] Read more.

Sesquiterpene lactones (SL), characterized by their high prevalence in the Asteraceae family, are one of the major groups of secondary metabolites found in plants. Researchers from distinct research fields, including pharmacology, medicine, and agriculture, are interested in their biological potential. With new SL discovered in the last years, new biological activities have been tested, different action mechanisms (synergistic and/or antagonistic effects), as well as molecular structure–activity relationships described. The review identifies the main sesquiterpene lactones with interconnections between immune responses and anti-inflammatory actions, within different cellular models as well in in vivo studies. Bioaccessibility and bioavailability, as well as molecular structure–activity relationships are addressed. Additionally, plant metabolic engineering, and the impact of sesquiterpene lactone extraction methodologies are presented, with the perspective of biological activity enhancement. Sesquiterpene lactones derivatives are also addressed. This review summarizes the current knowledge regarding the therapeutic potential of sesquiterpene lactones within immune and inflammatory activities, highlighting trends and opportunities for their pharmaceutical/clinical use. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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40 pages, 3385 KiB

Open AccessReview

Metabolic Features of Brain Function with Relevance to Clinical Features of Alzheimer and Parkinson Diseases

by David Allan Butterfield, Maria Favia, Iolanda Spera, Annalisa Campanella, Martina Lanza and Alessandra Castegna

Molecules 2022, 27(3), 951; https://doi.org/10.3390/molecules27030951 - 30 Jan 2022

Cited by 11 | Viewed by 4676

Abstract

Brain metabolism is comprised in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Since the brain primarily relies on metabolism of glucose, ketone bodies, and amino acids, aspects of these metabolic processes in these disorders—and particularly how these altered metabolic processes are related to [...] Read more.

Brain metabolism is comprised in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Since the brain primarily relies on metabolism of glucose, ketone bodies, and amino acids, aspects of these metabolic processes in these disorders—and particularly how these altered metabolic processes are related to oxidative and/or nitrosative stress and the resulting damaged targets—are reviewed in this paper. Greater understanding of the decreased functions in brain metabolism in AD and PD is posited to lead to potentially important therapeutic strategies to address both of these disorders, which cause relatively long-lasting decreased quality of life in patients. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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20 pages, 3493 KiB

Open AccessReview

Mechanistic Insight into Oxidative Stress-Triggered Signaling Pathways and Type 2 Diabetes

by Anju Singh, Ritushree Kukreti, Luciano Saso and Shrikant Kukreti

Molecules 2022, 27(3), 950; https://doi.org/10.3390/molecules27030950 - 30 Jan 2022

Cited by 105 | Viewed by 6845

Abstract

Oxidative stress (OS) is a metabolic dysfunction mediated by the imbalance between the biochemical processes leading to elevated production of reactive oxygen species (ROS) and the antioxidant defense system of the body. It has a ubiquitous role in the development of numerous noncommunicable [...] Read more.

Oxidative stress (OS) is a metabolic dysfunction mediated by the imbalance between the biochemical processes leading to elevated production of reactive oxygen species (ROS) and the antioxidant defense system of the body. It has a ubiquitous role in the development of numerous noncommunicable maladies including cardiovascular diseases, cancers, neurodegenerative diseases, aging and respiratory diseases. Diseases associated with metabolic dysfunction may be influenced by changes in the redox balance. Lately, there has been increasing awareness and evidence that diabetes mellitus (DM), particularly type 2 diabetes, is significantly modulated by oxidative stress. DM is a state of impaired metabolism characterized by hyperglycemia, resulting from defects in insulin secretion or action, or both. ROS such as hydrogen peroxide and the superoxide anion introduce chemical changes virtually in all cellular components, causing deleterious effects on the islets of β-cells, in turn affecting insulin production. Under hyperglycemic conditions, various signaling pathways such as nuclear factor-κβ (NF-κβ) and protein kinase C (PKC) are also activated by ROS. All of these can be linked to a hindrance in insulin signaling pathways, leading to insulin resistance. Hyperglycemia-induced oxidative stress plays a substantial role in complications including diabetic nephropathy. DM patients are more prone to microvascular as well as atherosclerotic macrovascular diseases. This systemic disease affects most countries around the world, owing to population explosion, aging, urbanization, obesity, lifestyle, etc. However, some modulators, with their free radical scavenging properties, can play a prospective role in overcoming the debilitating effects of OS. This review is a modest approach to summarizing the basics and interlinkages of oxidative stress, its modulators and diabetes mellitus. It may add to the understanding of and insight into the pathophysiology of diabetes and the crucial role of antioxidants to weaken the complications and morbidity resulting from this chronic disease. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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13 pages, 1047 KiB

Open AccessReview

Astaxanthin as a Modulator of Nrf2, NF-κB, and Their Crosstalk: Molecular Mechanisms and Possible Clinical Applications

by Sergio Davinelli, Luciano Saso, Floriana D’Angeli, Vittorio Calabrese, Mariano Intrieri and Giovanni Scapagnini

Molecules 2022, 27(2), 502; https://doi.org/10.3390/molecules27020502 - 14 Jan 2022

Cited by 32 | Viewed by 4123

Abstract

Astaxanthin (AST) is a dietary xanthophyll predominantly found in marine organisms and seafood. Due to its unique molecular features, AST has an excellent antioxidant activity with a wide range of applications in the nutraceutical and pharmaceutical industries. In the past decade, mounting evidence [...] Read more.

