Navigating IL-6: From molecular mechanisms to therapeutic breakthroughs.

This concise review navigates the intricate realm of Interleukin-6 (IL-6), an important member of the cytokine family. Beginning with an introduction to cytokines, this narrative review unfolds with the historical journey of IL-6, illuminating its evolving significance. A crucial section unravels the three distinct signaling modes employed by IL-6, providing a foundational understanding of its versatile interactions within cellular landscapes. Moving deeper, the review meticulously dissects IL-6's signaling mechanisms, unraveling the complexities of its pleiotropic effects in both physiological responses and pathological conditions. A significant focus is dedicated to the essential role IL-6 plays in inflammatory diseases, offering insights into its associations and implications for various health conditions. The review also takes a therapeutic turn by exploring the emergence of anti-IL-6 monoclonal inhibitors, marking a profound stride in treatment modalities. Diving into the molecular realm, the review explores small molecules as agents for IL-6 inhibition, providing a nuanced perspective on diverse intervention strategies. As the review embarks on the final chapters, it contemplates future aspects, offering glimpses into potential research trajectories and the evolving landscape of IL-6-related studies.

Design, Synthesis and In Vitro Evaluation of Levodopa Stearic Acid Hydrazide Conjugate for the Management of Parkinson's DiseaseNovel Conjugate for Parkinson's Disease.

Parkinson's disease is the highest prevalent neurodegenerative disease in elderly individuals after Alzheimer's disease. The pathological identification for Parkinson's disease is loss of dopaminergic neurons in substantia nigra region of the brain that in turn leads to dopamine deficiency that affects the body's normal physiological and neurological disorder. The important drawback in the modality of treatment is levodopa is only supplying depleted dopamine in the brain, it does not affect neurodegeneration. Even though levodopa manages the disease, an alternative treatment strategy is required to stop or prevent further degeneration of neuron. The compound with neuroprotector activity suits the requirement. Of them, stearic acid plays a vital role in protecting neurons against oxidative stress through a Phosphoinositide 3-kinase-dependent mechanism. Hence, our present study aimed to design, synthesize, and characterize the levodopa stearic acid hydrazide conjugate. Additionally, evaluate the cytotoxicity of synthesized compound in SHSY5Y: cell lines. In brief, levodopa was conjugated to the stearic acid successfully and was confirmed with Fourier-transform infrared spectroscopy, Nuclear magnetic resonance, and Mass Spectroscopy. In vitro cell viability study in SHSY5Y: cell lines showed elevated cell viability in 0.134 µm concentration of Conjugate, and 0.563 µm concentration of levodopa. Showing that the synthesized compound could offer an improved treatment strategy for Parkinson's disease.

The identification of cianidanol as a selective estrogen receptor beta agonist and evaluation of its neuroprotective effects on Parkinson's disease models.

AIM: The present study aims to identify selective estrogen receptor beta (ERß) agonists and to evaluate the neuroprotective mechanism in Parkinson's disease (PD) models. MAIN METHODS: In-silico studies were carried out using Maestro and GROMACS. Neuroprotective activity and apoptosis were evaluated using cytotoxicity assay and flow cytometry respectively. Gene expression studies were carried out by reverse transcription polymerase chain reaction. Motor and cognitive functions were assessed by actophotometer, rotarod, catalepsy, and elevated plus maze. The neuronal population in the substantia nigra and striatum of rats was assessed by hematoxylin and eosin staining. KEY FINDINGS: Cianidanol was identified as a selective ERß agonist through virtual screening. The cianidanol-ERß complex is stable during the 200 ns simulation and was able to retain the interactions with key amino acid residues. Cianidanol (25 µM) prevents neuronal toxicity and apoptosis induced by rotenone in differentiated SH-SY5Y cells. Additionally, cianidanol (25 µM) increases the expression of ERß, cathepsin D, and Nrf2 transcripts. The neuroprotective effects of cianidanol (25 µM) were reversed in the presence of a selective ERß antagonist. In this study, we found that selective activation of ERß could decrease the transcription of α-synuclein gene. Additionally, cianidanol (10, 20, 30 mg/kg, oral) improves the motor and cognitive deficit in rats induced by rotenone. SIGNIFICANCE: Cianidanol shows neuroprotective action in PD models and has the potential to serve as a novel therapeutic agent for the treatment of PD.

