102,280 research outputs found
Evidence on selective binding to G-quadruplex DNA of isoflavones from Maclura pomifera by mass spectrometry and molecular docking
No full textG-quadruplex DNA stabilization mediated by small molecules is an attractive approach to modulate the transcription of guanine-rich sequences and contrast unregulated cell proliferation. Natural alkaloids have been reported to target this macromolecular arrangement, and such mechanism may be among these underlying the antiproliferative effect of some flavonoids. The binding affinity for G-quadruplex and double stranded DNA of 4 isoflavones from Maclura pomifera, namely osajin, pomiferin, scandenone and auriculasin, was evaluated using electrospray mass spectrometry (ESI-MS). The experiments pointed out that osajin and scandenone preferentially bind G-quadruplex. Moreover, since G-quadruplex stabilization is a crucial aim for triggering biological effects such as gene expression, collision-induced dissociation (CID) assays were performed to study the relative gas-phase kinetic stability of the DNA/ligand complexes. Osajin was identified as the best G-quadruplex stabilizer of the set, and in silico docking studies indicate that stacking is the preferred interaction motif of this natural compound
Synthesis, characterization and biophysical evaluation of novel G-Quadruplex stabilizing agents
No full textThe so-called quadruplex forming DNA sequences, with their peculiar feature of being particularly rich in guanines, can be found in many portions of both human and non-human genome. Considering the human genetic information, while one of the traditional localization of these sequences, the telomere, still represents an appealing target in anticancer therapy through indirect telomerase inhibition, many novel involvements are emerging in other portions of the genome. It has to be considered, first of all, that more than 376000 guanine rich sequences were identified in the human genome, with a preferential localization in some regions represented by proto-oncogenes. In this context Gquadruplexes could act as switches turning on and off, or regulating, the transcription of some sequences, according to the fact that structured DNA usually is not processed by the involved enzymes. G-quadruplexes have also been described over the years to be involved in many other key cellular processes such as chromosomal alignment, replication, transcription, genome recombination. This year another important piece of information was added to the quest for G-quadruplex stabilizers as antiviral agents. BRACO-19, an already described acridine-based stabilizing agent, was reported to show anti HIV-1 effects. These attractive targets boost the interest for the discovery of novel G-quadruplex stabilizer and
for the investigation of their binding properties with different nucleic acids (DNA, RNA or hybrids), expanding their possible application from the anticancer to the antiviral field.
The research project is aimed to the synthesis of small molecules acting as potential stabilizers of this peculiar super molecular arrangement reported to be relatively easily formed by guanine-rich sequences, such as the ones in telomeres. The molecules that were synthesized during this project share, in general, the common structural motifs of previously reported G-quadruplex stabilizing agents (athraquinones, anthracenes, naphtalenediimides, acridines) and are inspired to a compound previously synthesized by the research group of Prof. Zagotto that showed a remarkable activity in stabilizing Gquadruplex DNA.
Enhanced techniques such as molecular modeling, fluorescence melting, ESI-MS binding studies and ion mobility MS were then employed for the investigation of the capability of the synthesized molecules of interacting with, and stabilizing, G-quadruplex DNA. These complementary techniques enlightened the relevance of some structural aspects of the synthesized compounds, such as conformational properties, in influencing the efficacy of the DNA stabilization. The results allow to describe preliminary structure-activity relationship data and some promising compounds were finally disclosed
Efficient Performance Analysis Techniques for Stochastic Well-Formed Nets and Stochastic Process Algebras
No full textStochastic Well Formed Nets and Stochastic Process Algebras are high level description languages for the specification and the performance evaluation of concurrent systems. In both formalisms the performance analysis of the modelled system can be performed by generating a continuous time Markov chain of the size of the model state space: this often leads to the so called state space explosion problem which can prevent the possibility of completing the desired analysis. In this chapter we will present two state space aggregation techniques, each working on one of the two formalisms, allowing efficient performance analysis. The advantages and disadvantages of the two techniques will be discussed and compared
Dissenso e polemica religiosa nella Spositione a Dante di Lodovico Castelvetro da Modena (con uno sguardo al commento a Petrarca)
No full textThe present article analyzes the Lodovico Castelvetro’s argumentative strategies in the commentaries to Dante and Petrarca by shedding light on his Nicodemism
5-Hydroxy-3-(4-hydroxyphenyl)-8,8-dimethyl-6- (3-methylbut-2-enyl)pyrano[2,3-h]chromen-4-one
No full textNatural and semi-synthetic compounds are being studied as novel phosphodiesterase 5 (PDE5) inhibitors for the treatment of erectile dysfunction, pulmonary hypertension, and lower urinary symptoms. Maclura pomifera is a source of flavonoids, one of the main classes of molecules investigated for these purposes. The extraction of the natural isoflavone osajin and its modification to obtain a semi-synthetic derivative are described in this short note. 1H and 13C-nuclear magnetic resonance spectroscopy (NMR), mass spectrometry, high-performance liquid chromatography (HPLC) and spectroscopic characterization of the title compound are also hereby provided. Two-dimensional (2D) nuclear Overhauser effect spectroscopy (NOESY) NMR, supported by in silico conformational studies, was used to achieve a complete assignment of the proton signals, assessing the correct chemical structure of the compound. Heteronuclear single quantum coherence spectroscopy (HSQC) and heteronuclear multiple bond correlation (HMBC) NMR experiments were performed to assign 13C chemical shifts. Calculated chemical properties and preliminary in silico docking suggest that this molecule might be a promising candidate as PDE5 inhibitor