Astaxanthin (AST) is a dietary xanthophyll predominantly found in marine organisms and seafood. Due to its unique molecular features, AST has an excellent antioxidant activity with a wide range of applications in the nutraceutical and pharmaceutical industries. In the past decade, mounting evidence has suggested a protective role for AST against a wide range of diseases where oxidative stress and inflammation participate in a self-perpetuating cycle. Here, we review the underlying molecular mechanisms by which AST regulates two relevant redox-sensitive transcription factors, such as nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor κB (NF-κB). Nrf2 is a cellular sensor of electrophilic stress that coordinates the expression of a battery of defensive genes encoding antioxidant proteins and detoxifying enzymes. Likewise, NF-κB acts as a mediator of cellular stress and induces the expression of various pro-inflammatory genes, including those encoding cytokines, chemokines, and adhesion molecules. The effects of AST on the crosstalk between these transcription factors have also been discussed. Besides this, we summarize the current clinical studies elucidating how AST may alleviate the etiopathogenesis of oxidative stress and inflammation. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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35 pages, 22752 KiB

Open AccessReview

Recent Progress in the Development of Indole-Based Compounds Active against Malaria, Trypanosomiasis and Leishmaniasis

by Paulo A. F. Pacheco and Maria M. M. Santos

Molecules 2022, 27(1), 319; https://doi.org/10.3390/molecules27010319 - 05 Jan 2022

Cited by 18 | Viewed by 3471

Abstract

Human protozoan diseases represent a serious health problem worldwide, affecting mainly people in social and economic vulnerability. These diseases have attracted little investment in drug discovery, which is reflected in the limited available therapeutic arsenal. Authorized drugs present problems such as low efficacy [...] Read more.

Human protozoan diseases represent a serious health problem worldwide, affecting mainly people in social and economic vulnerability. These diseases have attracted little investment in drug discovery, which is reflected in the limited available therapeutic arsenal. Authorized drugs present problems such as low efficacy in some stages of the disease or toxicity, which result in undesirable side effects and treatment abandonment. Moreover, the emergence of drug-resistant parasite strains makes necessary an even greater effort to develop safe and effective antiparasitic agents. Among the chemotypes investigated for parasitic diseases, the indole nucleus has emerged as a privileged molecular scaffold for the generation of new drug candidates. In this review, the authors provide an overview of the indole-based compounds developed against important parasitic diseases, namely malaria, trypanosomiasis and leishmaniasis, by focusing on the design, optimization and synthesis of the most relevant synthetic indole scaffolds recently reported. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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12 pages, 1699 KiB

Open AccessReview

Two Possible Strategies for Drug Modification of Gemcitabine and Future Contributions to Personalized Medicine

by Mariana Pereira and Nuno Vale

Molecules 2022, 27(1), 291; https://doi.org/10.3390/molecules27010291 - 04 Jan 2022

Cited by 5 | Viewed by 2437

Abstract

Drug repurposing is an emerging strategy, which uses already approved drugs for new medical indications. One such drug is gemcitabine, an anticancer drug that only works at high doses since a portion is deactivated in the serum, which causes toxicity. In this review, [...] Read more.

Drug repurposing is an emerging strategy, which uses already approved drugs for new medical indications. One such drug is gemcitabine, an anticancer drug that only works at high doses since a portion is deactivated in the serum, which causes toxicity. In this review, two methods were discussed that could improve the anticancer effect of gemcitabine. The first is a chemical modification by conjugation with cell-penetrating peptides, namely penetratin, pVEC, and different kinds of CPP6, which mostly all showed an increased anticancer effect. The other method is combining gemcitabine with repurposed drugs, namely itraconazole, which also showed great cancer cell inhibition growth. Besides these two strategies, physiologically based pharmacokinetic models (PBPK models) are also the key for predicting drug distribution based on physiological data, which is very important for personalized medicine, so that the correct drug and dosage regimen can be administered according to each patient’s physiology. Taking all of this into consideration, it is believed that gemcitabine can be repurposed to have better anticancer effects. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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32 pages, 4925 KiB

Open AccessFeature PaperReview

Development of Phenothiazine Hybrids with Potential Medicinal Interest: A Review

by Marina C. Posso, Fernanda C. Domingues, Susana Ferreira and Samuel Silvestre

Molecules 2022, 27(1), 276; https://doi.org/10.3390/molecules27010276 - 03 Jan 2022

Cited by 40 | Viewed by 4210

Abstract

The molecular hybridization approach has been used to develop compounds with improved efficacy by combining two or more pharmacophores of bioactive scaffolds. In this context, hybridization of various relevant pharmacophores with phenothiazine derivatives has resulted in pertinent compounds with diverse biological activities, interacting [...] Read more.

The molecular hybridization approach has been used to develop compounds with improved efficacy by combining two or more pharmacophores of bioactive scaffolds. In this context, hybridization of various relevant pharmacophores with phenothiazine derivatives has resulted in pertinent compounds with diverse biological activities, interacting with specific or multiple targets. In fact, the development of new drugs or drug candidates based on phenothiazine system has been a promising approach due to the diverse activities associated with this tricyclic system, traditionally present in compounds with antipsychotic, antihistaminic and antimuscarinic effects. Actually, the pharmacological actions of phenothiazine hybrids include promising antibacterial, antifungal, anticancer, anti-inflammatory, antimalarial, analgesic and multi-drug resistance reversal properties. The present review summarizes the progress in the development of phenothiazine hybrids and their biological activity. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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43 pages, 6265 KiB

Open AccessReview

Recent Advances in Bioactive Flavonoid Hybrids Linked by 1,2,3-Triazole Ring Obtained by Click Chemistry

by Daniela Pereira, Madalena Pinto, Marta Correia-da-Silva and Honorina Cidade

Molecules 2022, 27(1), 230; https://doi.org/10.3390/molecules27010230 - 30 Dec 2021

Cited by 26 | Viewed by 3472

Abstract

As a result of the biological activities of natural flavonoids, several synthetic strategies aiming to obtain analogues with improved potency and/or pharmacokinetic profile have been developed. Since the triazole ring has been associated with several biological activities and metabolic stability, hybridization with a [...] Read more.

