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Flavin-Dependent Thymidylate Synthase as a New Antibiotic Target

by Michael Choi, Kalani Karunaratne and Amnon Kohen

Molecules 2016, 21(5), 654; https://doi.org/10.3390/molecules21050654 - 20 May 2016

Cited by 19 | Viewed by 8681

In humans de novo synthesis of 2′-deoxythymidine-5′-monophosphate (dTMP), an essential building block of DNA, utilizes an enzymatic pathway requiring thymidylate synthase (TSase) and dihydrofolate reductase (DHFR). The enzyme flavin-dependent thymidylate synthase (FDTS) represents an alternative enzymatic pathway to synthesize dTMP, which is not [...] Read more.

In humans de novo synthesis of 2′-deoxythymidine-5′-monophosphate (dTMP), an essential building block of DNA, utilizes an enzymatic pathway requiring thymidylate synthase (TSase) and dihydrofolate reductase (DHFR). The enzyme flavin-dependent thymidylate synthase (FDTS) represents an alternative enzymatic pathway to synthesize dTMP, which is not present in human cells. A number of pathogenic bacteria, however, depend on this enzyme in lieu of or in conjunction with the analogous human pathway. Thus, inhibitors of this enzyme may serve as antibiotics. Here, we review the similarities and differences of FDTS vs. TSase including aspects of their structure and chemical mechanism. In addition, we review current progress in the search for inhibitors of flavin dependent thymidylate synthase as potential novel therapeutics. Full article

(This article belongs to the Special Issue 20th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (DDAH): Discovery, Synthesis and Development

by Rhys B. Murphy, Sara Tommasi, Benjamin C. Lewis and Arduino A. Mangoni

Molecules 2016, 21(5), 615; https://doi.org/10.3390/molecules21050615 - 11 May 2016

Cited by 26 | Viewed by 11881

Abstract

Dimethylarginine dimethylaminohydrolase (DDAH) is a highly conserved hydrolytic enzyme found in numerous species, including bacteria, rodents, and humans. In humans, the DDAH-1 isoform is known to metabolize endogenous asymmetric dimethylarginine (ADMA) and monomethyl arginine (l-NMMA), with ADMA proposed to be a [...] Read more.

Dimethylarginine dimethylaminohydrolase (DDAH) is a highly conserved hydrolytic enzyme found in numerous species, including bacteria, rodents, and humans. In humans, the DDAH-1 isoform is known to metabolize endogenous asymmetric dimethylarginine (ADMA) and monomethyl arginine (l-NMMA), with ADMA proposed to be a putative marker of cardiovascular disease. Current literature reports identify the DDAH family of enzymes as a potential therapeutic target in the regulation of nitric oxide (NO) production, mediated via its biochemical interaction with the nitric oxide synthase (NOS) family of enzymes. Increased DDAH expression and NO production have been linked to multiple pathological conditions, specifically, cancer, neurodegenerative disorders, and septic shock. As such, the discovery, chemical synthesis, and development of DDAH inhibitors as potential drug candidates represent a growing field of interest. This review article summarizes the current knowledge on DDAH inhibition and the derived pharmacokinetic parameters of the main DDAH inhibitors reported in the literature. Furthermore, current methods of development and chemical synthetic pathways are discussed. Full article

(This article belongs to the Special Issue 20th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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Elicitation, an Effective Strategy for the Biotechnological Production of Bioactive High-Added Value Compounds in Plant Cell Factories

by Karla Ramirez-Estrada, Heriberto Vidal-Limon, Diego Hidalgo, Elisabeth Moyano, Marta Golenioswki, Rosa M. Cusidó and Javier Palazon

Molecules 2016, 21(2), 182; https://doi.org/10.3390/molecules21020182 - 03 Feb 2016

Cited by 382 | Viewed by 21728

Abstract

Plant in vitro cultures represent an attractive and cost-effective alternative to classical approaches to plant secondary metabolite (PSM) production (the “Plant Cell Factory” concept). Among other advantages, they constitute the only sustainable and eco-friendly system to obtain complex chemical structures biosynthesized by rare [...] Read more.

