Press Release – Microwave-assisted iodine-catalyzed rapid synthesis of 6H-indolo[2,3-b]quinolines

This article by Dr. Bimal K. Banik et al. is published in Current Microwave Chemistry, Volume 4, 2017

 

Indoloquinoline alkaloids have received significant popularity because of their antimalarial and DNA intercalating properties as well as their use as folk medicines for the control of fever, amoebiasis and malaria. Related metabolites include cryptotackieine and norcryptotackieine which are linear indolo[2,3-b]quinoline alkaloids. These molecules have demonstrated numerous medicinal activities including antimicrobial, and cytotoxicity. They act through DNA intercalation and inhibition of topoisomerase II inhibition. Consequently, organic and medicinal chemists and biologists have become interested in their concise preparation and studies of their biological activities. A few synthetic routes have been developed for the preparation of these structurally unique and complex indole heterocycles. Interestingly, most of these available methods are one-pot methods. For example, high temperature reaction of molecular iodine-catalyzed reaction in diphenyl ether, pivalic acid and ruthenium-exchanged FAU-Y zeolite in 1,4-dioxane is performed. N-Bromosuccinimide at room temperature is found to be good for this purpose. The principal limitation is that almost all of these methods require a very long time. Moreover, the yields of the target molecules are low.

The current research is aimed to develop an efficient synthetic method for the synthesis of indoloquinoline alkaloids mentioned above. Considering the known procedures and analyzing the conditions of the experiments, the iodine-catalyzed tandem method is proved to be excellent. Despite the superiority of iodine, this method produces products with low to moderate yields, requires long reaction time and high temperature. Therefore, an improvement of molecular iodine-catalyzed reaction for this purpose is necessary.

Our research group has been exploring microwave-induced reactions for more than 25 years. Reactions conducted under microwave oven are known to be rapid and successful at much less drastic conditions. Moreover, they also produce the target molecules in better yields without giving side reactions in most of the examples. In conventional methods, unwanted side reactions in many instances lower the yields of the products or produce mixture of products and therefore, isolation of the desired compounds become tedious. On the basis of several successes on microwave-induced chemistry and our interests in the preparation of medicinally useful compounds, we have investigated the preparation of cryptotackieine and norcryptotackieine and their derivatives in automated microwave oven in tightly sealed reaction container.

Indole-3-carboxyaldehyde and two equivalents of aniline in presence of 10 mol% of molecular iodine at 600C and 300 watt power in a sealed vessel are irradiated in an automated microwave. It is interesting to note that the reaction proceeds rapidly with an increase in the yield of the product compared to the conventional heating (oil bath or heating mantle) at much higher temperature. The structure of the starting reactants and products suggests a most probable mechanism. Dehydration to imine from aldehyde and amine, nucleophilic reaction of the imine, annulation and subsequent aromatization occurs in a tandem process in a one-pot method.

This method is extended for the preparation of 6H-indolo[2,3-b]quinolines. As expected, the previously known compounds are synthesized very rapidly and with simple work-up, and without extensive purification. No solvent is used when one of the reactants is liquid or oil. These reactions are also performed in the presence of solvents (THF, MeOH, CHCl3, and CH2Cl2). THF and MeOH are proved to be the best solvent whereas CHCl3 and CH2Cl2 are moderately good for this method.

An expeditious simple and rapid microwave-assisted procedure for the synthesis of significant types of indoloquinolines using molecular iodine as catalyst in a one-pot is developed. The procedure described herein is the first rapid method for the synthesis of novel indoloquinolines. The rate acceleration by microwave-induced method is probably due to the alteration of the transition state of the series of reactions that occur in this tandem process. The benefit of this process is the lowered energy consumption compared to traditional method under reflux or high temperature that requires input of latent heat of vaporization. In this method, vaporization is not possible and so little expenditure of latent heat occurs. The non-ionizing radiation of the microwave is absorbed very efficiently by the reactants and polar solvents and thereby accelerates the process in an unbelievable way.

For more information about the article, please visit: http://www.eurekaselect.com/151565/article

Press Release for EurekAlert! Zebrafish as an animal model to study the effects of endocrine disruptors

zebra-fish

Water is vital for our survival. However, water quality is always a concern for public health authorities as it may contain diverse environmental pollutants, including endocrine disrupting chemicals (EDCs). Endocrine disrupting chemicals are one group of potentially hazardous substances that comprise natural and synthetic chemicals, with the ability to mimic endogenous hormones or interfere with their biosynthesis, metabolism, and normal functions. Common examples are bisphenol A, triclosan, phthalates, lead, mercury, nickel and polychlorinated biphenyls, among others.