As a result of the biological activities of natural flavonoids, several synthetic strategies aiming to obtain analogues with improved potency and/or pharmacokinetic profile have been developed. Since the triazole ring has been associated with several biological activities and metabolic stability, hybridization with a 1,2,3-triazole ring has been increasingly reported over the last years. The feasible synthesis through copper (I) catalyzed azide-alkyne cycloaddition (CuAAC) has allowed the accomplishment of several hybrids. Since 2017, almost 700 flavonoid hybrids conjugated with 1,2,3-triazole, including chalcones, flavones, flavanones and flavonols, among others, with antitumor, antimicrobial, antidiabetic, neuroprotective, anti-inflammatory, antioxidant, and antifouling activity have been reported. This review compiles the biological activities recently described for these hybrids, highlighting the mechanism of action and structure–activity relationship (SAR) studies. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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20 pages, 868 KiB

Open AccessReview

Nrf2 Regulation by Curcumin: Molecular Aspects for Therapeutic Prospects

by Seyed Hossein Shahcheraghi, Fateme Salemi, Niloufar Peirovi, Jamshid Ayatollahi, Waqas Alam, Haroon Khan and Luciano Saso

Molecules 2022, 27(1), 167; https://doi.org/10.3390/molecules27010167 - 28 Dec 2021

Cited by 45 | Viewed by 4310

Abstract

Nuclear factor erythroid 2 p45-related factor (2Nrf2) is an essential leucine zipper protein (bZIP) that is primarily located in the cytoplasm under physiological conditions. Nrf2 principally modulates endogenous defense in response to oxidative stress in the brain.In this regard, Nrf2 translocates into the [...] Read more.

Nuclear factor erythroid 2 p45-related factor (2Nrf2) is an essential leucine zipper protein (bZIP) that is primarily located in the cytoplasm under physiological conditions. Nrf2 principally modulates endogenous defense in response to oxidative stress in the brain.In this regard, Nrf2 translocates into the nucleus and heterodimerizes with the tiny Maf or Jun proteins. It then attaches to certain DNA locations in the nucleus, such as electrophile response elements (EpRE) or antioxidant response elements (ARE), to start the transcription of cytoprotective genes. Many neoplasms have been shown to have over activated Nrf2, strongly suggesting that it is responsible for tumors with a poor prognosis. Exactly like curcumin, Zinc–curcumin Zn (II)–curc compound has been shown to induce Nrf2 activation. In the cancer cell lines analyzed, Zinc–curcumin Zn (II)–curc compound can also display anticancer effects via diverse molecular mechanisms, including markedly increasing heme oxygenase-1 (HO-1) p62/SQSTM1 and the Nrf2 protein levels along with its targets. It also strikingly decreases the levels of Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1) protein.As a result, the crosstalk between p62/SQSTM1 and Nrf2 could be used to improve cancer patient response to treatments. The interconnected anti-inflammatory and antioxidative properties of curcumin resulted from its modulatory effects on Nrf2 signaling pathway have been shown to improve insulin resistance. Curcumin exerts its anti-inflammatory impact through suppressing metabolic reactions and proteins such as Keap1 that provoke inflammation and oxidation. A rational amount of curcumin-activated antioxidant Nrf2 HO-1 and Nrf2-Keap1 pathways and upregulated the modifier subunit of glutamate-cysteine ligase involved in the production of the intracellular antioxidant glutathione. Enhanced expression of glutamate-cysteine ligase, a modifier subunit (GLCM), inhibited transcription of glutamate-cysteine ligase, a catalytic subunit (GCLC). A variety of in vivo, in vitro and clinical studies has been done so far to confirm the protective role of curcumin via Nrf2 regulation. This manuscript is designed to provide a comprehensive review on the molecular aspects of curcumin and its derivatives/analogs via regulation of Nrf2 regulation. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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19 pages, 975 KiB

Open AccessReview

Insights into Structural Modifications of Valproic Acid and Their Pharmacological Profile

by Manish Kumar Mishra, Samiksha Kukal, Priyanka Rani Paul, Shivangi Bora, Anju Singh, Shrikant Kukreti, Luciano Saso, Karthikeyan Muthusamy, Yasha Hasija and Ritushree Kukreti

Molecules 2022, 27(1), 104; https://doi.org/10.3390/molecules27010104 - 24 Dec 2021

Cited by 20 | Viewed by 4347

Abstract

Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and neuropathic pain. Apart from this, VPA has potential therapeutic applications in other central nervous system (CNS) disorders and in various cancer types. [...] Read more.

Valproic acid (VPA) is a well-established anticonvulsant drug discovered serendipitously and marketed for the treatment of epilepsy, migraine, bipolar disorder and neuropathic pain. Apart from this, VPA has potential therapeutic applications in other central nervous system (CNS) disorders and in various cancer types. Since the discovery of its anticonvulsant activity, substantial efforts have been made to develop structural analogues and derivatives in an attempt to increase potency and decrease adverse side effects, the most significant being teratogenicity and hepatotoxicity. Most of these compounds have shown reduced toxicity with improved potency. The simple structure of VPA offers a great advantage to its modification. This review briefly discusses the pharmacology and molecular targets of VPA. The article then elaborates on the structural modifications in VPA including amide-derivatives, acid and cyclic analogues, urea derivatives and pro-drugs, and compares their pharmacological profile with that of the parent molecule. The current challenges for the clinical use of these derivatives are also discussed. The review is expected to provide necessary knowledgebase for the further development of VPA-derived compounds. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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26 pages, 2118 KiB

Open AccessReview

The Potential Role of Curcumin in Modulating the Master Antioxidant Pathway in Diabetic Hypoxia-Induced Complications

by Somayyeh Ghareghomi, Mahdie Rahban, Zainab Moosavi-Movahedi, Mehran Habibi-Rezaei, Luciano Saso and Ali Akbar Moosavi-Movahedi

Molecules 2021, 26(24), 7658; https://doi.org/10.3390/molecules26247658 - 17 Dec 2021

Cited by 23 | Viewed by 3784

Abstract

Oxidative stress is the leading player in the onset and development of various diseases. The Keap1-Nrf2 pathway is a pivotal antioxidant system that preserves the cells’ redox balance. It decreases inflammation in which the nuclear trans-localization of Nrf2 as a transcription factor promotes [...] Read more.