Effect of Calcitriol in Inhibiting the Cancer Cell Growth and Promoting Apoptosis in ErbB2-positive Breast Cancer Cells.

BACKGROUND: Targeted therapies, specifically ErbB family tyrosine kinase inhibitors, have demonstrated potential for improving outcomes in patients with ErbB2-positive breast cancer. Despite their effectiveness, these therapies are associated with limitations, including high costs, side effects, drug resistance, lack of specificity, and toxicity. To overcome these challenges, drug repurposing has emerged as a promising strategy in breast cancer treatment. OBJECTIVE: The aim of this investigation was to assess the influence of calcitriol on breast cancer cell lines expressing ErbB2 and comparing its effects with the conventional treatment, neratinib. METHODS: We employed an MTT test to determine cell viability and utilized staining techniques to assess cell apoptosis. Flow cytometry was used to evaluate cell cycle arrest, while a scratch wound healing test was performed to examine cancer cell migration ability. Additionally, gene expression studies were conducted for calcitriol and neratinib to support our hypothesis regarding the ErbB2 gene. RESULTS: The repurposing of calcitriol demonstrated enhanced efficacy in suppressing cancer cell growth in ErbB2- positive breast cancer. Proportionally, calcitriol significantly reduced the viability of SK-BR-3 cells, similar to neratinib. Furthermore, calcitriol exhibited significant cytotoxicity against neratinib and substantially reduced breast cancer cell growth. These findings were corroborated by the wound healing assay, cell cycle arrest analysis, and gene expression studies, demonstrating comparable efficacy to the standard treatment, neratinib. CONCLUSION: The findings from this investigation offer compelling proof that highlights the promising role of calcitriol as an adjuvant drug with antiproliferative and antitumoral effects in the management of ErbB2-positive breast carcinoma patients. Therefore, we recommend further evaluation of calcitriol in clinical settings, particularly for the treatment of ErbB2-positive breast cancer, as it shows promise as a valuable therapeutic option.

Leveraging decagonal in-silico strategies for uncovering IL-6 inhibitors with precision.

Interleukin-6 upregulation leads to various acute phase reactions such as local inflammation and systemic inflammation in many diseases like cancer, multiple sclerosis, rheumatoid arthritis, anemia, and Alzheimer's disease stimulating JAK/STAT3, Ras/MAPK, PI3K-PKB/Akt pathogenic pathways. Since no small molecules are available in the market against IL-6 till now, we have designed a class of small bioactive 1,3 - indanedione (IDC) molecules for inhibiting IL-6 using a decagonal approach computational studies. The IL-6 mutations were mapped in the IL-6 protein (PDB ID: 1ALU) from thorough pharmacogenomic and proteomics studies. The protein-drug interaction networking analysis for 2637 FFDA-approved drugs with IL-6 protein using Cytoscape software showed that 14 drugs have prominent interactions with IL-6. Molecular docking studies showed that the designed compound IDC-24 (-11.8 kcal/mol) and methotrexate (-5.20) bound most strongly to the 1ALU south asian population mutated protein. MMGBSA results indicated that IDC-24 (-41.78 kcal/mol) and methotrexate (-36.81 kcal/mol) had the highest binding energy when compared to the standard molecules LMT-28 (-35.87 kcal/mol) and MDL-A (-26.18 kcal/mol). These results we substantiated by the molecular dynamic studies in which the compound IDC-24 and the methotrexate had the highest stability. Further, the MMPBSA computations produced energies of -28 kcal/mol and -14.69 kcal/mol for IDC-24 and LMT-28. KDeep absolute binding affinity computations revealed energies of -5.81 kcal/mol and -4.74 kcal/mol for IDC-24 and LMT-28 respectively. Finally, our decagonal approach established the compound IDC-24 from the designed 1,3-indanedione library and methotrexate from protein drug interaction networking as suitable HITs against IL-6.

Repurposing of FDA Approved Drugs and Neuropep peptides as Anticancer Agents Against ErbB1 and ErbB2.