Fish are known to be quite sensitive to the effects of EDCs and therefore, are employed as research models to study the possible impacts of these chemicals in humans. In a review led by Purdue University (USA) and the University of Cartagena (Colombia), a team of researchers has proposed the zebrafish as a model to predict the effects of EDCs on humans using toxicogenomic tools, such as microarrays or whole-genome sequencing. This is possible due to the fact that zebrafish genes that have significantly altered expression after exposure to EDCs are very similar to those found in humans. In addition, many of the glandular system found in zebrafish have similarities with those in humans, making this fish model suitable to study alterations on the endocrine system.

According to the authors, vitellogenin and aromatase cytochrome P450 are key genes that can be monitored in zebrafish to detect the presence of EDCs in water samples, especially at environmentally relevant concentrations.

Toxicogenomic tools also offer the possibility to find new mechanisms by which EDCs alter the reproductive status of zebrafish, allowing its use to test the safety of new products entering the market. The possibilities are immense and the goal is to continue finding new markers of toxicity, and therefore alternative bridges to link EDC exposure to common diseases in humans.

Co-authors of the paper include Karina Caballero-Gallardo, Jesus Olivero-Verbel (University of Cartagena, Cartagena, Colombia) and Jennifer L. Freeman (Purdue University, USA).

Reference: Caballero-Gallardo, K.; et al (2016). Toxicogenomics to Evaluate Endocrine Disrupting Effects of Environmental Chemicals Using the Zebrafish Model., DOI: 10.2174/1389202917666160513105959

For more information about the article, please visithttp://benthamscience.com/journals/current-genomics/volume/17/issue/6/page/515/

Press Release for EurekAlert! An innovative active platform for wireless damage monitoring of concrete structures

Structural Health Monitoring (SHM) is playing an important role in evaluationprocess of structural integrity of concrete structures mainly because much of the expected construction demands will have to be accommodated on existing concrete structures with widespread signs of deterioration.

Electromechanical Impedance (EMI) sensing approach has been proven that could be an effective alternative experimental approach for the damage detection of concrete structures even at very early-age stages. The wireless monitoring system proposed in the present work, denoted as Wireless impedance or Admittance Monitoring System (WiAMS), retains the benefits of low-budgeted EMI-based monitoring system but is not limited by the data acquisition device sampling rate in conventional EMI monitoring systems. This is achieved by utilizing a credit card-sized Raspberry Pi single-board computer which is capable of transferring data without a base station, can perform processing-hungry operations like video streaming by just simply adding the WiAMS device to the home network and perform SHM.

Moreover, the use of the Raspberry Pi expands the available hardware interfaces making the sensing device to be ready not only as an SHM control unit, but also as a base station for many other useful sensing platforms like motion with video, audio or environmental sensors.

WiAMS, as a whole, additionally offers extensive features such as remote control, high processing power, wireless data upload to an SQL database, email notifications, scheduled and iterative impedance (or admittance) measurements and frequency spans from 5kHz to 300 kHz with resolution down to 1 Hz.

The proposed WiAMS is successfully applied on various concrete specimens detecting damage even in very early-age stages by establishing a damage identification index based on extreme value statistics.

Reference: Providakis, C.; et al (2016). An Innovative Active Sensing Platform for Wireless Damage Monitoring of Concrete Structures. Current Smart Materials., DOI: 10.2174/2405465801666160830155120

For More information about the article, please visit: http://benthamscience.com/journals/current-smart-materials/article/145156/

 

Press Release for EurekAlert! The effect of exercise on vascular function and stiffness in type 2 diabetes

A new study from the University of Sydney has found that regular aerobic exercise can improve artery health in people with type 2 diabetes (T2D). The findings from this study have been published in Current Diabetes Reviews, and shed new light on exercise as a therapy in this population.

Compromised arterial health is an underlying mechanism that promotes the progression of cardiovascular disease (CVD), which is the leading cause of death in individuals with T2D. Effectively managing CVD risk in this population is a major challenge for health professionals.

