The Multiple Properties of Gliotoxin and Other Epipolythiodioxopiperazine Metabolites

2015 ◽  
Vol 68 (2) ◽  
pp. 178 ◽  
Author(s):  
Paul Waring ◽  
Christina L. L. Chai
Keyword(s):  
Potential Role ◽  
Diagnostic Marker ◽  
Biological Activities ◽  
Disulfide Bridge ◽  
Fungal Metabolite ◽  
Activity Data ◽  
Cellular Targets ◽  
Structure Activity ◽  
Uptake Mechanisms

The bridged disulfide ring of the fungal metabolite gliotoxin presents both synthetic challenges and confers the molecule with a variety of interesting biological activities. This review summarises recent synthetic strategies used to insert the disulfide and polysulfide bridge across the diketopiperazine ring and briefly describes the limited structure–activity data available for this class of molecule which clearly shows the presence of the disulfide bridge dominates their biological activities. The review also covers possible cellular targets of these toxins, the possible role for the disulfide bridge in toxicity and cellular uptake mechanisms, and the nature of the cell death induced by the epipolythiopiperazinedione toxins. The potential role of this simple molecule as a diagnostic marker for invasive aspergillosis is also discussed.

scholarly journals It Takes Two: Dimerization Is Essential for the Broad-Spectrum Predatory and Defensive Activities of the Venom Peptide Mp1a from the Jack Jumper Ant Myrmecia pilosula

Biomedicines ◽  
2020 ◽  
Vol 8 (7) ◽  
pp. 185 ◽  
Author(s):  
Samantha A. Nixon ◽  
Zoltan Dekan ◽  
Samuel D. Robinson ◽  
Shaodong Guo ◽  
Irina Vetter ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Haemonchus Contortus ◽  
Parasitic Nematode ◽  
Biological Activities ◽  
Fruit Fly ◽  
Cell Types ◽  
Activity Data ◽  
Chemical Complexity ◽  
Rational Engineering ◽  
Structure Activity

Ant venoms have recently attracted increased attention due to their chemical complexity, novel molecular frameworks, and diverse biological activities. The heterodimeric peptide ∆-myrtoxin-Mp1a (Mp1a) from the venom of the Australian jack jumper ant, Myrmecia pilosula, exhibits antimicrobial, membrane-disrupting, and pain-inducing activities. In the present study, we examined the activity of Mp1a and a panel of synthetic analogues against the gastrointestinal parasitic nematode Haemonchus contortus, the fruit fly Drosophila melanogaster, and for their ability to stimulate pain-sensing neurons. Mp1a was found to be both insecticidal and anthelmintic, and it robustly activated mammalian sensory neurons at concentrations similar to those reported to elicit antimicrobial and cytotoxic activity. The native antiparallel Mp1a heterodimer was more potent than heterodimers with alternative disulfide connectivity, as well as monomeric analogues. We conclude that the membrane-disrupting effects of Mp1a confer broad-spectrum biological activities that facilitate both predation and defense for the ant. Our structure–activity data also provide a foundation for the rational engineering of analogues with selectivity for particular cell types.

scholarly journals Small Molecules with Anti-Prion Activity

2020 ◽  
Vol 27 (33) ◽  
pp. 5446-5479 ◽  
Author(s):  
Carlo Mustazza ◽  
Marco Sbriccoli ◽  
Paola Minosi ◽  
Carla Raggi
Keyword(s):  
High Throughput Screening ◽  
Prion Diseases ◽  
Membrane Domains ◽  
Native Conformation ◽  
Cellular Targets ◽  
Prion Strains ◽  
Structure Activity ◽  
Mediated Oxidation ◽  
Indirect Action

Prion pathologies are fatal neurodegenerative diseases caused by the misfolding of the physiological Prion Protein (PrP<sup>C</sup>) into a &#946;-structure-rich isoform called PrP<sup>Sc</sup>. To date, there is no available cure for prion diseases and just a few clinical trials have been carried out. The initial approach in the search of anti-prion agents had PrP<sup>Sc</sup> as a target, but the existence of different prion strains arising from alternative conformations of PrP<sup>Sc</sup>, limited the efficacy of the ligands to a straindependent ability. That has shifted research to PrP<sup>C</sup> ligands, which either act as chaperones, by stabilizing the native conformation, or inhibit its interaction with PrP<sup>Sc</sup>. The role of transition-metal mediated oxidation processes in prion misfolding has also been investigated. Another promising approach is the indirect action via other cellular targets, like membrane domains or the Protein- Folding Activity of Ribosomes (PFAR). Also, new prion-specific high throughput screening techniques have been developed. However, so far no substance has been found to be able to extend satisfactorily survival time in animal models of prion diseases. This review describes the main features of the Structure-Activity Relationship (SAR) of the various chemical classes of anti-prion agents.

