[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

Privileged structures have been widely used as an effective template in medicinal chemistry for drug discovery. Chalcone is a common simple scaffold found in many naturally occurring compounds. Many chalcone derivatives have also been prepared due to their convenient synthesis. These natural products and synthetic compounds have shown numerous interesting biological activities with clinical potentials against various diseases. This review aims to highlight the recent evidence of chalcone as a privileged scaffold in medicinal chemistry. Multiple aspects of chalcone will be summarized herein, including the isolation of novel chalcone derivatives, the development of new synthetic methodologies, the evaluation of their biological properties, and the exploration of the mechanisms of action as well as target identification. This review is expected to be a comprehensive, authoritative, and critical review of the chalcone template to the chemistry community.

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Chalcone: A Privileged Structure in Medicinal Chemistry.

Imidazole ring is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron-rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole-based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole-based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.

Comprehensive Review in Current Developments of Imidazole‐Based Medicinal Chemistry

Reactive oxygen species (ROS) play a pivotal role in biological processes and continuous ROS production in normal cells is controlled by the appropriate regulation between the silver lining of low and high ROS concentration mediated effects. Interestingly, ROS also dynamically influences the tumor microenvironment and is known to initiate cancer angiogenesis, metastasis, and survival at different concentrations. At moderate concentration, ROS activates the cancer cell survival signaling cascade involving mitogen-activated protein kinase/extracellular signal-regulated protein kinases 1/2 (MAPK/ERK1/2), p38, c-Jun N-terminal kinase (JNK), and phosphoinositide-3-kinase/ protein kinase B (PI3K/Akt), which in turn activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF). At high concentrations, ROS can cause cancer cell apoptosis. Hence, it critically depends upon the ROS levels, to either augment tumorigenesis or lead to apoptosis. The major issue is targeting the dual actions of ROS effectively with respect to the concentration bias, which needs to be monitored carefully to impede tumor angiogenesis and metastasis for ROS to serve as potential therapeutic targets exogenously/endogenously. Overall, additional research is required to comprehend the potential of ROS as an effective anti-tumor modality and therapeutic target for treating malignancies.

https://www.mdpi.com/2218-273X/9/11/735/pdf

Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements.

Untangling the most selective kinase inhibitors via pharmacological intervention remains one of the challenging affairs to date. Inaccordance to this drift, herein we describe the design and synthesis of a set of new heterocyclic analogues consisting of 6,7 dimethyl Quinoxaline, appended to a connector, employing Schiff base strategy (Compounds I - IX ). The compounds were characterised by various spectroscopic techniques and the kinase inhibition assay were performed on few prime members of the CMGC family namely the GSK3 b , DYRK1A and CLK1 receptors respectively, that have been known to be directly involved in hyperphosphorylation of Tau. Interestingly the biological evaluation results revealed that Compounds IV & V , with bromo/chloro functionalities in the aromatic core were advantaged of being highly selective towards the target GSK3b over others. To strengthen our analysis, we adopted molecular modelling studies, where compounds IV /V were redocked in the same grid 4AFJ, as that of the reference ligand, 5-Aryl-4-Carboxamide-1,3-Oxazole. Surprisingly, our investigation underpined that for both the compounds IV/V, a primary H-bonding existed between the designed molecules ( IV/V) and Val 135 residue in the receptor GSK3b, inline with the reference ligand. We attribute this interaction to instigate potency in the compounds. Indeed the other non-covalent interaction, between the derivative's aromatic nucleus and Arg 141/Thr 138 in the receptor GSK3b, might have been responsible for enhancing the selectivity in the targets. Overall, we feel that the present work depicts a logical demonstration towards fine tuning the efficacy of the inhibitors through systematic adjustment of electron density at appropriate positions in the aromatic ring be it the main quinoxaline or the other aromatic nucleus. Thus this pathway offers a convenient strategy for the development of efficient therapeutics for diversified neurodegenerative diseases like that of Alzheimer's.

Unravelling the Selectivity of 6,7-Dimethyl Quinoxaline Analogs for Kinase Inhibition: An Insight towards the Development of Alzheimer's Therapeutics.