Exercise is one of the first lines of treatment recommended by health professionals to manage the array of complications associated with T2D, such as controlling blood sugar. While it has been consistently shown that exercise is exceptionally beneficial for managing CVD, blood pressure medication is the main treatment used to manage arterial health problems.

This new study combined the results of nine randomised controlled clinical trials investigating the effects of exercise in T2D. Kimberley Way, who leads the research, says: “We focussed on measures looking at arterial stiffness, vascular reactivity and smooth muscle function, because there is evidence that suggests they are closely associated with disease progression and CVD mortality.”

Ms Way statesadds: “What we found from our analysis, is that aerobic exercise, such as brisk walking or cycling appears to have a significantly beneficial effect on the stiffness and the function of the smooth muscles in the arteries. This makes our findings very valuable to health professionals, because aerobic exercise can be used as a primary treatment strategy for arterial health, while also assisting with other health complications associated with T2D. “

Citation: Way, K.L., Keating, S. E., Baker, M.K., Chuter, V.H., & Johnson, N.A. (2016). The Effect of Exercise on Vascular Function and Stiffness In Type 2 Diabetes: A Systematic Review and Meta-Analysis. Current Diabetes Reviews, 12(4), 369-383.

For more information about the article, please visit http://benthamscience.com/journals/current-diabetes-reviews/article/134035/

Press Release for EurekAlert! Nanomaterials for neurology: State-of-the-art

Despite the numerous challenges associated with the application of nanotechnology in neuroscience, it promises to have a significant impact on our understanding of how the nervous system works, how it fails in disease, and the development of earlier and less-invasive diagnostic procedures so we can intervene in the pre-clinical stage of neurological disease before extensive neurological damage has taken place.

Chronic neurodegenerative disorders are disease processes in which intrinsic functions of brain cells and systems are progressively altered. The enormous growth in our understanding of the brain that has taken place over the past several decades has not been accompanied by a comparable increase in the efficacy of treatment of neurological disorders.

Because nanotechnology uses bio-engineered systems that interact with biological systems at a molecular level, it can offer impressive improvement in the treatment of these disorders. Nanotechnological tools operate on a dimensional scale that facilitates physical interactions with neurons as well as with the smaller glial cells. These small-scale tools and devices have great potential for medicinal and pharmaceutical applications. Nanomedicine has already made the current drug regimen more effective with attributes like sustained release, increased half-life, higher drug concentrations at target sites, reduced toxicity and fewer side effects.

Nanotechnology shows great promise for the diagnosis and therapy of neurodegenerative disorders by supporting and promoting functional regeneration of damaged neurons, providing neuroprotection, and enabling the delivery of drugs, growth factors, genes and cells across the blood brain barrier.

In this review we provide a neurobiological overview of key neurological disorders and describe the different types of nanomaterials in use. We present many of the different applications that advances in nanotechnology are having in the field of neurological sciences and discuss the issue of toxicity of the nanomaterials.

In conclusion, we weigh in on what the promises and challenges lie ahead of researchers for future developments in this groundbreaking field.

 

For More information about the article, please visit: http://benthamscience.com/journals/cns-and-neurological-disorders-drug-targets/volume/15/issue/10/page/1306/

Reference: Veloz-Castillo, M.F.; et al (2016). Nanomaterials for Neurology: State-of-the-Art. CNS Neurol. Disord. Drug Targets., DOI: 10.2174/1871527315666160801144637

Press Release for EurekAlert! Antibody drug conjugates have shown clinical efficacy with acceptable toxicity

press-release

 

Antibody Drug Conjugates (ADCs) have shown a clearly documented efficacy and acceptable toxicity and can be easily implemented in oncology departments where chemotherapy administration is a routine practice. A similar efficacy with acceptable toxicity has been documented with Antibody Radionuclide Conjugates (ARCs) which need to be injected with the help of a nuclear medicine department which can be a limitation for referral from an oncologist.

In a review collecting the clinical results of 11 studies including 598 patients treated with 6 ADCs and 9 studies (including 377 patients treated with 5 ARCs), toxicity was generally less frequent with ADCs than with ARCs but often led to more uncomfortable side effects. Both conjugates have shown some clinical efficacy in terms of survival (progression free survival or overall survival) depending on the tumor type, radiosensitive or not.

The good results of both conjugates could be significantly improved in the future.Targeting Cancer Stem Cells (CSC) using both cytotoxic payloads (drugs or radionuclides) could delay tumor relapse. Preclinical studies have shown a promising therapeutic index with long-term tumor regression warranting a clinical application.

