35 results on '"Natarajan SR"'
Search Results
2. Signal processing framework for the detection of ventricular ectopic beat episodes
- Author
-
Avvaru Srinivasulu and Natarajan Sriraam
- Subjects
cardiac episode detection ,cross-database ,electrocardiogram ,machine learning classification ,ventricular ectopic beat ,Medical technology ,R855-855.5 - Abstract
The Holter monitor captures the electrocardiogram (ECG) and detects abnormal episodes, but physicians still use manual cross-checking. It takes a considerable time to annotate a long-term ECG record. As a result, research continues to be conducted to produce an effective automatic cardiac episode detection technique that will reduce the manual burden. The current study presents a signal processing framework to detect ventricular ectopic beat (VEB) episodes in long-term ECG signals of cross-database. The proposed study has experimented with the cross-database of open-source and proprietary databases. The ECG signals were preprocessed and extracted the features such as pre-RR interval, post-RR interval, QRS complex duration, QR slope, and RS slope from each beat. In the proposed work, four models such as support vector machine, k-means nearest neighbor, nearest mean classifier, and nearest RMS (NRMS) classifiers were used to classify the data into normal and VEB episodes. Further, the trained models were used to predict the VEB episodes from the proprietary database. NRMS has reported better performance among four classification models. NRMS has shown the classification accuracy of 98.68% and F1-score of 94.12%, recall rate of 100%, specificity of 98.53%, and precision of 88.89% with an open-source database. In addition, it showed an accuracy of 99.97%, F1-score of 94.54%, recall rate of 98.62%, specificity of 99.98%, and precision of 90.79% to detect the VEB cardiac episodes from the proprietary database. Therefore, it is concluded that the proposed framework can be used in the automatic diagnosis system to detect VEB cardiac episodes.
- Published
- 2023
- Full Text
- View/download PDF
3. Next-generation sequencing--based genetic testing and phenotype correlation in retinitis pigmentosa patients from India
- Author
-
Parveen Sen, Natarajan Srikrupa, Puja Maitra, Sundaramurthy Srilekha, Periyasamy Porkodi, Harshavardhini Gnanasekaran, Muna Bhende, Vikas Khetan, Sinnakaruppan Mathavan, Pramod Bhende, Dhanashree Ratra, Rajiv Raman, Chetan Rao, and Sarangapani Sripriya
- Subjects
genotype–phenotype correlation ,next-generation sequencing ,retinitis pigmentosa ,Ophthalmology ,RE1-994 - Abstract
Purpose: Inherited retinal dystrophies (IRD) are a heterogeneous group of retinal diseases leading to progressive loss of photoreceptors through apoptosis. Retinitis pigmentosa (RP) is considered the most common form of IRD. Panel-based testing in RP has proven effective in identifying the causative genetic mutations in 70% and 80% of the patients. This is a retrospective, observational, single-center study of 107 RP patients who had undergone next-generation sequencing-based targeted gene panel testing for IRD genes. These patients were inspected for common phenotypic features to arrive at meaningful genotype–phenotype correlation. Methods: Patients underwent complete ophthalmic examination, and blood was collected from the proband for DNA extraction after documenting the pedigree. Targeted Next Generation Sequencing (NGS) was done by panel-based testing for IRD genes followed by co-segregation analysis wherever applicable. Results: Of the 107 patients, 72 patients had pathogenic mutations. The mean age of onset of symptoms was 14 ± 12 years (range: 5–55). Mean (Best Corrected Visual Acuity) BCVA was 6/48 (0.9 logMAR) (range 0.0–3.0). At presentation, over one-third of eyes had BCVA worse than 6/60 (
- Published
- 2023
- Full Text
- View/download PDF
4. An evaluation of concordance between linear measurements obtained from conventional, digital and reconstructed three-dimensional printed orthodontic models: An in vitro study
- Author
-
Shetty Shravan, Natarajan Srikant, Nambiar Supriya, Shetty Prithvi, Chengappa Kavery, and Shetty Mukul
- Subjects
dental models ,digital technology ,three-dimensional printing ,Medicine - Abstract
Objective: To evaluate the potential use of digital and reconstructed three-dimensional printed models as an alternative to conventional plaster models by assessing the accuracy of their linear measurements.