scholarly journals Critical Role of Cys168 in Noggin Protein's Biological Function

2005 ◽  
Vol 37 (3) ◽  
pp. 181-185
Author(s):  
Wei-Dong Liu ◽  
Xiang-Ling Feng ◽  
Cai-Ping Ren ◽  
Jian-Ling Shi ◽  
Xu-Yu Yang ◽  
...  
Keyword(s):  
Biological Activities ◽  
Critical Role ◽  
Ectopic Expression ◽  
Disulfide Bridge ◽  
Site Directed Mutagenesis ◽  
Morphogenetic Protein ◽  
Neural Cell Adhesion ◽  
A Site ◽  
The Relationship

Abstract Previous that noggin exerts its neural inducing effect by binding and antagonizing bone morphogenetic protein 4 (BMP4). In order to further clarify the relationship between the structure and the function of noggin, and elucidate the possible mechanism responsible for noggin-BMP4 interaction, we generated three noggin mutants, C168S, C174S and C197S, by using a site-directed mutagenesis method. Ectopic expression of wild-type (WT) noggin, C174S or C197S, in Xenopus animal caps (ACs) by mRNA injection converted the explants (prospective ectoderm) into neural tissue, as indicated by the neural-like morphology and expression of the neural cell adhesion molecule (NCAM) in the ACs. In contrast, ACs expressing C168S suffered an epidermal fate similar to the control caps. Similarly, among the three mutants, only C168S lost the dorsalizing function. These studies highlight the critical role played by Cys168 in noggin's biological activities. It probably participates in the formation of an intermolecular disulfide bridge.

scholarly journals The Potential Role of Flavonoids in Ameliorating Diabetic Cardiomyopathy via Alleviation of Cardiac Oxidative Stress, Inflammation and Apoptosis

2021 ◽  
Vol 22 (10) ◽  
pp. 5094
Author(s):  
Fatin Farhana Jubaidi ◽  
Satirah Zainalabidin ◽  
Izatus Shima Taib ◽  
Zariyantey Abd Hamid ◽  
Siti Balkis Budin
Keyword(s):  
Oxidative Stress ◽  
Risk Factors ◽  
Diabetic Cardiomyopathy ◽  
Mortality Risk ◽  
Potential Role ◽  
Therapeutic Potential ◽  
Biological Activities ◽  
Diabetic Patients ◽  
Remedial Actions

Diabetic cardiomyopathy is one of the major mortality risk factors among diabetic patients worldwide. It has been established that most of the cardiac structural and functional alterations in the diabetic cardiomyopathy condition resulted from the hyperglycemia-induced persistent oxidative stress in the heart, resulting in the maladaptive responses of inflammation and apoptosis. Flavonoids, the most abundant phytochemical in plants, have been reported to exhibit diverse therapeutic potential in medicine and other biological activities. Flavonoids have been widely studied for their effects in protecting the heart against diabetes-induced cardiomyopathy. The potential of flavonoids in alleviating diabetic cardiomyopathy is mainly related with their remedial actions as anti-hyperglycemic, antioxidant, anti-inflammatory, and anti-apoptotic agents. In this review, we summarize the latest findings of flavonoid treatments on diabetic cardiomyopathy as well as elucidating the mechanisms involved.

scholarly journals Potential Role of Garcinol as an Anticancer Agent

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Nadia Saadat ◽  
Smiti V. Gupta
Keyword(s):  
Potential Role ◽  
Therapeutic Potential ◽  
Biological Activities ◽  
Tropical Regions ◽  
Anticancer Properties ◽  
Garcinia Indica ◽  
Scientific Investigations

Garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit ofGarcinia indica, a plant found extensively in tropical regions. Although the fruit has been consumed traditionally over centuries, its biological activities, specifically its anticancer potential is a result of recent scientific investigations. The anticarcinogenic properties of garcinol appear to be moderated via its antioxidative, anti-inflammatory, antiangiogenic, and proapoptotic activities. In addition, garcinol displays effective epigenetic influence by inhibiting histone acetyltransferases (HAT 300) and by possible posttranscriptional modulation by mi RNA profiles involved in carcinogenesis.In vitroas well as somein vivostudies have shown the potential of this compound against several cancers types including breast, colon, pancreatic, and leukemia. Although this is a promising molecule in terms of its anticancer properties, investigations in relevant animal models, and subsequent human trials are warranted in order to fully appreciate and confirm its chemopreventative and/or therapeutic potential.

scholarly journals Concise Chemoenzymatic Total Synthesis and Identification of Cellular Targets of Cepafungin I

2020 ◽  
Author(s):  
Alexander Amatuni ◽  
Anton Shuster ◽  
Alexander Adibekian ◽  
Hans Renata
Keyword(s):  
Total Synthesis ◽  
Natural Product ◽  
Product Family ◽  
Enzymatic Oxidation ◽  
Hydroxyl Group ◽  
Cellular Targets ◽  
Structure Activity ◽  
Covalent Inhibitors

The natural product cepafungin I was recently reported to be one of the most potent covalent inhibitors of the 20S proteasome core particle through a series of in vitro activity assays. Here, we report a short chemoenzymatic total synthesis of cepafungin I featuring the use of a regioselective enzymatic oxidation to prepare a key hydroxylated amino acid building block in a scalable fashion. The strategy developed herein enabled access to a chemoproteomic probe, which in turn revealed the exceptional selectivity and potency of cepafungin I towards the b2 and b5 subunits of the proteasome. Further structure-activity relationship studies suggest the key role of the hydroxyl group in the macrocycle and the identity of the lipid tail in modulating the potency of this natural product family. This study lays the groundwork for further medicinal chemistry exploration to fully realize the anticancer potential of cepafungin I. <br>

scholarly journals Chemical Profiling and Cholinesterase Inhibitory Activity of Five Phaedranassa Herb. (Amaryllidaceae) Species from Ecuador

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2092 ◽  
Author(s):  
Raúl Moreno ◽  
Luciana R. Tallini ◽  
Cristina Salazar ◽  
Edison H. Osorio ◽  
Evelin Montero ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Potential Role ◽  
Biological Activities ◽  
New Drugs ◽  
Inhibitory Effects ◽  
Chemical Profiling ◽  
Cholinesterase Inhibitory Activity ◽  
Insight Into

It is estimated that 50 million people in the world live with dementia, 60–70% of whom suffer from Alzheimer’s disease (AD). Different factors are involved in the development of AD, including a reduction in the cholinergic neurotransmission level. The Amaryllidaceae plant family contains an exclusive, large, and still understudied alkaloid group characterized by a singular skeleton arrangement and a broad spectrum of biological activities. The chemistry and biodiversity of Ecuadorian representatives of the Phaedranassa genus (Amaryllidaceae) have not been widely studied. In this work, five Ecuadorian Phaedranassa species were examined in vitro for their activity towards the enzymes acetyl- (AChE) and butyrylcholinesterase (BuChE), and the alkaloid profile of bulb extracts was analyzed by GC-MS. The species Phaedranassa cuencana and Phaedranassa dubia showed the most AChE and BuChE inhibitory activity, respectively. To obtain insight into the potential role of the identified alkaloids in these inhibitory effects, docking experiments were carried out, and cantabricine showed in silico inhibitory activity against both cholinesterase structures. Our results show that Amaryllidaceae species from Ecuador are a potential source of new drugs for the palliative treatment of AD.

A Review on Anticancer Activities of Thiophene and Its Analogs

2020 ◽  
Vol 20 (19) ◽  
pp. 1944-1965
Author(s):  
Raghav Mishra ◽  
Nitin Kumar ◽  
Isha Mishra ◽  
Neetu Sachan
Keyword(s):  
Cancer Therapy ◽  
Biological Activities ◽  
Mortality Rates ◽  
Oxygen Species ◽  
Apoptosis Induction ◽  
Significant Progress ◽  
Anticancer Activities ◽  
Structure Activity ◽  
Thiophene Moiety