ErbB1 and ErbB2 are the most important biological targets in cancer drug discovery and development of dual inhibitors for the cancer therapy. FDA approved drugs and Neuropep peptides were used to fit into the ATP binding site of the tyrosine kinases; ErbB1 and ErbB2 proteins. Cytoscape, iGEMDOCK, HPEPDOCK and DataWarrior softwares were used to study the role of these agents as anticancer drugs. Eleven FDA approved drugs and eleven Neuropep peptides showed the strongest 2D interactions and significant binding energy with the proteins. Invitro MTT anticancer assay revealed that, the test compounds, peptide YSFGL and doxorubicin showed significant IC50 value (µM) of 26.417±0.660 and 7.675±0.278 respectively which are compared with the lapatinib standard IC50 value (µM) of 2.380±0.357 against A549 cells and IC50 value (µM) of 39.047±0.770 and 8.313±0.435 respectively which are compared with the lapatinib standard IC50 value (µM) of 3.026±0.180 against MDA-MB-231 cells.

Vitamin D analog calcitriol for breast cancer therapy; an integrated drug discovery approach.

As breast cancer remains leading cause of cancer death globally, it is essential to develop an affordable breast cancer therapy in underdeveloped countries. Drug repurposing offers potential to address gaps in breast cancer treatment. Molecular networking studies were performed for drug repurposing approach by using heterogeneous data. The PPI networks were built to select the target genes from the EGFR overexpression signaling pathway and its associated family members. The selected genes EGFR, ErbB2, ErbB4 and ErbB3 were allowed to interact with 2637 drugs, leads to PDI network construction of 78, 61, 15 and 19 drugs, respectively. As drugs approved for treating non cancer-related diseases or disorders are clinically safe, effective, and affordable, these drugs were given considerable attention. Calcitriol had shown significant binding affinities with all four receptors than standard neratinib. The RMSD, RMSF, and H-bond analysis of protein-ligand complexes from molecular dynamics simulation (100 ns), confirmed the stable binding of calcitriol with ErbB2 and EGFR receptors. In addition, MMGBSA and MMP BSA also affirmed the docking results. These in-silico results were validated with in-vitro cytotoxicity studies in SK-BR-3 and Vero cells. The IC50 value of calcitriol (43.07 mg/ml) was found to be lower than neratinib (61.50 mg/ml) in SK-BR-3 cells. In Vero cells the IC50 value of calcitriol (431.05 mg/ml) was higher than neratinib (404.95 mg/ml). It demonstrates that calcitriol suggestively downregulated the SK-BR-3 cell viability in a dose-dependent manner. These implications revealed calcitriol has shown better cytotoxicity and decreased the proliferation rate of breast cancer cells than neratinib.Communicated by Ramaswamy H. Sarma.

Metal-Organic Framework in Pharmaceutical Drug Delivery.

Metal-organic frameworks (MOFs) are porous, crystalline materials made up of organic ligands and metal ions/metal clusters linked by coordinative bonds. This large family is becoming increasingly popular for drug delivery due to their tuneable porosity, chemical composition, size and shape, and ease of surface functionalization. There has been a growing interest over the last decades in the design of engineered MOFs with controlled sizes for a variety of biomedical applications. Starting with the MOFs classification adapted for drug delivery systems (DDSs) based on the types of constituting metals and ligands. MOFs are appealing drug delivery vehicles because of their substantial drug absorption capacity and slow-release processes, which protect and convey sensitive drug molecules to target areas. Other guest materials have been incorporated into MOFs to create MOF-composite materials, which have added additional functionalities such as externally triggered drug release, improved pharmacokinetics, and diagnostic aids. Magnetic nanoparticles in MOFs for MRI image contrast and polymer coatings that increase blood circulation time are examples of synthetically adaptable MOF-composites. By including photosensitizers, which exert lethal effects on cancer cells by converting tumour oxygen into reactive singlet oxygen (1O2), metalorganic frameworks have been employed for photodynamic treatment (PDT) of malignancies among a multitude of nanosized therapies. Importantly, a variety of representative MOF applications are described from the perspectives of pharmaceutics, disease therapy, and advanced drug delivery systems. However, because of their weak conductivity, selectivity, and lack of modification sites, MOF materials' uses in electrochemical biosensing are restricted. MOF-based composites provide excellent electrical conductivity and robust catalytic activity by adding functionalized nanoparticles into MOF structures, which process benefits over single component MOFs.