Oxidative stress is the leading player in the onset and development of various diseases. The Keap1-Nrf2 pathway is a pivotal antioxidant system that preserves the cells’ redox balance. It decreases inflammation in which the nuclear trans-localization of Nrf2 as a transcription factor promotes various antioxidant responses in cells. Through some other directions and regulatory proteins, this pathway plays a fundamental role in preventing several diseases and reducing their complications. Regulation of the Nrf2 pathway occurs on transcriptional and post-transcriptional levels, and these regulations play a significant role in its activity. There is a subtle correlation between the Nrf2 pathway and the pivotal signaling pathways, including PI3 kinase/AKT/mTOR, NF-κB and HIF-1 factors. This demonstrates its role in the development of various diseases. Curcumin is a yellow polyphenolic compound from Curcuma longa with multiple bioactivities, including antioxidant, anti-inflammatory, anti-tumor, and anti-viral activities. Since hyperglycemia and increased reactive oxygen species (ROS) are the leading causes of common diabetic complications, reducing the generation of ROS can be a fundamental approach to dealing with these complications. Curcumin can be considered a potential treatment option by creating an efficient therapeutic to counteract ROS and reduce its detrimental effects. This review discusses Nrf2 pathway regulation at different levels and its correlation with other important pathways and proteins in the cell involved in the progression of diabetic complications and targeting these pathways by curcumin. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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25 pages, 4928 KiB

Open AccessReview

Current Photoactive Molecules for Targeted Therapy of Triple-Negative Breast Cancer

by Cristina J. Dias, Luisa Helguero and Maria Amparo F. Faustino

Molecules 2021, 26(24), 7654; https://doi.org/10.3390/molecules26247654 - 17 Dec 2021

Cited by 10 | Viewed by 3209

Abstract

Cancer is the second leading cause of death worldwide; therefore, there is an urgent need to find safe and effective therapies. Triple-negative breast cancer (TNBC) is diagnosed in ca. 15–20% of BC and is extremely aggressive resulting in reduced survival rate, which is [...] Read more.

Cancer is the second leading cause of death worldwide; therefore, there is an urgent need to find safe and effective therapies. Triple-negative breast cancer (TNBC) is diagnosed in ca. 15–20% of BC and is extremely aggressive resulting in reduced survival rate, which is mainly due to the low therapeutic efficacy of available treatments. Photodynamic therapy (PDT) is an interesting therapeutic approach in the treatment of cancer; the photosensitizers with good absorption in the therapeutic window, combined with their specific targeting of cancer cells, have received particular interest. This review aims to revisit the latest developments on chlorin-based photoactive molecules for targeted therapy in TNBC. Photodynamic therapy, alone or combined with other therapies (such as chemotherapy or photothermal therapy), has potential to be a safe and a promising approach against TNBC. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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31 pages, 6131 KiB

Open AccessReview

The Development of BTK Inhibitors: A Five-Year Update

by Bruno Tasso, Andrea Spallarossa, Eleonora Russo and Chiara Brullo

Molecules 2021, 26(23), 7411; https://doi.org/10.3390/molecules26237411 - 06 Dec 2021

Cited by 32 | Viewed by 5969

Abstract

Bruton’s tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been [...] Read more.

Bruton’s tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using “BTK” and “BTK inhibitors” as keywords. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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30 pages, 2972 KiB

Open AccessReview

The Phosphorylated Form of the Histone H2AX (γH2AX) in the Brain from Embryonic Life to Old Age

by Adalberto Merighi, Nadia Gionchiglia, Alberto Granato and Laura Lossi

Molecules 2021, 26(23), 7198; https://doi.org/10.3390/molecules26237198 - 27 Nov 2021

Cited by 16 | Viewed by 7753

Abstract

The γ phosphorylated form of the histone H2AX (γH2AX) was described more than 40 years ago and it was demonstrated that phosphorylation of H2AX was one of the first cellular responses to DNA damage. Since then, γH2AX has been implicated in diverse cellular [...] Read more.

The γ phosphorylated form of the histone H2AX (γH2AX) was described more than 40 years ago and it was demonstrated that phosphorylation of H2AX was one of the first cellular responses to DNA damage. Since then, γH2AX has been implicated in diverse cellular functions in normal and pathological cells. In the first part of this review, we will briefly describe the intervention of H2AX in the DNA damage response (DDR) and its role in some pivotal cellular events, such as regulation of cell cycle checkpoints, genomic instability, cell growth, mitosis, embryogenesis, and apoptosis. Then, in the main part of this contribution, we will discuss the involvement of γH2AX in the normal and pathological central nervous system, with particular attention to the differences in the DDR between immature and mature neurons, and to the significance of H2AX phosphorylation in neurogenesis and neuronal cell death. The emerging picture is that H2AX is a pleiotropic molecule with an array of yet not fully understood functions in the brain, from embryonic life to old age. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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25 pages, 2892 KiB

Open AccessReview

Antineoplastics Encapsulated in Nanostructured Lipid Carriers

by Gustavo Henrique Rodrigues da Silva, Ludmilla David de Moura, Fabíola Vieira de Carvalho, Gabriela Geronimo, Talita Cesarim Mendonça, Fernando Freitas de Lima and Eneida de Paula

Molecules 2021, 26(22), 6929; https://doi.org/10.3390/molecules26226929 - 17 Nov 2021

Cited by 9 | Viewed by 2875

Abstract

Ideally, antineoplastic treatment aims to selectively eradicate cancer cells without causing systemic toxicity. A great number of antineoplastic agents (AAs) are available nowadays, with well-defined therapeutic protocols. The poor bioavailability, non-selective action, high systemic toxicity, and lack of effectiveness of most AAs have [...] Read more.