Plant in vitro cultures represent an attractive and cost-effective alternative to classical approaches to plant secondary metabolite (PSM) production (the “Plant Cell Factory” concept). Among other advantages, they constitute the only sustainable and eco-friendly system to obtain complex chemical structures biosynthesized by rare or endangered plant species that resist domestication. For successful results, the biotechnological production of PSM requires an optimized system, for which elicitation has proved one of the most effective strategies. In plant cell cultures, an elicitor can be defined as a compound introduced in small concentrations to a living system to promote the biosynthesis of the target metabolite. Traditionally, elicitors have been classified in two types, abiotic or biotic, according to their chemical nature and exogenous or endogenous origin, and notably include yeast extract, methyl jasmonate, salicylic acid, vanadyl sulphate and chitosan. In this review, we summarize the enhancing effects of elicitors on the production of high-added value plant compounds such as taxanes, ginsenosides, aryltetralin lignans and other types of polyphenols, focusing particularly on the use of a new generation of elicitors such as coronatine and cyclodextrins. Full article

(This article belongs to the Special Issue 20th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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Is Stevia rebaudiana Bertoni a Non Cariogenic Sweetener? A Review

by Gianmaria Fabrizio Ferrazzano, Tiziana Cantile, Brunella Alcidi, Marco Coda, Aniello Ingenito, Armando Zarrelli, Giovanni Di Fabio and Antonino Pollio

Molecules 2016, 21(1), 38; https://doi.org/10.3390/molecules21010038 - 26 Dec 2015

Cited by 80 | Viewed by 19992

Abstract

Stevia rebaudiana Bertoni is a small perennial shrub of the Asteraceae (Compositae) family that is native to South America, particularly Brazil and Paraguay, where it is known as “stevia” or “honey leaf” for its powerful sweetness. Several studies have suggested that in addition [...] Read more.

Stevia rebaudiana Bertoni is a small perennial shrub of the Asteraceae (Compositae) family that is native to South America, particularly Brazil and Paraguay, where it is known as “stevia” or “honey leaf” for its powerful sweetness. Several studies have suggested that in addition to their sweetness, steviosides and their related compounds, including rebaudioside A and isosteviol, may offer additional therapeutic benefits. These benefits include anti-hyperglycaemic, anti-hypertensive, anti-inflammatory, anti-tumor, anti-diarrheal, diuretic, and immunomodulatory actions. Additionally, critical analysis of the literature supports the anti-bacterial role of steviosides on oral bacteria flora. The aim of this review is to show the emerging results regarding the anti-cariogenic properties of S. rebaudiana Bertoni. Data shown in the present paper provide evidence that stevioside extracts from S. rebaudiana are not cariogenic. Future research should be focused on in vivo studies to evaluate the effects on dental caries of regular consumption of S. rebaudiana extract-based products. Full article

(This article belongs to the Special Issue 20th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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Soy Isoflavones and Breast Cancer Cell Lines: Molecular Mechanisms and Future Perspectives

by Alina Uifălean, Stefanie Schneider, Corina Ionescu, Michael Lalk and Cristina Adela Iuga

Molecules 2016, 21(1), 13; https://doi.org/10.3390/molecules21010013 - 22 Dec 2015

Cited by 73 | Viewed by 14795

Abstract

The potential benefit of soy isoflavones in breast cancer chemoprevention, as suggested by epidemiological studies, has aroused the interest of numerous scientists for over twenty years. Although intensive work has been done in this field, the preclinical results continue to be controversial and [...] Read more.

The potential benefit of soy isoflavones in breast cancer chemoprevention, as suggested by epidemiological studies, has aroused the interest of numerous scientists for over twenty years. Although intensive work has been done in this field, the preclinical results continue to be controversial and the molecular mechanisms are far from being fully understood. The antiproliferative effect of soy isoflavones has been commonly linked to the estrogen receptor interaction, but there is growing evidence that other pathways are influenced as well. Among these, the regulation of apoptosis, cell proliferation and survival, inhibition of angiogenesis and metastasis or antioxidant properties have been recently explored using various isoflavone doses and various breast cancer cells. In this review, we offer a comprehensive perspective on the molecular mechanisms of isoflavones observed in in vitro studies, emphasizing each time the dose-effect relationship and estrogen receptor status of the cells. Furthermore, we present future research directions in this field which could provide a better understanding of the inner molecular mechanisms of soy isoflavones in breast cancer. Full article

(This article belongs to the Special Issue 20th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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Unfolded Protein Response and Macroautophagy in Alzheimer’s, Parkinson’s and Prion Diseases

by Irina Milisav, Dušan Šuput and Samo Ribarič

Molecules 2015, 20(12), 22718-22756; https://doi.org/10.3390/molecules201219865 - 18 Dec 2015

Cited by 27 | Viewed by 10622

Abstract

Proteostasis are integrated biological pathways within cells that control synthesis, folding, trafficking and degradation of proteins. The absence of cell division makes brain proteostasis susceptible to age-related changes and neurodegeneration. Two key processes involved in sustaining normal brain proteostasis are the unfolded protein [...] Read more.

