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Monday, November 21, 2016
Tuesday, November 8, 2016
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Current Medicinal Chemistry
Tuesday, November 1, 2016
Highlighted Article: Dis-organizing Centrosomal Clusters: Specific Cancer Therapy for a Generic Spread?
Dis-organizing Centrosomal Clusters: Specific Cancer Therapy for a Generic Spread?
Author(s):
D. Bhakta-Guha, M.E.M. Saeed, H.J. Greten and T. Efferth Pages 685 - 694 ( 10 )
Abstract:
Cancer is a leading cause of mortality and the annual incidence of new cancer cases is rising worldwide. Due to the frequent development of resistance and the side effects of established anti-cancer drugs, the quest for new drugs with improved therapeutic features goes on. In contrast to cytotoxic chemotherapy of the past, the concept of targeted chemotherapy attempts to increase specificity of therapy by attacking tumor-related mechanisms. A novel emerging treatment concept represents the inhibition of centrosomal clustering. The centrosome regulates mitotic spindle formation assuring uniform separation of chromosomes to daughter cells. Many tumors contain supernumerary centrosomes, which contribute to aneuploidy induction via multipolar mitotic spindle formation. As spindle multipolarity leads to cell death, tumor cells developed centrosomal clustering mechanism to prevent multipolar spindle formation by coalescence of multiple centrosomes into two functional spindle poles. Inhibition of centrosome clustering represents a novel strategy for drug development and leads to the formation of multipolar spindles and subsequent cell death. In the present review, we report advances in understanding the biology of centrosomal clustering as well as enlist compounds capable of inducing the formation of multipolar spindles such as indolquinolizines, integrin-linked kinase inhibitors (QLT-0267), noscapinoids (EM011), phthalamide derivatives (TC11), griseofulvin, phenanthridines (PJ-34), CCC1-01, CW069 GF-15, colcemid, nocodazole, paclitaxel, and vinblastine. We also present in silico result of compounds that bind to γ-tubulin under the ambit of centrosomal clustering inhibition. We observed maximum binding efficacy in GF-15, CW069, paclitaxel and larotaxel with GF-15 exhibiting least energy of -8.4 Kcal/mol and 0.7 μM Pki value.
Keywords:
Cancer, centrosomal clustering, multipolar spindle inducers, natural products, supernumerary centrosomes.
Affiliation:
Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Staudinger Weg 5, 55128 Mainz, Germany.
For More Information Please Visit Our Website Current Medicinal Chemistry
Sunday, October 23, 2016
Most Cited Article: Daclatasvir: The First of a New Class of Drugs Targeted Against Hepatitis C Virus NS5A
Daclatasvir: The First
of a New Class of Drugs Targeted Against Hepatitis C Virus NS5A
Author(s):
I. Gentile, F. Borgia, N. Coppola, A.R.
Buonomo, G. Castaldo and G. Borgia Pages 1391-1404 (14)
Abstract:
Hepatitis C virus (HCV) infection affects
about 160 million people worldwide. It is treated with pegylatedinterferon
(peg-IFN) and ribavirin, and in the case of patients affected by genotype 1,
also with a protease inhibitor (telaprevir or boceprevir). Despite a good
success rate, IFN-based combinations are contraindicated in several patients
(e.g. decompensated cirrhosis, patients with psychiatric disorders, severe
heart diseases or autoimmune disorders) and are associated with frequent
adverse events that ultimately reduce their use. Numerous oral drugs are in an
advanced phase of clinical development, and in some cases, in IFN-free
combinations. This review focuses on preclinical and clinical data regarding
daclatasvir (BMS-790052), which is a highly selective HCV NS5A replication
complex inhibitor effective against HCV genotypes 1, 2, 3 and 4. In vitro data
show that daclatasvir exerts a very potent antiviral effect against several HCV
genotypes. Its pharmacokinetics is optimal and allows once-a-day oral administration.
Its adverse event profile is good. Clinical data regarding its efficacy in
combination with peg-IFN, ribavirin or other direct antiviral agents are
impressive (rates of sustained virological response range between 60% and 100%
in treatment-naïve patients). The only drawback of this drug appears to be a
relatively low genetic barrier to resistance. In conclusion, daclatasvir,
especially in combinations with other antiviral agents, is a very promising
drug for the treatment of chronic hepatitis C.