- Published
- 2022
- Full Text
- View/download PDF
5. Anxiety, Depression, and Other Emotional Disorders during the COVID-19 Pandemic: A Narrative Review of the Risk Factors and Risk Groups
- Author
-
Polina Kassaeva, Elena Belova, Ekaterina Shashina, Denis Shcherbakov, Valentina Makarova, Boris Ershov, Vitaly Sukhov, Nadezhda Zabroda, Natarajan Sriraam, Oleg Mitrokhin, and Yury Zhernov
- Subjects
COVID-19 ,risk factors ,self-isolation ,lockdown ,mental health ,emotional disorders ,Science - Abstract
The COVID-19 pandemic has affected many aspects of our lives, including mental health. Identifying risk factors and risk groups associated with anxiety, depression, and other emotional disorders for reasons related to the COVID-19 pandemic is highly relevant. This narrative review aims to summarize the evidence to date on risk factors for emotional disorders during the COVID-19 pandemic in order to identify the risk groups of people in need of early psychiatric and psychological assistance, point out the controversial data on the influence of risk factors on emotional disorders in COVID-19, and finally offer recommendations for alleviating symptoms of anxiety, depression, and other emotional disorders in such people. According to the current literature, being under the age of 40, being female, having contact with a COVID-infected person, and watching the news about COVID-19 for more than 3 h a day all increase the likelihood of anxiety, depression, and sleep disturbances. Healthcare workers, particularly nurses, working in the COVID-19 hot zone suffer more from sleep disorders, anxiety, and depression. It is also noted that people with a previous psychiatric history, in addition to increased risks of anxiety and depression, have an increased risk of relapse during the COVID-19 pandemic. The same is true for people who have had episodes of substance abuse in the past. Aside from socioeconomic factors, the mental wellbeing of those who have had COVID-19 is also impacted by biological factors (using anti-COVID-19 drugs, COVID-19-associated immunothrombosis and venous thromboembolism, interferon-gamma-related cytokine storm, etc.), resulting in a wide range of acute and long-term cognitive disorders. During the restricted resource time, the aforementioned risk groups should be prioritized for prevention, early identification, and proper treatment of potential emotional disorders. The risk factors that were found in this narrative review, as well as how they interact and change over time, will help understand why some studies of at-risk groups do not agree with each other, justify new preventive measures, and strengthen existing programs to keep people’s mental health in check during this pandemic and other emergencies.
- Published
- 2022
- Full Text
- View/download PDF
6. Amplification of light in sol-gel based Nd-glass waveguides
- Author
-
Natarajan, SR, Ramamurthi, Anand V, Selvarajan, Ananth, Muthuraman, M, Patil, KC, Honkanen, Seppo, and Jiang, Shibin
- Subjects
Electrical Communication Engineering - Abstract
Integrated optic planar waveguides fabricated by sol-gel method by doping neodymium $(Nd^{3+})$ in glass were studied for gain properties. To our knowledge, this is the first time that a theoretical model based on atomic susceptibility $(X_{as})$ is applied to the study of sol-gel based Nd-glass waveguide amplifier. Single pass amplification through these waveguides using this theory correlates well with the experimental results. As we see a strong dependence of $X_{as}$ in the observed gain coefficient, it is also possible to extend this theory to the case of inhomogeneously distributed Nd-atomic clusters in the gain medium. Studies on the absorption spectra of the samples showed a strong peak at $\lambda=585 nm$, which was used as the wavelength for pumping the waveguide. We note that a net gain of over 15 dB is achievable over a few cm's of the waveguide, assuming a homogeneous dispersion of the dopant ions in the medium. The precursors for the sol were TEOS (Tetraethyl orthosilicate) and TPOT (Titanium(IV) isopropoxide) in the ratio of 4:1 and $Nd_2O_3$ was used as the dopant. The concentration of the $Nd^{3+}$ in the waveguide was 2.5 at.%. On a clean glass substrate, with typical dimensions of 2 cm x 1 cm, spincoated films comprising of multi-layers, produced a thickness of approximately 4 micrometers and a refractive index change of 0.0476 as revealed by the in-line measurements using the prism coupling technique. The samples supported two modes at $\lambda=633 nm$.