Phytochemical and in-vitro Biological Investigation of Indian Traditional Medicinal Plants for their Cytotoxicity and Hepatoprotective Potential.

OBJECTIVE: This study aimed to select 16 medicinal plants based on their folklore remedy for treating various diseases like inflammation, cancer, etc., and scientifically validate their potency. METHODS: Five among them, namely Centella asiatica (CA), Myristica fragrans (MF), Trichosanthes palmata (TP), Woodfordia fruticosa (WF), and Curculigo orchioides (CO), were scientifically confirmed through the extraction and in-vitro cytotoxic and hepatoprotective evaluation. Based on the cytotoxic and hepatoprotective results, the various fractions of CO were chosen for an in-depth phytochemical study to isolate and characterize active compounds by GC-MS. RESULTS: The results showed promising cytotoxic activity (i.e., IC50=<100 µg/ml) against HeLa cell lines and significant hepatoprotective activity in a dose-dependent manner on CCl4 intoxicated isolated hepatocyte cells. CONCLUSION: The present study confirmed the scientific evidence regarding the effectiveness of selected medicinal plants in HeLa and hepatocyte cells. Furthermore, a detailed study on their mechanism of action and clinical application is suggested.

Relevance of Machine Learning to Predict the Inhibitory Activity of Small Thiazole Chemicals on Estrogen Receptor.

BACKGROUND: Drug discovery requires the use of hybrid technologies for the discovery of new chemical substances. One of those interesting strategies is QSAR via applying an artificial intelligence system that effectively predicts how chemical alterations can impact biological activity via in-silico. AIM: Our present study aimed to work on a trending machine learning approach with a new opensource data analysis python script for the discovery of anticancer lead via building the QSAR model by using 53 compounds of thiazole derivatives. METHODS: A python script has been executed with 53 small thiazole chemicals using Google collaboratory interface. A total of 82 CDK molecular descriptors were downloaded from "chemdes" web server and used for our study. After training the model, we checked the model performance via cross-validation of the external test set. RESULTS: The generated QSAR model afforded the ordinary least squares (OLS) regression as R2 = 0.542, F=8.773, and adjusted R2 (Q2) =0.481, std. error = 0.061, reg.coef_ developed were of, - 0.00064 (PC1), -0.07753 (PC2), -0.09078 (PC3), -0.08986 (PC4), 0.05044 (PC5), and reg.intercept_ of 4.79279 developed through stats models, formula module. The performance of test set prediction was done by multiple linear regression, support vector machine, and partial least square regression classifiers of sklearn module, which generated the model score of 0.5424, 0.6422 and 0.6422 respectively. CONCLUSION: Hence, we conclude that the R2values (i.e. the model score) obtained using this script via three diverse algorithms were correlated well and there is not much difference between them and may be useful in the design of a similar group of thiazole derivatives as anticancer agents.

Plant Derived Immunomodulators; A Critical Review.

The concept of immunomodulation was proposed by Edward Jenner, while working on polio vaccine in 1796. Many of the autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, psoriatic arthritis and system lupus erythematosus, viral diseases and, some cancers are characterized with elevated levels of "immunocytokine" gene expression, including, tumor necrosis factor-α, various interleukins, cytotoxic T-cell antigen-4, B-cell activating factor. For the treatment of these diseases, the immunologically-based therapies play the major role. In these lines, the usage of phytomedicines as immunostimulants/ immunosuppressants have been enhanced considerably in last few decades and also used as a prophylactic treatment for various ailments. Phytochemicals such as flavonoids, terpenoids, polysaccharides, lactones, alkaloids, glycosides and saponins present in several plants, have been confirmed to exhibit immunomodulating properties. This review focuses on the traditional plants and their constituents which have been extensively used as immunomodulators. We have also highlighted the mechanism of action of these plant constituents related to autophagy and adjuvanticity of drugs.

Network-based Drug Repurposing: A Critical Review.