Keywords:
Combination therapy, daclatasvir, hepatitis C
virus, Interferon-free, pegylated-interferon, polymerase inhibitors,
resistance, ribavirin.
Affiliation:
Department of Clinical Medicine and Surgery
(Ed. 18) – University of Naples “Federico II”, via S. Pansini, 5 I-80131
Naples, Italy.
Monday, October 17, 2016
Recent Trends in the Discovery of Small Molecule Blockers of Sodium Channels Volume 23, Issue 22
Article Details
Recent Trends in the Discovery of Small Molecule Blockers of
Sodium Channels
Voltage-gated sodium channels (VGSC) are responsible for the selective influx
of sodium ions in excitable cells. A number of physiological phenomena such as
muscle contraction, pain sensation, processing of neuronal information in the brain
as well as neuronal regulation of peripheral tissues rely on the activity of
these channels. On the other hand, abnormal activity of VGSC are implicated in
several pathological processes (e.g., cardiac arrhythmias, epilepsy, and
chronic pain) which in some cases (e.g., channelopathies such as myotonias) are
linked to specific gene mutations. As a result, VGSC have never stopped
attracting the attention of medicinal chemists and the quest for novel drugs to
treat these ion channels-associated diseases continues. In this review, VGSC
blocking agents reported in the last lustrum are scrutinised with the aim to
give a medicinal chemistry perspective on the most interesting compounds
classified on the basis of (i) potential therapeutic application, (ii) targeted
VGSC isoforms, and (iii) chemical scaffolds. Finally, the clinical potential of
selected drug candidates from each chemotype is evaluated by comparing their
ligand efficiency metrics. Possible routes for improvement of these preclinical
candidates are also discussed.
Voltage-gated sodium channels (VGSC) are responsible for the selective influx of sodium ions in excitable cells. A number of physiological phenomena such as muscle contraction, pain sensation, processing of neuronal information in the brain as well as neuronal regulation of peripheral tissues rely on the activity of these channels. On the other hand, abnormal activity of VGSC are implicated in several pathological processes (e.g., cardiac arrhythmias, epilepsy, and chronic pain) which in some cases (e.g., channelopathies such as myotonias) are linked to specific gene mutations. As a result, VGSC have never stopped attracting the attention of medicinal chemists and the quest for novel drugs to treat these ion channels-associated diseases continues. In this review, VGSC blocking agents reported in the last lustrum are scrutinised with the aim to give a medicinal chemistry perspective on the most interesting compounds classified on the basis of (i) potential therapeutic application, (ii) targeted VGSC isoforms, and (iii) chemical scaffolds. Finally, the clinical potential of selected drug candidates from each chemotype is evaluated by comparing their ligand efficiency metrics. Possible routes for improvement of these preclinical candidates are also discussed.
Sunday, October 9, 2016
Podcast From Peptides to Small Molecules: An Intriguing but Intricated Way to New Drugs
Podcast From Peptides to Small Molecules: An Intriguing but Intricated Way to New Drugs
Tuesday, October 4, 2016
Podcast Intracranial Aneurysms
Podcast Intracranial Aneurysms
Current Medicinal Chemistry , 23 Issue 21
Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
Articles from the journal Current Medicinal Chemistry , 23 Issue 21
- Update on Therapeutic Approaches for Rheumatoid Arthritis
- Current Trends on Antipsychotics: Focus on Asenapine
- Biosimilar Filgrastim in Autologous Peripheral Blood Hematopoietic Stem Cell Mobilization and Post-Transplant Hematologic Recovery
- G-Quadruplex Aptamers to Human Thrombin Versus Other Direct Thrombin Inhibitors: The Focus on Mechanism of Action and Drug Efficiency as Anticoagulants
- Human Tuberculosis. III. Current and Prospective Approaches in Anti-Tubercular Therapy
- Pompe Disease and Autophagy: Partners in Crime, or Cause and Consequence?