- Published
- 1998
7. Analysis of gain characteristics of Nd-doped sol-gel based waveguide amplifier
- Author
-
Natarajan, SR, Srinivas, T, and Selvarajan, A
- Subjects
Electrical Communication Engineering - Abstract
In this paper, we present an analysis of optical amplification properties of Nd-doped planar waveguides on glass substrates fabricated by sol-gel process. Modified gain characteristics are determined from the susceptibility profile and the waveguide dispersion properties. The waveguide dispersion properties are represented by the propagation coefficient variation with optical frequency, \beta(\omega). This is determined by solving the non-linear dispersion equation using the waveguide structural parameters, such as, the transverse refractive index profile, the waveguide film thickness and the operating optical frequency. The susceptibility profile, \chi(\omega), is determined using the measured absorption spectra from the fabricated waveguide samples. The analysis is facilitated by fitting an appropriate Gaussian distribution to the measured absorption spectra at the resonant frequency. It is observed that the gain profile is modified asymmetrically by the waveguide parameters
- Published
- 1998
8. Fabrication of rare-earth doped sol-gel based composite planar optical waveguides on glass
- Author
-
Natarajan, SR, Srinivas, T, Joseph, MJ, Selvarajan, A, Lampropoulos, George A, and Lessard, Roger A
- Subjects
Electrical Communication Engineering - Abstract
Incorporation of active materials, such as neodymium $(Nd^{3+})$ and erbium $(Er^{3+})$ in suitable host media has potential applications in lasers and amplifiers. We have fabricated composite planar waveguides on glass substrates doped with $Nd^{3+}$ and $Er^{3+}$ ions using the sol-gel process. The composite sol-gel was prepared using polyvinylpyrrolidone as the organic part, while tetraethyl orthosilicate and titanium isopropoxide formed the inorganic part. The samples were prism coupled and it was found that they supported a single mode at λ=633 nm. The gain measurement of the $Nd^{3+}$ samples have also been carried out
- Published
- 1998
9. Overweight people have low levels of implicit weight bias, but overweight nations have high levels of implicit weight bias.
- Author
-
Maddalena Marini, Natarajan Sriram, Konrad Schnabel, Norbert Maliszewski, Thierry Devos, Bo Ekehammar, Reinout Wiers, Cai HuaJian, Mónika Somogyi, Kimihiro Shiomura, Simone Schnall, Félix Neto, Yoav Bar-Anan, Michelangelo Vianello, Alfonso Ayala, Gabriel Dorantes, Jaihyun Park, Selin Kesebir, Antonio Pereira, Bogdan Tulbure, Tuulia Ortner, Irena Stepanikova, Anthony G Greenwald, and Brian A Nosek
- Subjects
Medicine ,Science - Abstract
Although a greater degree of personal obesity is associated with weaker negativity toward overweight people on both explicit (i.e., self-report) and implicit (i.e., indirect behavioral) measures, overweight people still prefer thin people on average. We investigated whether the national and cultural context - particularly the national prevalence of obesity - predicts attitudes toward overweight people independent of personal identity and weight status. Data were collected from a total sample of 338,121 citizens from 71 nations in 22 different languages on the Project Implicit website (https://implicit.harvard.edu/) between May 2006 and October 2010. We investigated the relationship of the explicit and implicit weight bias with the obesity both at the individual (i.e., across individuals) and national (i.e., across nations) level. Explicit weight bias was assessed with self-reported preference between overweight and thin people; implicit weight bias was measured with the Implicit Association Test (IAT). The national estimates of explicit and implicit weight bias were obtained by averaging the individual scores for each nation. Obesity at the individual level was defined as Body Mass Index (BMI) scores, whereas obesity at the national level was defined as three national weight indicators (national BMI, national percentage of overweight and underweight people) obtained from publicly available databases. Across individuals, greater degree of obesity was associated with weaker implicit negativity toward overweight people compared to thin people. Across nations, in contrast, a greater degree of national obesity was associated with stronger implicit negativity toward overweight people compared to thin people. This result indicates a different relationship between obesity and implicit weight bias at the individual and national levels.
- Published
- 2013
- Full Text
- View/download PDF
10. Challenges in the development of an immunochromatographic interferon-gamma test for diagnosis of pleural tuberculosis.