The Medicinal Chemistry of Natural and Semisynthetic Compounds against Parkinson's and Huntington's Diseases
No full textAmong the diseases affecting the central nervous system (CNS), neurodegenerations attract the interest of both the clinician and the medicinal chemist. The increasing average age of population, the growing number of patients, and the lack of long-term effective remedies push ahead the quest for novel tools against this class of pathologies. We present a review on the state of the art of the molecules (or combination of molecules) of natural origin that are currently under study against two well-defined pathologies: Parkinson's disease (PD) and Huntington's disease (HD). Nowadays, very few tools are available for preventing or counteracting the progression of such diseases. Two major parameters were considered for the preparation of this review: particular attention was reserved to these research works presenting well-defined molecular mechanisms for the studied compounds, and where available, papers reporting in vivo data were preferred. A literature search for peer-reviewed articles using PubMed, Scopus, and Reaxys databases was performed, exploiting different keywords and logical operators: 91 papers were considered (preferentially published after 2015). The review presents a brief overview on the etiology of the studied neurodegenerations and the current treatments, followed by a detailed discussion of the natural and semisynthetic compounds dividing them in different paragraphs considering their several mechanisms of action. © 2017 American Chemical Society
Overcoming resistance in non-small-cell lung cancer: A practical lesson for the medicinal chemist
No full textThe introduction of tyrosine kinase inhibitors (TKIs) in the clinical management of oncological patients spread the light on the use of selective, rationally designed small molecules for the treatment of cancer. First-generation TKIs bared high response against these malignancies, although the unavoidable shadow of resistance limits their long-term efficacy. Non-small-cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, and it is the first cause of cancer deaths worldwide for men and women. Traditional chemotherapy is marginally effective against this form, and erlotinib and gefitinib were introduced as first-line treatments based on the observation that the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), is mutated in several cases and, thus, represents a druggable target. EGFR-mutant and anaplastic lymphoma kinase (ALK)-positive patients are more responsive to these treatments, even if secondary mutations causing resistance soon emerged. The efforts of medicinal chemists are currently oriented toward the development of new generations of TKIs overcoming these obstacles. We here overview the novel strategies from the point of view of the medicinal chemist: the rational structure-based drug design that led to the development of irreversible and non-ATP-competitive inhibitors. Such improvements parallel the novel therapeutic strategies adopted in the clinic, which are also discussed
An overview of new possible treatments of Alzheimer's disease, based on natural products and semi-synthetic compounds
No full textBackground: Dementias and all related neurodegenerative diseases of the Central Nervous System (CNS) are a current issue arousing a great deal of interest in the international scientific community. This is due to the increasing number of patients suffering from these diseases. These pathologies represent a serious problem, not only concerning the quality of life of the patient, but in addition, the enormous economic efforts that society has to do for their treatment. There are currently a few strategies that are available in order to prevent the progression or to mitigate symptoms of the aforementioned diseases. This consideration is particularly true if we consider the specific pathology of Alzheimer's Disease (AD). Methods: We performed a literature search for peer-reviewed articles using different databases, such as PubMed or Scopus, and exploiting different keywords and different logical operators. Results: Ninety-eight papers were included in the review. Four papers give an overview of the background of the dementias all over the world. The remaining papers are focused on new possibilities of treatment with natural and semi-synthetic compounds for AD. Conclusion: The aim of this review is to give an overview of new and promising natural products and semi-synthetic compounds which could represent a source of "lead compounds" for the development of new potential drugs that could be a valid therapeutic strategy for the treatment of this pathology
A chemical approach to overcome tyrosine kinase inhibitors resistance: learning from chronic myeloid leukemia
No full textBackground: The possibilities of treatment for oncological diseases are growing enormously in the last decades. Unfortunately, these developments have led to the onset of resistances with regards to the new treatments. This is particularly true if we face with the therapeutic field of Tyrosine Kinase Inhibitors (TKIs). This review gives an overview of possible TKI resistances that can occur during the treatment of an oncologic diesease and available strategies that can be adopted, taking cues from a successful example such as CML. Methods: We performed a literature search for peer-reviewed articles using different databases, such as PubMed and Scopus, and exploiting different keywords and different logical operators. Results: 68 papers were included in the review. Twenty-four papers give an overview of the causes of TKIs resistances in the wide oncologic field. The remaining papers deal CML, deeply analysing the TKIs Resistances present in this pathology and the strategies adopted to overcome them. Conclusion: The aim of this review is to furnish an overview and a methodological guideline for the approach and the overcoming of TKIs Resistances
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