Proteostasis are integrated biological pathways within cells that control synthesis, folding, trafficking and degradation of proteins. The absence of cell division makes brain proteostasis susceptible to age-related changes and neurodegeneration. Two key processes involved in sustaining normal brain proteostasis are the unfolded protein response and autophagy. Alzheimer’s disease (AD), Parkinson’s disease (PD) and prion diseases (PrDs) have different clinical manifestations of neurodegeneration, however, all share an accumulation of misfolded pathological proteins associated with perturbations in unfolded protein response and macroautophagy. While both the unfolded protein response and macroautophagy play an important role in the prevention and attenuation of AD and PD progression, only macroautophagy seems to play an important role in the development of PrDs. Macroautophagy and unfolded protein response can be modulated by pharmacological interventions. However, further research is necessary to better understand the regulatory pathways of both processes in health and neurodegeneration to be able to develop new therapeutic interventions. Full article

(This article belongs to the Special Issue 20th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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Progress in Studies on Rutaecarpine. II.—Synthesis and Structure-Biological Activity Relationships

by Jong-Keun Son, Hyeun Wook Chang and Yurngdong Jahng

Molecules 2015, 20(6), 10800-10821; https://doi.org/10.3390/molecules200610800 - 11 Jun 2015

Cited by 53 | Viewed by 7990

Abstract

Rutaecarpine is a pentacyclic indolopyridoquinazolinone alkaloid found in Evodia rutaecarpa and other related herbs. It has a variety of intriguing biological properties, which continue to attract the academic and industrial interest. Studies on rutaecarpine have included isolation from new natural sources, development of [...] Read more.

Rutaecarpine is a pentacyclic indolopyridoquinazolinone alkaloid found in Evodia rutaecarpa and other related herbs. It has a variety of intriguing biological properties, which continue to attract the academic and industrial interest. Studies on rutaecarpine have included isolation from new natural sources, development of new synthetic methods for its total synthesis, the discovery of new biological activities, metabolism, toxicology, and establishment of analytical methods for determining rutaecarpine content. The present review focuses on the synthesis, biological activities, and structure-activity relationships of rutaecarpine derivatives, with respect to their antiplatelet, vasodilatory, cytotoxic, and anticholinesterase activities. Full article

(This article belongs to the Special Issue 20th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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Potential Role of Olive Oil Phenolic Compounds in the Prevention of Neurodegenerative Diseases

by Jose Rodríguez-Morató, Laura Xicota, Montse Fitó, Magí Farré, Mara Dierssen and Rafael De la Torre

Molecules 2015, 20(3), 4655-4680; https://doi.org/10.3390/molecules20034655 - 13 Mar 2015

Cited by 182 | Viewed by 18838

Abstract

Adherence to the Mediterranean Diet (MD) has been associated with a reduced incidence of neurodegenerative diseases and better cognitive performance. Virgin olive oil, the main source of lipids in the MD, is rich in minor phenolic components, particularly hydroxytyrosol (HT). HT potent antioxidant [...] Read more.

Adherence to the Mediterranean Diet (MD) has been associated with a reduced incidence of neurodegenerative diseases and better cognitive performance. Virgin olive oil, the main source of lipids in the MD, is rich in minor phenolic components, particularly hydroxytyrosol (HT). HT potent antioxidant and anti-inflammatory actions have attracted researchers’ attention and may contribute to neuroprotective effects credited to MD. In this review HT bioavailability and pharmacokinetics are presented prior to discussing health beneficial effects. In vitro and in vivo neuroprotective effects together with its multiple mechanisms of action are reviewed. Other microconstituents of olive oil are also considered due to their potential neuroprotective effects (oleocanthal, triterpenic acids). Finally, we discuss the potential role of HT as a therapeutic tool in the prevention of neurodegenerative diseases. Full article

(This article belongs to the Special Issue 20th Anniversary of Molecules—Recent Advances in Medicinal Chemistry)

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