- Author
-
Claudia M Denkinger, Yatiraj Kalantri, Samuel G Schumacher, Joy S Michael, Deepa Shankar, Arvind Saxena, Natarajan Sriram, Thangakunam Balamugesh, Robert Luo, Nira R Pollock, Madhukar Pai, and Devasahayam J Christopher
- Subjects
Medicine ,Science - Abstract
Existing diagnostic tests for pleural tuberculosis (TB) have inadequate accuracy and/or turnaround time. Interferon-gamma (IFNg) has been identified in many studies as a biomarker for pleural TB. Our objective was to develop a lateral flow, immunochromatographic test (ICT) based on this biomarker and to evaluate the test in a clinical cohort. Because IFNg is commonly present in non-TB pleural effusions in low amounts, a diagnostic IFNg-threshold was first defined with an enzyme-linked immunosorbent assay (ELISA) for IFNg in samples from 38 patients with a confirmed clinical diagnosis (cut-off of 300 pg/ml; 94% sensitivity and 93% specificity). The ICT was then designed; however, its achievable limit of detection (5000 pg/ml) was over 10-fold higher than that of the ELISA. After several iterations in development, the prototype ICT assay for IFNg had a sensitivity of 69% (95% confidence interval (CI): 50-83) and a specificity of 94% (95% CI: 81-99%) compared to ELISA on frozen samples. Evaluation of the prototype in a prospective clinical cohort (72 patients) on fresh pleural fluid samples, in comparison to a composite reference standard (including histopathological and microbiologic test results), showed that the prototype had 65% sensitivity (95% CI: 44-83) and 89% specificity (95% CI: 74-97). Discordant results were observed in 15% of samples if testing was repeated after one freezing and thawing step. Inter-rater variability was limited (3%; 1 out of 32). In conclusion, despite an iterative development and optimization process, the performance of the IFNg ICT remained lower than what could be expected from the published literature on IFNg as a biomarker in pleural fluid. Further improvements in the limit of detection of an ICT for IFNg, and possibly combination of IFNg with other biomarkers such as adenosine deaminase, are necessary for such a test to be of value in the evaluation of pleural tuberculosis.
- Published
- 2013
- Full Text
- View/download PDF
11. Improving the statistical detection of regulated genes from microarray data using intensity-based variance estimation
- Author
-
Natarajan Sripriya, Comander Jason, Gimbrone Michael A, and García-Cardeña Guillermo
- Subjects
Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Gene microarray technology provides the ability to study the regulation of thousands of genes simultaneously, but its potential is limited without an estimate of the statistical significance of the observed changes in gene expression. Due to the large number of genes being tested and the comparatively small number of array replicates (e.g., N = 3), standard statistical methods such as the Student's t-test fail to produce reliable results. Two other statistical approaches commonly used to improve significance estimates are a penalized t-test and a Z-test using intensity-dependent variance estimates. Results The performance of these approaches is compared using a dataset of 23 replicates, and a new implementation of the Z-test is introduced that pools together variance estimates of genes with similar minimum intensity. Significance estimates based on 3 replicate arrays are calculated using each statistical technique, and their accuracy is evaluated by comparing them to a reliable estimate based on the remaining 20 replicates. The reproducibility of each test statistic is evaluated by applying it to multiple, independent sets of 3 replicate arrays. Two implementations of a Z-test using intensity-dependent variance produce more reproducible results than two implementations of a penalized t-test. Furthermore, the minimum intensity-based Z-statistic demonstrates higher accuracy and higher or equal precision than all other statistical techniques tested. Conclusion An intensity-based variance estimation technique provides one simple, effective approach that can improve p-value estimates for differentially regulated genes derived from replicated microarray datasets. Implementations of the Z-test algorithms are available at http://vessels.bwh.harvard.edu/software/papers/bmcg2004.
- Published
- 2004
- Full Text
- View/download PDF
12. In silico and in vitro studies for the identification of small molecular inhibitors from Euphorbia hirta Linn for rheumatoid arthritis: targeting TNF-α-mediated inflammation.
- Author
-
Velmurugan Y, Natarajan SR, Chakkarapani N, Jayaraman S, Madhukar H, and Venkatachalam R
- Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that is now potentially lethal and has a significant detrimental influence on people's daily lives by affecting bone joints. Inflammation plays a vital role in this type of autoimmune disorder. In rheumatoid arthritis, long-term production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) stimulates the immune system against cells in bone joints and helps to develop the pathogenesis of rheumatoid arthritis. So, while treating rheumatoid arthritis, we need to block these kinds of mechanisms. We employed soxhlet extraction, thin-layer chromatography (TLC), and gas chromatography-mass spectroscopy (GC-MS) to analyze the phytocompound information in E. hirta leaves. Furthermore, our research included in vitro investigations using Western blotting and mRNA expression analysis (TNF-α, IL-1β, IL-6) to affirm the anti-inflammatory effectiveness of our extract. For identifying the lead-like molecules, virtual screening and molecular dynamics simulations were used. TLC results confirmed the presence of phytocompounds in E. hirta crude through spots. The structure elucidation of the phytocompounds was confirmed by the GC-MS chromatogram. The in vitro outcomes collectively underscore the inhibitory influence of E. hirta on cell proliferation and its capacity to attenuate the expression of TNF- α within THP-1 cells. The results of in silico methodologies confirmed six lead-like molecules. We could conclude that phytocompounds from ethanol leaf crude have effective lead-like molecules against the TNF-α., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
- Published
- 2024
- Full Text
- View/download PDF
13. Blueberry extract and its bioactive compounds mitigate oxidative stress and suppress human lung cancer cell (A549) growth by modulating the expression of p53/EGFR/STAT3/IL6-mediated signaling molecules.