For details on the articles, please visit this link :: http://bit.ly/2bTRaly
courtesy by : https://benthamsciencepublishers.wordpress.com/2016/09/16/new-issue-current-medicinal-chemistry-23-issue-21/
Current Medicinal Chemistry, 23 Issue 15
Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
Articles from the journal in Current Medicinal Chemistry, 23 Issue 15
- Role of the Receptor Tyrosine Kinase Axl and its Targeting in Cancer Cells
- New Insight into 2-Methoxyestradiol- a Possible Physiological Link between Neurodegeneration and Cancer Cell Death
- Diaryl Urea: A Privileged Structure in Anticancer Agents
- Abscisic Acid: A Phytohormone and Mammalian Cytokine as Novel Pharmacon with Potential for Future Development into Clinical Applications
- Identifying S100B as a Biomarker and a Therapeutic Target For Brain Injury and Multiple Diseases
For details on the articles, please visit this link :: http://bit.ly/1UosfnO
courtesy by: https://benthamsciencepublishers.wordpress.com/2016/07/07/new-issue-current-medicinal-chemistry-23-issue-15/
Highlighted Article Flyer for the journal “Current Medicinal Chemistry”
courtesy by https://benthamsciencepublishers.wordpress.com/2016/08/01/highlighted-article-flyer-for-the-journal-current-medicinal-chemistry/
Thursday, August 11, 2016
Friday, June 24, 2016
Role of Tyrosine Isomers in Acute and Chronic Diseases Leading to Oxidative Stress - A Review
Author(s):
Gergő A. Molnár, Szilárd Kun, Eszter Sélley, Melinda Kertész, Lívia Szélig, Csaba Csontos, Katalin Böddi, Lajos Bogár, Attila Miseta and István WittmannPages 667-685 (19)
Abstract:
Oxidative stress plays a major role in the pathogenesis of a variety of acute and chronic diseases. Measurement of the oxidative stress-related end products may be performed, e.g. that of structural isomers of the physiological para-tyrosine, namely meta- and ortho-tyrosine, that are oxidized derivatives of phenylalanine. Recent data suggest that in sepsis, serum level of meta-tyrosine increases, which peaks on the 2nd and 3rd days (p<0.05 vs. controls), and the kinetics follows the intensity of the systemic inflammation correlating with serum procalcitonin levels. In a similar study subset, urinary meta-tyrosine excretion correlated with both need of daily insulin dose and the insulin-glucose product in non-diabetic septic cases (p<0.01 for both). Using linear regression model, meta-tyrosine excretion, urinary meta-tyrosine/para-tyrosine, urinary ortho-tyrosine/para-tyrosine and urinary (meta- + orthotyrosine)/ para-tyrosine proved to be markers of carbohydrate homeostasis.
In a chronic rodent model, we tried to compensate the abnormal tyrosine isomers using para-tyrosine, the physiological amino acid. Rats were fed a standard high cholesterol-diet, and were given para-tyrosine or vehicle orally. High-cholesterol feeding lead to a significant increase in aortic wall meta-tyrosine content and a decreased vasorelaxation of the aorta to insulin and the glucagon-like peptide-1 analogue, liraglutide, that both could be prevented by administration of para-tyrosine.
Concluding, these data suggest that meta- and ortho-tyrosine are potential markers of oxidative stress in acute diseases related to oxidative stress, and may also interfere with insulin action in septic humans. Competition of meta- and ortho-tyrosine by supplementation of para-tyrosine may exert a protective role in oxidative stress-related diseases.
Keywords:
Meta-tyrosine, ortho-tyrosine, para-tyrosine, sepsis, inflammation, oxidative stress, hormone resistance, carbohydrate metabolism.