Efficacy of ARCs could be improved with the use of alpha-emitting radionuclides which deliver a high fraction of their energy inside the targeted tumor cell leading to highly efficient killing especially for isolated tumor cells or clusters of malignant cells in the body.

The efficacy of both ADCs and ARCs could be enhanced by parallel treatment with immune checkpoint inhibitors thus providing synergistic immunogenic cell death.

In conclusion therapeutic immunoconjugates using chemotherapeutic drug or radionuclides as cytotoxic payloads have clearly shown clinical efficacy, which could be significantly improved in the near future.

For more information about the article, please visit: http://benthamscience.com/journals/current-cancer-therapy-reviews/volume/12/issue/1/page/54/

Reference: Chatal J.F. et al Therapeutic immunoconjugates. Which cytotoxic payload: chemotherapeutic drug (ADC) or radionuclide (ARC)? Current Cancer Therapy reviews, 2016 DOI: 10.2174/1573394712666160805121312

 

Press Release for EurekAlert! Nanomaterials for neurology: State-of-the-art

Despite the numerous challenges associated with the application of nanotechnology in neuroscience, it promises to have a significant impact on our understanding of how the nervous system works, how it fails in disease, and the development of earlier and less-invasive diagnostic procedures so we can intervene in the pre-clinical stage of neurological disease before extensive neurological damage has taken place.

Chronic neurodegenerative disorders are disease processes in which intrinsic functions of brain cells and systems are progressively altered. The enormous growth in our understanding of the brain that has taken place over the past several decades has not been accompanied by a comparable increase in the efficacy of treatment of neurological disorders.

Because nanotechnology uses bio-engineered systems that interact with biological systems at a molecular level, it can offer impressive improvement in the treatment of these disorders. Nanotechnological tools operate on a dimensional scale that facilitates physical interactions with neurons as well as with the smaller glial cells. These small-scale tools and devices have great potential for medicinal and pharmaceutical applications. Nanomedicine has already made the current drug regimen more effective with attributes like sustained release, increased half-life, higher drug concentrations at target sites, reduced toxicity and fewer side effects.

Nanotechnology shows great promise for the diagnosis and therapy of neurodegenerative disorders by supporting and promoting functional regeneration of damaged neurons, providing neuroprotection, and enabling the delivery of drugs, growth factors, genes and cells across the blood brain barrier.

In this review we provide a neurobiological overview of key neurological disorders and describe the different types of nanomaterials in use. We present many of the different applications that advances in nanotechnology are having in the field of neurological sciences and discuss the issue of toxicity of the nanomaterials.

In conclusion, we weigh in on what the promises and challenges lie ahead of researchers for future developments in this groundbreaking field.

For More information about the article, please visit http://benthamscience. com/ journals/ cns-and-neurological-disorders-drug-targets/ volume/ 15/ issue/ 10/ page/ 1306/

Reference: Veloz-Castillo, M.F.; et al (2016). Nanomaterials for Neurology: State-of-the-Art. CNS Neurol. Disord. Drug Targets., DOI: 10.2174/1871527315666160801144637

Press Release for EurekAlert! Recent advances in site specific conjugations of antibody drug conjugates

Antibody-drug conjugates take the advantage of antigen specificity of monoclonal antibodies to deliver highly potent cytotoxic drugs selectively to antigen-expressing tumor cells.

The recent approval of Adcetris™ and Kadcyla™ as well as emerging data from numerous ongoing clinical trials underscore the role of antibody-drug conjugates (ADCs) as a new therapeutic option for cancer patients. The site-specific conjugation technologies to develop next-generation ADCs have grown rapidly since then and have proven to be robust platform for generating next-generation homogeneous ADCs. These homogeneous ADCs have exhibited superior properties in terms of stability, manufacturing, and therapeutic index over the conventional ADCs. Although most ADCs currently in clinical development rely on conventional conjugation chemistries, the first wave of site-specific ADCs has been promoted to clinical trials. The increased understanding from the clinical investigation of current ADCs and site-specific bio-conjugation technologies has enabled scientists to accelerate the discovery and development of the next generation ADCs with defined and homogeneous compositions. Ongoing efforts to improve conjugation technologies and understanding of structure-activity relationship will certainly broaden the role of ADCs and other conjugates for the treatment of cancer and potentially other immuno-mediated diseases.