Ideally, antineoplastic treatment aims to selectively eradicate cancer cells without causing systemic toxicity. A great number of antineoplastic agents (AAs) are available nowadays, with well-defined therapeutic protocols. The poor bioavailability, non-selective action, high systemic toxicity, and lack of effectiveness of most AAs have stimulated the search for novel chemotherapy protocols, including technological approaches that provide drug delivery systems (DDS) for gold standard medicines. Nanostructured lipid carriers (NLC) are DDS that contain a core of solid and lipid liquids stabilised by surfactants. NLC have high upload capacity for lipophilic drugs, such as the majority of AAs. These nanoparticles can be prepared with a diversity of biocompatible (synthetic or natural) lipid blends, administered by different routes and functionalised for targeting purposes. This review focused on the research carried out from 2000 to now, regarding NLC formulations for AAs (antimetabolites, antimitotics, alkylating agents, and antibiotics) encapsulation, with special emphasis on studies carried out in vivo. NLC systems for codelivery of AAs were also considered, as well as those for non-classical drugs and therapies (natural products and photosensitisers). NLC have emerged as powerful DDS to improve the bioavailability, targeting and efficacy of antineoplastics, while decreasing their toxic effect in the treatment of different types of cancer. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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33 pages, 6704 KiB

Open AccessReview

3-Phenylcoumarins as a Privileged Scaffold in Medicinal Chemistry: The Landmarks of the Past Decade

by Maria J. Matos, Eugenio Uriarte and Lourdes Santana

Molecules 2021, 26(21), 6755; https://doi.org/10.3390/molecules26216755 - 08 Nov 2021

Cited by 7 | Viewed by 2829

Abstract

3-Phenylcoumarins are a family of heterocyclic molecules that are widely used in both organic and medicinal chemistry. In this overview, research on this scaffold, since 2010, is included and discussed, focusing on aspects related to its natural origin, synthetic procedures and pharmacological applications. [...] Read more.

3-Phenylcoumarins are a family of heterocyclic molecules that are widely used in both organic and medicinal chemistry. In this overview, research on this scaffold, since 2010, is included and discussed, focusing on aspects related to its natural origin, synthetic procedures and pharmacological applications. This review paper is based on the most relevant literature related to the role of 3-phenylcoumarins in the design of new drug candidates. The references presented in this review have been collected from multiple electronic databases, including SciFinder, Pubmed and Mendeley. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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17 pages, 2798 KiB

Open AccessReview

Ligands as Stabilizers of G-Quadruplexes in Non-Coding RNAs

by Joana Figueiredo, Tiago Santos, André Miranda, Daniela Alexandre, Bernardo Teixeira, Pedro Simões, Jéssica Lopes-Nunes and Carla Cruz

Molecules 2021, 26(20), 6164; https://doi.org/10.3390/molecules26206164 - 13 Oct 2021

Cited by 10 | Viewed by 3562

Abstract

The non-coding RNAs (ncRNA) are RNA transcripts with different sizes, structures and biological functions that do not encode functional proteins. RNA G-quadruplexes (rG4s) have been found in small and long ncRNAs. The existence of an equilibrium between rG4 and stem−loop structures in ncRNAs [...] Read more.

The non-coding RNAs (ncRNA) are RNA transcripts with different sizes, structures and biological functions that do not encode functional proteins. RNA G-quadruplexes (rG4s) have been found in small and long ncRNAs. The existence of an equilibrium between rG4 and stem−loop structures in ncRNAs and its effect on biological processes remains unexplored. For example, deviation from the stem−loop leads to deregulated mature miRNA levels, demonstrating that miRNA biogenesis can be modulated by ions or small molecules. In light of this, we report several examples of rG4s in certain types of ncRNAs, and the implications of G4 stabilization using small molecules, also known as G4 ligands, in the regulation of gene expression, miRNA biogenesis, and miRNA−mRNA interactions. Until now, different G4 ligands scaffolds were synthesized for these targets. The regulatory role of the above-mentioned rG4s in ncRNAs can be used as novel therapeutic approaches for adjusting miRNA levels. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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34 pages, 8483 KiB

Open AccessReview

Antimalarial Inhibitors Targeting Epigenetics or Mitochondria in Plasmodium falciparum: Recent Survey upon Synthesis and Biological Evaluation of Potential Drugs against Malaria

by Christina L. Koumpoura, Anne Robert, Constantinos M. Athanassopoulos and Michel Baltas

Molecules 2021, 26(18), 5711; https://doi.org/10.3390/molecules26185711 - 21 Sep 2021

Cited by 5 | Viewed by 3745

Abstract

Despite many efforts, malaria remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by P. falciparum. Over the past decade, new essential pathways have been emerged to fight against malaria. Among them, epigenetic processes and mitochondrial [...] Read more.

Despite many efforts, malaria remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by P. falciparum. Over the past decade, new essential pathways have been emerged to fight against malaria. Among them, epigenetic processes and mitochondrial metabolism appear to be important targets. This review will focus on recent evolutions concerning worldwide efforts to conceive, synthesize and evaluate new drug candidates interfering selectively and efficiently with these two targets and pathways. The focus will be on compounds/scaffolds that possess biological/pharmacophoric properties on DNA methyltransferases and HDAC’s for epigenetics, and on cytochrome bc1 and dihydroorotate dehydrogenase for mitochondrion. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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27 pages, 2290 KiB

Open AccessReview

Joint Cardioprotective Effect of Vitamin C and Other Antioxidants against Reperfusion Injury in Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention

by Ramón Rodrigo, Juan Carlos Prieto, Rubén Aguayo, Cristóbal Ramos, Ángel Puentes, Abraham Gajardo, Emiliano Panieri, Catalina Rojas-Solé, José Lillo-Moya and Luciano Saso

Molecules 2021, 26(18), 5702; https://doi.org/10.3390/molecules26185702 - 21 Sep 2021

Cited by 23 | Viewed by 3630

Abstract

Percutaneous coronary intervention (PCI) has long remained the gold standard therapy to restore coronary blood flow after acute myocardial infarction (AMI). However, this procedure leads to the development of increased production of reactive oxygen species (ROS) that can exacerbate the damage caused by [...] Read more.