Chewing gum cause waste management problems around the world.Many consumers of chewing gum do not dispose product properly and gum is littered in public places.The syenthetic polymer based chewing gum have adhesive texture which help it to stick to various places and make it difficult to clean of surfaces .Their is constant need to modify chewing gum base in such a manner that they are chemically degradable. In current study corn zein,which is a major corn endosperm protein is used to make chewing gum.Various plastisizer are used for formulation of corn zein gum.Corn zein shows sufficient biodegradation property.In current study charectarization of chewing gum is performed using texture analyser and results are reported

https://www.imedpub.com/articles/formulation-optimization-and-texture-characterization-of-environment-friendly-gum.pdf

Formulation, optimization and texture characterization of environment friendly gum

Cancer is a leading cause of death worldwide. The Janus kinase (JAK) signal transducer and activator of transcription (STAT) signalling pathway is activated abnormally, which promotes carcinogenesis. Several cytokines are important cancer drivers. These proteins bind to receptors and use the Janus kinase (JAK) and STAT pathways to communicate their responses. Cancer risks are linked to genetic differences in the JAK-STAT system. JAK inhibitors have shown to reduce STAT initiation, tissue propagation, and cell existence in preclinical investigations in solid tumour cell line models. JAK inhibitors, notably ruxolitinib, a, JAK1 or 2 blockers, make cell lines and mouse models more susceptible to radiotherapy, biological response modifier therapy, and oncolytic viral treatment. Numerous JAK antagonists have been or are now being evaluated in cancerous patients as monotherapy or by combining with other drugs in clinical studies. In preclinical investigations, certain JAK inhibitors showed promise anticancer effects; however, clinical trials explicitly evaluating their effectiveness against the JAK/STAT system in solid tumours have yet to be completed. JAK inhibition is a promising strategy to target the JAK/STAT system in solid tumours, and it deserves to be tested further in clinical studies. The function of directing Janus kinases (JAKs), an upstream accelerator of STATs, as a technique for lowering STAT activity in various malignant circumstances is summarized in this article, which will help scientists to generate more specific drug molecules in future.

The Emerging Role of Janus Kinase Inhibitors in the Treatment of Cancer.

Purpose: To prepare technetium-99m (99mTc)-labelled nanogel loaded with 5-fluorouracil (5-FU) containing synthesized gallic acid-stearylamine (GA-SA) conjugate in order to reduce its systemic toxicity and provide site-specific delivery to skin lesions.
Methods: Lipid nanocarrier-based 1 % (w/w) 5-FU nanogel containing GA-SA conjugate was successfully formulated. Parameters that included pH, viscosity and entrapment efficiency were measured. Furthermore, 1 % (w/w) 5-FU nanogel and 1 % (w/w) 5-FU commercial formulations were radiolabelled with 99mTc. The radiolabelled 99mTc-5-FU nanogel and commercial formulations were subjected to successive preclinical assessments with respect to radiochemical stability, biodistribution, and gamma scintigraphy in BALB/c mice, and pharmacokinetic studies in New Zealand albino rabbits.
Results: The entrapment efficiency of 5-FU in the nanogel preparation was 82.12 ± 1.2 %. The 5-FU nanogel formulation exhibited excellent radiolabelling efficiency (> 93 %) and high stability. Skin/blood localization ratios of 274.93 and 167.89 were obtained for topical radiolabelled drug-loaded 5-FU nanogel formulation and 5-FU commercial formulation, respectively, after 1 h of administration. Gamma scintigraphy and biodistribution studies showed that topically administered 99mTc-5-FU nanogel was distributed mostly in skin, when compared to marketed 5-FU formulation. Pharmacokinetic studies revealed low maximum activity in the blood (Cmax = 34.20 µg/mL), with low intensity (AUC) for topically administered 99mTc-5-FU nanogel formulation.
Conclusion: 5-FU nanogel enhances specific delivery of 5-FU at targeted sites and decreases its toxicity in tissues distant from the site of application. The results suggest that nanogel loaded with 5-FU containing synthesized GA-SA conjugate is a novel effective approach for the treatment of skin lesions.

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Biodistribution and pharmacokinetic studies on topically delivered technetium-99m-labeled 5-FU nanogel formulation for management of pre-cancerous skin lesions

QSAR study on N- (Aryl)-4-(azolylethyl) thiazole-5-carboxamides analogues, which are novel potent inhibitor of VEGF receptor II and I, were performed using topological, electronic and physicochemical descriptors. The results obtained demonstrate in detail, which specify that topological descriptors of the compounds play a significant role in developing QSAR models. The significance of presence and absence of substituents on particular position is successfully explored with the help of indicator variables. The results are critically discussed on the basis of multiple linear regression parameters.

Piyush Trivedi

Papers

Unravelling the Selectivity of 6,7-Dimethyl Quinoxaline Analogs for Kinase Inhibition: An Insight towards the Development of Alzheimer's Therapeutics.

Formulation, optimization and texture characterization of environment friendly gum

The Emerging Role of Janus Kinase Inhibitors in the Treatment of Cancer.

Biodistribution and pharmacokinetic studies on topically delivered technetium-99m-labeled 5-FU nanogel formulation for management of pre-cancerous skin lesions

QSAR study on N-(aryl)-4-(azolylethyl) thiazole-5-carboxamides: novel potent inhibitors of VEGF receptors I and II.