Cancer is the world's second-largest cause of mortality and one of the biggest global health concerns. The prevalence and mortality rates of cancer remain high despite significant progress in cancer therapy. The search for more effective, as well as less toxic treatment methods for cancer, is at the focus of current studies. Thiophene and its derivatives have surged as an influential scaffold, which, because of their appreciable diversity in biological activities, has drawn the concerned interest of the researchers in the field of medicinal chemistry. By the affluent introduction of its derivatives, which have antioxidant, anti-inflammatory, antimicrobial, and anticancer activities, the adaptability of the thiophene moiety has been displayed. The nature and positioning of the substitutions significantly impacted thiophene moiety activity. This decent array in the living response account about this moiety has picked plentiful researcher’s consideration to inquire about it to its peculiar potential across certain activities. In the field of cancer therapy against different cancer cells, the structure-activity relationship for each of the derivatives showed an excellent understanding of thiophene moiety. Information from the various articles revealed the key role of thiophene moiety and its derivatives to develop the vital lead compound. The essential anticancer mechanisms identified include inhibition of the topoisomerase, inhibition of tyrosine kinase, tubulin interaction and apoptosis induction through the activation of reactive oxygen species. This review is an endeavor to promote the anticancer potential of the derivatives, whether having thiophene or condensed thiophene as a core moiety or as a substituent that can lead in the future to synthesize varieties of chemotherapeutic entities in the field of cancer treatment.

scholarly journals Concise Chemoenzymatic Total Synthesis and Identification of Cellular Targets of Cepafungin I

2020 ◽  
Author(s):  
Alexander Amatuni ◽  
Anton Shuster ◽  
Alexander Adibekian ◽  
Hans Renata
Keyword(s):  
Total Synthesis ◽  
Natural Product ◽  
Product Family ◽  
Enzymatic Oxidation ◽  
Hydroxyl Group ◽  
Cellular Targets ◽  
Structure Activity ◽  
Covalent Inhibitors

The natural product cepafungin I was recently reported to be one of the most potent covalent inhibitors of the 20S proteasome core particle through a series of in vitro activity assays. Here, we report a short chemoenzymatic total synthesis of cepafungin I featuring the use of a regioselective enzymatic oxidation to prepare a key hydroxylated amino acid building block in a scalable fashion. The strategy developed herein enabled access to a chemoproteomic probe, which in turn revealed the exceptional selectivity and potency of cepafungin I towards the b2 and b5 subunits of the proteasome. Further structure-activity relationship studies suggest the key role of the hydroxyl group in the macrocycle and the identity of the lipid tail in modulating the potency of this natural product family. This study lays the groundwork for further medicinal chemistry exploration to fully realize the anticancer potential of cepafungin I. <br>

scholarly journals Role of Chemokine Network in the Development and Progression of Ovarian Cancer: A Potential Novel Pharmacological Target

2010 ◽  
Vol 2010 ◽  
pp. 1-15 ◽  
Author(s):  
Federica Barbieri ◽  
Adriana Bajetto ◽  
Tullio Florio
Keyword(s):  
Ovarian Cancer ◽  
Cancer Biology ◽  
Potential Role ◽  
Biological Activities ◽  
Cancer Cell Proliferation ◽  
Aberrant Expression ◽  
Chemokine Ligand ◽  
Immunosuppressive Cells ◽  
Cxcr4 Axis

Ovarian cancer is the most common type of gynecologic malignancy. Despite advances in surgery and chemotherapy, the survival rate is still low since most ovarian cancers relapse and become drug-resistant. Chemokines are small chemoattractant peptides mainly involved in the immune responses. More recently, chemokines were also demonstrated to regulate extra-immunological functions. It was shown that the chemokine network plays crucial functions in the tumorigenesis in several tissues. In particular the imbalanced or aberrant expression of CXCL12 and its receptor CXCR4 strongly affects cancer cell proliferation, recruitment of immunosuppressive cells, neovascularization, and metastasization. In the last years, several molecules able to target CXCR4 or CXCL12 have been developed to interfere with tumor growth, including pharmacological inhibitors, antagonists, and specific antibodies. This chemokine ligand/receptor pair was also proposed to represent an innovative therapeutic target for the treatment of ovarian cancer. Thus, a thorough understanding of ovarian cancer biology, and how chemokines may control these different biological activities might lead to the development of more effective therapies. This paper will focus on the current biology of CXCL12/CXCR4 axis in the context of understanding their potential role in ovarian cancer development.

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