Percutaneous coronary intervention (PCI) has long remained the gold standard therapy to restore coronary blood flow after acute myocardial infarction (AMI). However, this procedure leads to the development of increased production of reactive oxygen species (ROS) that can exacerbate the damage caused by AMI, particularly during the reperfusion phase. Numerous attempts based on antioxidant treatments, aimed to reduce the oxidative injury of cardiac tissue, have failed in achieving an effective therapy for these patients. Among these studies, results derived from the use of vitamin C (Vit C) have been inconclusive so far, likely due to suboptimal study designs, misinterpretations, and the erroneous conclusions of clinical trials. Nevertheless, recent clinical trials have shown that the intravenous infusion of Vit C prior to PCI-reduced cardiac injury biomarkers, as well as inflammatory biomarkers and ROS production. In addition, improvements of functional parameters, such as left ventricular ejection fraction (LVEF) and telediastolic left ventricular volume, showed a trend but had an inconclusive association with Vit C. Therefore, it seems reasonable that these beneficial effects could be further enhanced by the association with other antioxidant agents. Indeed, the complexity and the multifactorial nature of the mechanism of injury occurring in AMI demands multitarget agents to reach an enhancement of the expected cardioprotection, a paradigm needing to be demonstrated. The present review provides data supporting the view that an intravenous infusion containing combined safe antioxidants could be a suitable strategy to reduce cardiac injury, thus improving the clinical outcome, life quality, and life expectancy of patients subjected to PCI following AMI. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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20 pages, 2541 KiB

Open AccessReview

Recent Chemical and Pharmacological Developments on 14-Oxygenated-N-methylmorphinan-6-ones

by Mariana Spetea and Helmut Schmidhammer

Molecules 2021, 26(18), 5677; https://doi.org/10.3390/molecules26185677 - 18 Sep 2021

Cited by 8 | Viewed by 4632

Abstract

Adequate pain management, particularly chronic pain, remains a major challenge associated with modern-day medicine. Current pharmacotherapy offers unsatisfactory long-term solutions due to serious side effects related to the chronic administration of analgesic drugs. Morphine and structurally related derivatives (e.g., oxycodone, oxymorphone, buprenorphine) are [...] Read more.

Adequate pain management, particularly chronic pain, remains a major challenge associated with modern-day medicine. Current pharmacotherapy offers unsatisfactory long-term solutions due to serious side effects related to the chronic administration of analgesic drugs. Morphine and structurally related derivatives (e.g., oxycodone, oxymorphone, buprenorphine) are highly effective opioid analgesics, mediating their effects via the activation of opioid receptors, with the mu-opioid receptor subtype as the primary molecular target. However, they also cause addiction and overdose deaths, which has led to a global opioid crisis in the last decades. Therefore, research efforts are needed to overcome the limitations of present pain therapies with the aim to improve treatment efficacy and to reduce complications. This review presents recent chemical and pharmacological advances on 14-oxygenated-N-methylmorphinan-6-ones, in the search of safer pain therapeutics. We focus on drug design strategies and structure–activity relationships on specific modifications in positions 5, 6, 14 and 17 on the morphinan skeleton, with the goal of aiding the discovery of opioid analgesics with more favorable pharmacological properties, potent analgesia and fewer undesirable effects. Targeted molecular modifications on the morphinan scaffold can afford novel opioids as bi- or multifunctional ligands targeting multiple opioid receptors, as attractive alternatives to mu-opioid receptor selective analgesics. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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13 pages, 296 KiB

Open AccessReview

Oxidative Stress in Mucopolysaccharidoses: Pharmacological Implications

by Karolina Pierzynowska, Lidia Gaffke, Zuzanna Cyske, Grzegorz Węgrzyn, Brigitta Buttari, Elisabetta Profumo and Luciano Saso

Molecules 2021, 26(18), 5616; https://doi.org/10.3390/molecules26185616 - 16 Sep 2021

Cited by 11 | Viewed by 2571

Abstract

Although mucopolysaccharidoses (MPS) are caused by mutations in genes coding for enzymes responsible for degradation of glycosaminoglycans, storage of these compounds is crucial but is not the only pathomechanism of these severe, inherited metabolic diseases. Among various factors and processes influencing the course [...] Read more.

Although mucopolysaccharidoses (MPS) are caused by mutations in genes coding for enzymes responsible for degradation of glycosaminoglycans, storage of these compounds is crucial but is not the only pathomechanism of these severe, inherited metabolic diseases. Among various factors and processes influencing the course of MPS, oxidative stress appears to be a major one. Oxidative imbalance, occurring in MPS and resulting in increased levels of reactive oxidative species, causes damage of various biomolecules, leading to worsening of symptoms, especially in the central nervous system (but not restricted to this system). A few therapeutic options are available for some types of MPS, including enzyme replacement therapy and hematopoietic stem cell transplantation, however, none of them are fully effective in reducing all symptoms. A possibility that molecules with antioxidative activities might be useful accompanying drugs, administered together with other therapies, is discussed in light of the potential efficacy of MPS treatment. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

31 pages, 1421 KiB

Open AccessReview

The Nrf2 Pathway in Ischemic Stroke: A Review

by Marcelo Farina, Leonardo Eugênio Vieira, Brigitta Buttari, Elisabetta Profumo and Luciano Saso

Molecules 2021, 26(16), 5001; https://doi.org/10.3390/molecules26165001 - 18 Aug 2021

Cited by 51 | Viewed by 6859

Abstract

Ischemic stroke, characterized by the sudden loss of blood flow in specific area(s) of the brain, is the leading cause of permanent disability and is among the leading causes of death worldwide. The only approved pharmacological treatment for acute ischemic stroke (intravenous thrombolysis [...] Read more.

Ischemic stroke, characterized by the sudden loss of blood flow in specific area(s) of the brain, is the leading cause of permanent disability and is among the leading causes of death worldwide. The only approved pharmacological treatment for acute ischemic stroke (intravenous thrombolysis with recombinant tissue plasminogen activator) has significant clinical limitations and does not consider the complex set of events taking place after the onset of ischemic stroke (ischemic cascade), which is characterized by significant pro-oxidative events. The transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of a great number of antioxidant and/or defense proteins, has been pointed as a potential pharmacological target involved in the mitigation of deleterious oxidative events taking place at the ischemic cascade. This review summarizes studies concerning the protective role of Nrf2 in experimental models of ischemic stroke, emphasizing molecular events resulting from ischemic stroke that are, in parallel, modulated by Nrf2. Considering the acute nature of ischemic stroke, we discuss the challenges in using a putative pharmacological strategy (Nrf2 activator) that relies upon transcription, translation and metabolically active cells in treating ischemic stroke patients. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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22 pages, 2963 KiB