New drug development for a disease is a tedious, time-consuming, complex, and expensive process. Even if it is done, the chances for success of newly developed drugs are still very low. Modern reports state that repurposing the pre-existing drugs will have more efficient functioning than newly developed drugs. This repurposing process will save time, reduce expenses and provide more success rate. The only limitation for this repurposing is getting a desired pharmacological and characteristic parameter of various drugs from vast data about medications, their effects, and target mechanisms. This drawback can be avoided by introducing computational methods of analysis. This includes various network analysis types that use various biological processes and relationships with various drugs to simplify data interpretation. Some of the data sets now available in standard, and simplified forms include gene expression, drug-target interactions, protein networks, electronic health records, clinical trial results, and drug adverse event reports. Integrating various data sets and interpretation methods allows a more efficient and easy way to repurpose an exact drug for the desired target and effect. In this review, we are going to discuss briefly various computational biological network analysis methods like gene regulatory networks, metabolic networks, protein-protein interaction networks, drug-target interaction networks, drugdisease association networks, drug-drug interaction networks, drug-side effects networks, integrated network-based methods, semantic link networks, and isoform-isoform networks. Along with this, we briefly discussed the drug's limitations, prediction methodologies, and data sets utilised in various biological networks for drug repurposing.

Chandamarutha Chenduram, an Indian traditional Siddha preparation attenuated the neuronal degeneration in ischemic mice through ameliorating cytokines and oxy-radicals mediated EAAT-2 dysfunction.

ETHNOPHARMACOLOGICAL RELEVANCE: Chandamarutha Chenduram (CC), an Indian traditional Siddha preparation officially recorded in the Siddha formulary of India and its composition are widely used in the Siddha practice of neurological disorders like stroke/paralysis in India. However, the scientific validation and mechanistic evidence is lacking and yet to be elucidated. AIM OF THE STUDY: To establish the scientific evidences and to explore the possible neuroprotective mechanism of CC in cerebral ischemia. MATERIALS AND METHODS: Chemical standardization of the CC was performed using atomic absorption spectroscopy and gravimetric analysis. Acute toxicity study for CC in mice was performed in accordance with OECD 423 guidelines. CC (5 mg/kg) and CC (10 mg/kg) were investigated in bilateral common carotid occlusion (BCCAo) model in mice. After, behavioral assessments, the brain samples were collected and the hippocampus region was micro-dissected for neurotransmitter, neurobiochemicals and inflammatory cytokines estimation. The excitatory amino acid transporter-2 (EAAT-2) expressions was analyzed by RT-PCR to understand the possible molecular mechanism. In addition, hematoxylin and eosin staining of CA1 hippocampal brain region was performed to support the neuroprotective effect of CC in ischemic condition. RESULTS: Chemical standardization analysis showed that CC has acceptable range of mercury (0.82 ppm) and elemental sulphur (11% w/w). Also, other heavy metal limits were found to be less or not detectable. Toxicity study also evidenced the safety profile of CC. CC has significantly reversed the behavioral dysfunctions (p < 0.001) in global ischemic mice. Treatment with CC has attenuated the excitatory neurotransmitter glutamate, lipid peroxide, nitric oxide, cytokines (IL-1ß, TNF-α) (p < 0.001) and increased the antioxidant enzymes (SOD, CAT, GSH) and EAAT-2 expression level (p < 0.001) in ischemic brain. The hematoxylin and eosin staining in CA1 region of hippocampus also evidence the neuroprotective effect exhibited by CC. CONCLUSIONS: Treatment with CC has exhibited dose dependent effect and CC10 has shown significant protective effect in comparison to CC5 in most of the parameters studied. CC prevented further degeneration of neurons in cerebral ischemic mice through ameliorating inflammatory cytokines and oxy-radicals mediated EAAT-2 dysfunction and subsequent excitotoxicity in neurons.

Molecular docking analysis of α-Topoisomerase II with δ-Carboline derivatives as potential anticancer agents.