Read the recently published research on “Recent Advances in Site Specific Conjugations of Antibody Drug Conjugates (ADCs)” from the journal Current Cancer Drug Targets”

Press Release for EurekAlert!Cyclic opioid peptides

Peptide based drug candidates are being discovered at an increasingly rapid pace as therapeutics for many diseases and pain management. . For decades the opioid receptors have been an attractive therapeutic target for pain management and many endogenous opioid peptides have been known to produce opioid activity and analgesia. However, their therapeutic potential has been limited due to a major drawback regarding their use as CNS drugs, mainly due to a lack of biodistribution to the brain caused by poor metabolic stability and an inability to penetrate the blood brain barrier.

Cyclic opioid peptides with more constrained topographical structure possess high potential to overcome these drawbacks compared to their linear parent peptides. The benefits that come with employing cyclization can be further enhanced through the generation of polycyclic peptides by implementing additional cycles. The increased rigidity/topological geometry of polycyclic peptides further attenuates the dynamic nature of the compound, promoting greater affinities and selectivities at target receptors as well as increased in vivo stability. Opioid ligands generally have a short peptide chain and thus the realm of polycyclic peptides has yet to be explored, but should be considered for future designs in opioid receptor ligands.

In this review, a brief history of designing ligands for the opioid receptors, including classic linear and cyclic ligands, is discussed along with recent approaches and successes of cyclic peptide ligands for the receptors. Various scaffolds and approaches have been successfully used that highlight the benefit of cyclization and have provided many promising leads for novel therapeutics. The future of providing relief from disease states at the opioid receptors is encouraging as recent developments in our understanding about cyclic opioid peptide ligands are augmenting our capabilities of using biologically derived molecules as strong therapeutic agents.

Read the recently published research on Cyclic opioid peptides from the journal “Current Medicinal Chemistry”

Press Release for EurekAlert!Polypharamocological drugs in the treatment of epilepsy: The comprehensive review of marketed and new emerging molecules

The researchers in the laboratory of Dr. Manisha Tiwari have recently reviewed “Polypharamocological Drugs in the Treatment of Epilepsy: The Comprehensive Review of Marketed and New Emerging Molecules”. In this article, they have comprehensively discussed the role of polypharmacological drugs for the therapy of epilepsy. A comparable effect of polypharmacological drugs versus single-targeted drugs has also been discussed in detail. As we know epilepsy is a chronic neurological disorder having complex pathophysiology involving various enzymes, receptors and ion channels. The currently used antiepileptic drugs (AEDs) predominately target voltage-gated ion channels (Na+, Ca2+ and K+), GABAA receptor, glutamate receptor, synaptic vesicle 2A protein and carbonic anhydrase. One group of AEDs acts on a single target while another group acts via multiple targets to control seizure episodes. AEDs which act via multiple mechanisms or polypharmacological mechanisms of action have appeared as broad spectrum anticonvulsant agent and therefore, they provide a better choice to clinicians to manage drug-resistant epilepsies and various other epileptic syndromes.

For example, polypharmacological AEDs such as Phenobarbitone, Valproic acid, Oxcarbazepine, Felbamate, Topiramate, Gabapentin, Retigabine, Safinamide, Seletracetam, Fluorofelbamte, Carisbamate etc. are vital for managing epilepsy successfully, since decades. These polypharmacological drug treatment for epilepsy could be a better choice for management of various classes of seizures as compare to single target AEDs which may be effective in a limited class of seizures.

Many studies have shown that multi-targeted AEDs also reducedepression, anxiety, mood disorders, cognitive deficits and suicidal rates besides stopping seizure episodes, which leads to improvement of quality of life. Moreover, some of these polypharmacological drugs effectively cure more complex forms of epilepsy such as Lennox- gastaut syndrome, Rasmussen syndrome and status epilepticus. The detailed discussion in this review on polypharmacological AEDs may open a new avenue for discovery and development of more potentantiepileptic drug which prove better therapeutic regimen for epilepticpatients. So, in this race “polypharmacological drugs” stands out first for the treatment of epilepsy in comparison to single targeted antiepileptic drugs.

Read the recently published research on “Polypharmacological Drugs in the Treatment of Epilepsy: The Comprehensive Review of Marketed and New Emerging Molecules” from the journal “Current Pharmaceutical Design” by Dr. Shikha Kumari.

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