Open AccessReview

Cytoprotective Mechanisms of DJ-1: Implications in Cardiac Pathophysiology

by James N. Tsoporis, Ioannis-Alexandros Drosatos, Sahil Gupta, Hajera Amatullah, Shehla Izhar, Claudia C. dos Santos, Vasileos Salpeas, Angelos G. Rigopoulos, Ioannis K. Toumpoulis, Andreas S. Triantafyllis, Eleftharios Sakadakis, Nikolaos Kavantzas, John C. Marshall, Ioannis K. Rizos and Thomas G. Parker

Molecules 2021, 26(13), 3795; https://doi.org/10.3390/molecules26133795 - 22 Jun 2021

Cited by 10 | Viewed by 2830

Abstract

DJ-1 was originally identified as an oncogene product while mutations of the gene encoding DJ-1/PARK7 were later associated with a recessive form of Parkinson’s disease. Its ubiquitous expression and diversity of function suggest that DJ-1 is also involved in mechanisms outside the central [...] Read more.

DJ-1 was originally identified as an oncogene product while mutations of the gene encoding DJ-1/PARK7 were later associated with a recessive form of Parkinson’s disease. Its ubiquitous expression and diversity of function suggest that DJ-1 is also involved in mechanisms outside the central nervous system. In the last decade, the contribution of DJ-1 to the protection from ischemia-reperfusion injury has been recognized and its involvement in the pathophysiology of cardiovascular disease is attracting increasing attention. This review describes the current and gaps in our knowledge of DJ-1, focusing on its role in regulating cardiovascular function. In parallel, we present original data showing an association between increased DJ-1 expression and antiapoptotic and anti-inflammatory markers following cardiac and vascular surgical procedures. Future studies should address DJ-1’s role as a plausible novel therapeutic target for cardiovascular disease. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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29 pages, 3691 KiB

Open AccessReview

Phytochemical and Ethnopharmacological Perspectives of Ehretia laevis

by Pooja Sharma, Richa Shri, Fidele Ntie-Kang and Suresh Kumar

Molecules 2021, 26(12), 3489; https://doi.org/10.3390/molecules26123489 - 08 Jun 2021

Cited by 12 | Viewed by 8537

Abstract

Ehretia laevis Roxb. (Boraginaceae) has been extensively used as a traditional remedy for the treatment of a diverse range of ailments related to the respiratory system, the gastrointestinal tract, the reproductive system, and against several infections. This review critically assesses and documents, for [...] Read more.

Ehretia laevis Roxb. (Boraginaceae) has been extensively used as a traditional remedy for the treatment of a diverse range of ailments related to the respiratory system, the gastrointestinal tract, the reproductive system, and against several infections. This review critically assesses and documents, for the first time, the fragmented information on E. laevis, including its botanical description, folklore uses, bioactive phyto metabolites and pharmacological activities. The goal is to explore this plant therapeutically. Ethnomedicinal surveys reveal that E. laevis has been used by tribal communities in Asian countries for the treatment of various disorders. Quantitative and qualitative phytochemical investigations of E. laevis showed the presence of important phytoconstituents such as pentacyclic triterpenoids, phenolic acids, flavonoids, fatty acids, steroids, alkaloids, aliphatic alcohols, hydrocarbons, amino acids, carbohydrates, vitamins and minerals. Fresh plant parts, crude extracts, fractions and isolated compounds have been reported to exhibit broad spectrum of therapeutic activities viz., antioxidant, antiarthritic, antidiabetic, anti-inflammatory, antiulcer, antidiarrheal, antidysenteric, wound healing and anti-infective activities. E. laevis is shown to be an excellent potential source of drugs for the mitigation of jaundice, asthma, dysentery, ulcers, diarrhea, ringworm, eczema, diabetes, fissure, syphilis, cuts and wounds, inflammation, liver problems, venereal and infectious disorders. Although few investigations authenticated its traditional uses but employed uncharacterized crude extracts of the plant, the major concerns raised are reproducibility of therapeutic efficacy and safety of plant material. The outcomes of limited pharmacological screening and reported bioactive compounds of E. laevis suggest that there is an urgent need for in-depth pharmacological investigations of the plant. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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21 pages, 1312 KiB

Open AccessReview

Regulatory Role of Nrf2 Signaling Pathway in Wound Healing Process

by Ipek Süntar, Sümeyra Çetinkaya, Emiliano Panieri, Sarmistha Saha, Brigitta Buttari, Elisabetta Profumo and Luciano Saso

Molecules 2021, 26(9), 2424; https://doi.org/10.3390/molecules26092424 - 21 Apr 2021

Cited by 26 | Viewed by 4010

Abstract

Wound healing involves a series of cellular events in damaged cells and tissues initiated with hemostasis and finally culminating with the formation of a fibrin clot. However, delay in the normal wound healing process during pathological conditions due to reactive oxygen species, inflammation [...] Read more.

Wound healing involves a series of cellular events in damaged cells and tissues initiated with hemostasis and finally culminating with the formation of a fibrin clot. However, delay in the normal wound healing process during pathological conditions due to reactive oxygen species, inflammation and immune suppression at the wound site represents a medical challenge. So far, many therapeutic strategies have been developed to improve cellular homeostasis and chronic wounds in order to accelerate wound repair. In this context, the role of Nuclear factor erythroid 2-related factor 2 (Nrf2) during the wound healing process has been a stimulating research topic for therapeutic perspectives. Nrf2 is the main regulator of intracellular redox homeostasis. It increases cytoprotective gene expression and the antioxidant capacity of mammalian cells. It has been reported that some bioactive compounds attenuate cellular stress and thus accelerate cell proliferation, neovascularization and repair of damaged tissues by promoting Nrf2 activation. This review highlights the importance of the Nrf2 signaling pathway in wound healing strategies and the role of bioactive compounds that support wound repair through the modulation of this crucial transcription factor. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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28 pages, 3993 KiB

Open AccessFeature PaperReview

Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches

by Pedro Cruz-Vicente, Luís A. Passarinha, Samuel Silvestre and Eugenia Gallardo

Molecules 2021, 26(8), 2193; https://doi.org/10.3390/molecules26082193 - 11 Apr 2021

Cited by 23 | Viewed by 5391

Abstract

Neurodegenerative diseases (ND), including Alzheimer’s (AD) and Parkinson’s Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability [...] Read more.