The enzyme, α-topoisomerase II (α-Topo II), is known to regulate efficiently the topology of DNA. It is highly expressed in rapidly proliferating cells and plays an important role in replication, transcription and chromosome organisation. This has prompted several investigators to pursue α-Topo II inhibitors as anticancer agents. δ-Carboline, a natural product, and its synthetic derivatives are known to exert potent anticancer activity by selectively targeting α-Topo II. Therefore, it is of interest to design carboline derivatives fused with pyrrolidine-2,5-dione in this context. δ-Carbolines fused with pyrrolidine-2,5-dione are of interest because the succinimide part of fused heteroaromatic molecule can interact with the ATP binding pocket via the hydrogen bond network with selectivity towards α-Topo II. The 300 derivatives designed were subjected to the Lipinski rule of 5, ADMET and toxicity prediction. The designed compounds were further analysed using molecular docking analysis on the active sites of the α-Topo II crystal structure (PDB ID:1ZXM). Molecular dynamic simulations were also performed to compare the binding mode and stability of the protein-ligand complexes. Compounds with ID numbers AS89, AS104, AS119, AS209, AS239, AS269, and AS299 show good binding activity compared to the co-crystal ligand. Molecular Dynamics simulation studies show that the ligand binding to α-Topo II in the ATP domain is stableand the protein-ligand conformation remains unchanged. Binding free energy calculations suggest that seven molecules designed are potential inhibitors for α-Topo II for further consideration as anticancer agents.

Identification of Drug Candidates for Breast Cancer Therapy Through Scaffold Repurposing: A Brief Review.

Conventional drug discovery is a time consuming and expensive expedition with less clinical preference achievement proportion intended for breast cancer therapy. Even if numerous novel approaches to the conformation of drugs have been introduced for breast cancer therapy, they are yet to be implemented in clinical practice. This tempting strategy facilitates a remarkable chance to take the entire benefit of existing drugs. Despite drug repurposing significantly decrease the investigational period and cost, it has got many objections and issues. Scaffold repurposing is an approach that procures a novel significance on the decrepit motto of "to commencement with a pristine drug" . Hence, we move into a probable and nearer approach, the exploitation of scaffolds, which was originally developed for other purposes, including anti-tumor activity. In this review, we summarize different drugs and scaffolds used in breast cancer therapy.

Identification of (2R,3R)-2-(3,4-dihydroxyphenyl)chroman-3-yl-3,4,5-trihydroxy benzoate as multiple inhibitors of SARS-CoV-2 targets; a systematic molecular modelling approach.

Coronavirus disease of 2019 (COVID-19) is a zoonotic disease caused by a new severe acute respiratory syndrome (SARS-CoV-2) which has quickly resulted in a pandemic. Recent anti-COVID-19 drug discoveries are leaning towards repurposing phytochemicals which have been previously reported for SARS and MERS-CoV outbreaks. However, they have been either virtually screened or tested so far against mono targets and the potent derivatives of virtually sorted lead molecules remain elusive. We aimed to identify the phytochemicals having potentials to inhibit SARS CoV-2 infection via multiple targets. The selected 132 phytochemicals were virtually screened using a structure based in silico technique against main protease (Mpro) which is a potential target of SARS CoV-2. Six compounds were selected based on the LibDock scores and further subjected to induced fit docking using the CDOCKER module of DS. Two compounds namely cinnamtannin-B and gallocatechin gallate were identified as top HITS against main protease (Mpro). Based on the Lipinski rule of five (L-ROF) and synthetic feasibility, gallocatechin gallate was taken for our further studies. Six analogues of gallocatechin gallate were screened against the next important targets such as RNA-dependent RNA polymerase (RdRp), angiotensin converting enzyme-2 (ACE2), transmembrane protease serine -2 (TMPRSS2) and interleukin-6 (IL-6) along with main protease (Mpro). Our molecular docking results reveal that a gallocatechin analogue (GC-2) namely (2R,3R)-2-(3,4-dihydroxyphenyl)chroman-3-yl-3,4,5-trihydroxy benzoate has shown potential to inhibit multiple targets of SARS CoV-2. Further, the molecular dynamics study was carried out to ascertain the stability of the GC-2 and RdRp complex.

Withdrawal Notice: Review on Dengue Virus Fusion/Entry Process and Their Inhibition by Small Bioactive Molecules

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Coumarin-Fatty Acid Conjugates as Potential ERα/AKT-1 Antagonists for ER Positive Breast Cancer.