Affiliation:
2nd Department of Medicine and Nephrological Center, Medical School, University of Pécs, Pacsirta str. 1., H-7624 Pécs, Hungary
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Serotonin 1A Receptors on Astrocytes as a Potential Target for the Treatment of Parkinson’s Disease
Author(s):
Ikuko Miyazaki and Masato AsanumaPages 686-700 (15)
Abstract:
Astrocytes are the most abundant neuron-supporting glial cells in the central nervous system. The neuroprotective role of astrocytes has been demonstrated in various neurological disorders such as amyotrophic lateral sclerosis, spinal cord injury, stroke and Parkinson’s disease (PD). Astrocyte dysfunction or loss-of-astrocytes increases the susceptibility of neurons to cell death, while astrocyte transplantation in animal studies has therapeutic advantage. We reported recently that stimulation of serotonin 1A (5-HT1A) receptors on astrocytes promoted astrocyte proliferation and upregulated antioxidative molecules to act as a neuroprotectant in parkinsonian mice. PD is a progressive neurodegenerative disease with motor symptoms such as tremor, bradykinesia, rigidity and postural instability, that are based on selective loss of nigrostriatal dopaminergic neurons, and with non-motor symptoms such as orthostatic hypotension and constipation based on peripheral neurodegeneration. Although dopaminergic therapy for managing the motor disability associated with PD is being assessed at present, the main challenge remains the development of neuroprotective or disease- modifying treatments. Therefore, it is desirable to find treatments that can reduce the progression of dopaminergic cell death. In this article, we summarize first the neuroprotective properties of astrocytes targeting certain molecules related to PD. Next, we review neuroprotective effects induced by stimulation of 5-HT1A receptors on astrocytes. The review discusses new promising therapeutic strategies based on neuroprotection against oxidative stress and prevention of dopaminergic neurodegeneration.
Keywords:
5-HT1A receptor, S100β, astrocyte, Parkinson’s disease, neuroprotection, dopaminergic neuron.
Affiliation:
Department of Medical Neurobiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
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Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases
Author(s):
Marisa Cabeza, Araceli Sánchez-Márquez, Mariana Garrido, Aylín Silva and Eugene BratoeffPages 792-815 (24)
Abstract:
This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate cancer and benign prostatic hyperplasia. It is a well known fact that dihydrotestosterone (DHT) is associated with the development of androgen-dependent afflictions. At the present time, several research groups are attempting to develop new steroidal and non-steroidal molecules with the purpose of inhibiting the synthesis and biological response of DHT. This review also discusses the most recent studies reported in the literature that describe the therapeutic potential of novel compounds, as well as the new drugs, principally inhibitors of 5α-reductase.
Keywords:
Benign prostatic hyperplasia, prostate cancer, 5-alpha reductase, 17-beta hydroxysteroid dehydrogenase, protein kinase A, androgen receptor, dehydroepiandrosterone derivatives, non-permeable testosterone conjugates, G proteins, PKA.
Affiliation:
Departamento De Sistemas Biológicos, Universidad Autónoma Metropolitana- Xochimilco Calzada Del Hueso No. 1100, México, D.F., C.P. 04960, México.
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Structure and Expression of Different Serum Amyloid A (SAA) Variants and their Concentration-Dependent Functions During Host Insults
Author(s):
Mieke De Buck, Mieke Gouwy, Ji Ming Wang, Jacques Van Snick, Ghislain Opdenakker, Sofie Struyf and Jo Van DammePages 1725-1755 (31)
Abstract:
Serum amyloid A (SAA) is, like C-reactive protein (CRP), an acute phase protein and can be used as a diagnostic, prognostic or therapy follow-up marker for many diseases. Increases in serum levels of SAA are triggered by physical insults to the host, including infection, trauma, inflammatory reactions and cancer. The order of magnitude of increase in SAA levels varies considerably, from a 10- to 100- fold during limited inflammatory events to a 1000-fold increase during severe bacterial infections and acute exacerbations of chronic inflammatory diseases. This broad response range is reflected by SAA gene duplications resulting in a cluster encoding several SAA variants and by multiple biological functions of SAA. SAA variants are single-domain proteins with simple structures and few post-translational modifications. SAA1 and SAA2 are inducible by inflammatory cytokines, whereas SAA4 is constitutively produced. We review here the regulated expression of SAA in normal and transformed cells and compare its serum levels in various disease states. At low concentrations (10-100 ng/ml), early in an inflammatory response, SAA induces chemokines or matrix degrading enzymes via Toll-like receptors and functions as an activator and chemoattractant through a G protein-coupled receptor. When an infectious or inflammatory stimulus persists, the liver continues to produce more SAA (≥ 1000 ng/ml) to become an antimicrobial agent by functioning as a direct opsonin of bacteria or by interference with virus infection of host cells. Thus, SAA regulates innate and adaptive immunity and this information may help to design better drugs to treat specific diseases.
Keywords:
SAA variants, FPR2, TLR2, leukocytes, chemotaxis, cytokines, inflammatory diseases, amyloidosis.
Affiliation:
University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, Minderbroedersstraat 10, 3000 Leuven, Belgium.
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