Neurodegenerative diseases (ND), including Alzheimer’s (AD) and Parkinson’s Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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21 pages, 4040 KiB

Open AccessReview

Highlights on Steroidal Arylidene Derivatives as a Source of Pharmacologically Active Compounds: A Review

by Vanessa Brito, Gilberto Alves, Paulo Almeida and Samuel Silvestre

Molecules 2021, 26(7), 2032; https://doi.org/10.3390/molecules26072032 - 02 Apr 2021

Cited by 10 | Viewed by 2670

Abstract

Steroids constitute a unique class of chemical compounds, playing an important role in physiopathological processes, and have high pharmacological interest. Additionally, steroids have been associated with a relatively low toxicity and high bioavailability. Nowadays, multiple steroidal derivatives are clinically available for the treatment [...] Read more.

Steroids constitute a unique class of chemical compounds, playing an important role in physiopathological processes, and have high pharmacological interest. Additionally, steroids have been associated with a relatively low toxicity and high bioavailability. Nowadays, multiple steroidal derivatives are clinically available for the treatment of numerous diseases. Moreover, different structural modifications on their skeleton have been explored, aiming to develop compounds with new and improved pharmacological properties. Thus, steroidal arylidene derivatives emerged as a relevant example of these modifications. This family of compounds has been mainly described as 17β-hydroxysteroid dehydrogenase type 1 and aromatase inhibitors, as well as neuroprotective and anticancer agents. Besides, due to their straightforward preparation and intrinsic chemical reactivity, steroidal arylidene derivatives are important synthetic intermediates for the preparation of other compounds, particularly bearing heterocyclic systems. In fact, starting from arylidenesteroids, it was possible to develop bioactive steroidal pyrazolines, pyrazoles, pyrimidines, pyridines, spiro-pyrrolidines, amongst others. Most of these products have also been studied as anti-inflammatory and anticancer agents, as well as 5α-reductase and aromatase inhibitors. This work aims to provide a comprehensive overview of steroidal arylidene derivatives described in the literature, highlighting their bioactivities and importance as synthetic intermediates for other pharmacologically active compounds. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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14 pages, 10304 KiB

Open AccessFeature PaperReview

The Pharmaceutical Industry in 2020. An Analysis of FDA Drug Approvals from the Perspective of Molecules

by Beatriz G. de la Torre and Fernando Albericio

Molecules 2021, 26(3), 627; https://doi.org/10.3390/molecules26030627 - 25 Jan 2021

Cited by 83 | Viewed by 9524

Abstract

Although the pharmaceutical industry will remember 2020 as the year of COVID-19, it is important to highlight that this year has been the second-best—together with 1996—in terms of the number of drugs accepted by the US Food and Drug Administration (FDA). Each of [...] Read more.

Although the pharmaceutical industry will remember 2020 as the year of COVID-19, it is important to highlight that this year has been the second-best—together with 1996—in terms of the number of drugs accepted by the US Food and Drug Administration (FDA). Each of these two years witnessed the authorization of 53 drugs—a number surpassed only in 2018 with 59 pharmaceutical agents. The 53 approvals in 2020 are divided between 40 new chemical entities and 13 biologic drugs (biologics). Of note, ten monoclonal antibodies, two antibody–drug conjugates, three peptides, and two oligonucleotides have been approved in 2020. Close inspection of the so-called small molecules reveals the significant presence of fluorine atoms and/or nitrogen aromatic heterocycles. This report analyzes the 53 new drugs of the 2020 harvest from a strictly chemical perspective, as it did for those authorized in the previous four years. On the basis of chemical structure alone, the drugs that received approval in 2020 are classified as the following: biologics (antibodies, antibody-drug conjugates, and proteins); TIDES (peptide and oligonucleotides); natural products; fluorine-containing molecules; nitrogen aromatic heterocycles; and other small molecules. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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13 pages, 1343 KiB

Open AccessSystematic Review

In Vivo Anticancer Activity of AZD3965: A Systematic Review

by Ana Silva, Beatriz Antunes, Alberta Batista, Filipa Pinto-Ribeiro, Fátima Baltazar and Julieta Afonso

Molecules 2022, 27(1), 181; https://doi.org/10.3390/molecules27010181 - 29 Dec 2021

Cited by 27 | Viewed by 3456

Abstract

Proliferating cancer cells have high energy demands, which is mainly obtained through glycolysis. The transmembrane trafficking of lactate, a major metabolite produced by glycolytic cancer cells, relies on monocarboxylate transporters (MCTs). MCT1 optimally imports lactate, although it can work bidirectionally, and its activity [...] Read more.

Proliferating cancer cells have high energy demands, which is mainly obtained through glycolysis. The transmembrane trafficking of lactate, a major metabolite produced by glycolytic cancer cells, relies on monocarboxylate transporters (MCTs). MCT1 optimally imports lactate, although it can work bidirectionally, and its activity has been linked to cancer aggressiveness and poor outcomes. AZD3965, a specific MCT1 inhibitor, was tested both in vitro and in vivo, with encouraging results; a phase I clinical trial has already been undertaken. Thus, analysis of the experimental evidence using AZD3965 in different cancer types could give valuable information for its clinical use. This systematic review aimed to assess the in vivo anticancer activity of AZD3965 either alone (monotherapy) or with other interventions (combination therapy). Study search was performed in nine different databases using the keywords “AZD3965 in vivo” as search terms. The results show that AZD3965 successfully decreased tumor growth and promoted intracellular lactate accumulation, which confirmed its effectiveness, especially in combined therapy. These results support the setup of clinical trials, but other important findings, namely AZD3965 enhanced activity when given in combination with other therapies, or MCT4-induced treatment resistance, should be further considered in the clinical trial design to improve therapy response. Full article

(This article belongs to the Special Issue Molecules Medicinal Chemistry Reviews)

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