BACKGROUND: Current drugs used for the treatment of hormone-dependent breast cancer function as anti-estrogens in the breast, in addition to Estrogen Receptor (ER) agonists in the uterus, thus elevate a woman's risk of developing uterine cancer. This is due to the lack of selective binding and partial agonistic effect of these drugs towards estrogen receptors. In recent years, therefore, researchers have turned their attention towards antiestrogens devoid of these agonist properties and thus have a mechanism of action different from the existing drugs. OBJECTIVE: In this context, we report here the design, development and in vitro evaluation of some novel pharmacophores containing coumarin and fatty acid scaffolds for their anti-breast cancer activity. METHODS: A library of coumarin-fatty acid conjugates was designed using structure-based drug design approach. The conjugates which have shown good in silico results were then synthesized, characterized and evaluated for their anti-breast cancer activity by MTT assay, Apoptotic assay, Cell proliferation assay, Estrogen binding assay and Gene expression study. RESULTS: Out of the fifteen compounds screened, two compounds, SAC-2 and LNAC-2, showed good activity with IC50 values 22µg/ml, 25µg/ml, respectively. These compounds suppressed the proliferation of ER overexpressed MCF-7 cells, increased ERα degradation and hence inactivate the ERα pathway. ER binding assay and gene expression RT-PCR study reveal that SAC-2 downregulated the expression of ERα receptor and AKT-1 gene. CONCLUSION: Compound SAC-2 is a good antagonist to ER and hence has a potential for treating breast cancer and other cancers where AKT plays an important role.

Enhanced oral bioavailability of an antipsychotic drug through nanostructured lipid carriers.

Olanzapine is an atypical antipsychotic, undergoes extensive first pass metabolism, also has poor aqueous solubility and belongs to BCS (Biopharmaceutical Classification System) Class II drug) exhibit low oral bioavailability. To overcome this and to enhance the bioavailability, intestinal lymphatic transport of drugs can be exploited through Nano structured lipid carriers (NLCs). The NLCs were formulated by solvent diffusion method using solid lipid (glyceryl tripalmitate), liquid lipid (castor oil) and surfactants (Pluronic F-68, Soylecithin). The formulated NLCs were characterized for physico-chemical properties, in-vitro release studies and in-vivo oral bioavailability. F6 has shown average particle size of 158.5 nm with PI of 0.115 indicating narrow particle size distribution and follows uni modal distribution. It was found that the batch with stearyl amine has a zeta potential of 28.39 mV which confers stability to the dispersion. Bioavailability studies indicate that there was more than 5½-fold increase in oral bioavailability in case of NLCs (F6) compared to olanzapine suspension which indicates that NLCs provided sustained release of the drugs, and these systems can be the preferred as drug carriers for lipophilic drugs in long term disease conditions such as schizophrenia for enhanced bioavailability.

Potential Pharmacological Inhibitors of Pim Kinase Under Clinical Trials.

Pim kinases, also known as Serine/Threonine kinases, are intensively studied protein drug targets in cancer research. They play crucial role in the regulation of signal transduction cascades that promote cell survival, proliferation and drug resistance. Pim kinases are overexpressed in several hematopoietic and solid tumors and support in vitro/in vivo malignant cell growth and survival, through cell cycle regulation and inhibition of apoptosis. Pim kinases do not have an identified regulatory domain, as they are constitutively active. They appear to be critical downstream effectors of a number of oncoproteins. When overexpressed, they mediate drug resistance to agents such as Rapamycin. X-ray crystallographic studies reveal that unlike other kinases, Pim kinases have a hinge region, which forms a unique binding pocket for ATP, offering a target for a large number of potent small-molecule Pim kinase inhibitors. Combination therapy of Pim kinase inhibitors with chemotherapeutic and other kinase modulators seems to produce an additive cytotoxic effect in cancer cells. Though clinical trials have been carried out on the first Pim inhibitory agent, SGI-1776, no concept data could be generated due to its early withdrawal. However, it has helped in accelerating the discovery of several novel Pim inhibitors in recent years. Current research on Pim kinase is expected to lead to a new generation of potent Pim kinase inhibitors with appropriate pharmacological profiles suitable for human cancer therapy in the near future. Herein, we review the synthetic route and mechanistical studies of Pim kinase inhibitors which are currently in human trials.