- Author
-
Krishnamoorthy K, Natarajan SR, Veeraraghavan VP, and Jayaraman S
- Subjects
- Humans, A549 Cells, Interleukin-6 metabolism, Molecular Docking Simulation, Lung Neoplasms metabolism, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Cell Survival drug effects, Antioxidants pharmacology, Antioxidants chemistry, Antioxidants metabolism, Antineoplastic Agents, Phytogenic pharmacology, Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic isolation & purification, Drug Screening Assays, Antitumor, Plant Extracts pharmacology, Plant Extracts chemistry, Blueberry Plants chemistry, Oxidative Stress drug effects, STAT3 Transcription Factor metabolism, Tumor Suppressor Protein p53 metabolism, Signal Transduction drug effects, Cell Proliferation drug effects, ErbB Receptors metabolism
- Abstract
Bioactive phytocompounds are crucial components in all plants. Since the time of traditional medicine, the utilization of plants has been grounded in the potential of these bioactive compounds to treat or manage specific illnesses. These natural bioactive compounds have sparked growing interest in employing medicinal plants for addressing various conditions, such as inflammatory diseases, diabetes, and cancer. This study focuses on assessing the qualitative phytochemical composition, antioxidant potential, and cytotoxic effects of blueberry (Vaccinium sect. Cyanococcus) extract using three different solvents, namely water, ethanol, and methanol. The extract exhibited notable antioxidant activities, as evidenced by DPPH and H
2 O2 free radical scavenging assays. The cell viability assay also demonstrated cell growth inhibition in A549 cells. Furthermore, nine specific phytocompounds sourced from existing literature were selected for molecular docking studies against CDK6 and, AMPK key protein kinases which enhance the cancer progression. The molecular docking results also revealed favorable binding scores, with a high score of -9.5 kcal/mol in CDK6 protein and a maximum score of AMPK with targets of -8.8 kcal/mol. The selected phytocompounds' pharmacodynamic properties such as ADMET also supported the study. Furthermore, rutin stated that pre-dominantly present in blueberry plants shows a potent cytotoxicity effect in A549 cells. Functional annotations by bioinformatic analysis for rutin also revealed the strong enrichment in the involvement of PI3K/AKT1/STAT, and p53 signaling pathways. Based on this analysis, the identified rutin and other compounds hold a promising anticancer activity. Overall, the comprehensive evaluation of both in vitro and in silico data suggests that the Vaccinium sect. Cyanococcus extract could serve as a valuable source of pharmaceutical agents and may prove effective in future therapeutic applications., (© 2024 John Wiley & Sons Ltd.)- Published
- 2024
- Full Text
- View/download PDF
14. Study on Antidiabetic Potential of Sessuvium Portulacastrum Aqueous Extract: An In-Silico and In-Vitro Analysis.
- Author
-
Mukundh ST, Natarajan SR, Veeraraghavan VP, and Jayaraman S
- Abstract
Diabetes mellitus is a persistent metabolic condition marked by elevated blood glucose levels due to compromised insulin secretion or functionality. The search for natural antidiabetic agents has gained attention due to their potential effectiveness and safety profiles. Sessuvium portulacastrum , a coastal plant, has been traditionally used for various medicinal purposes. This study investigates the antidiabetic potential of Sessuvium portulacastrum aqueous extract by analyzing its inhibitory effects on key enzymes involved in carbohydrate metabolism and exploring its molecular interactions with critical target proteins. The aqueous extract of Sessuvium portulacastrum was prepared and used for in vitro analysis. The reduced activity of the extract against α-amylase and α-glucosidase enzymes, crucial in glucose absorption and postprandial hyperglycemia, was assessed. Molecular docking techniques were employed to explore the potential interactions between active compounds in the extract and diabetes-related proteins, including BAX, GSK3β, and CADH. The study revealed significant inhibition of both alpha-amylase and alpha-glucosidase enzymes by Sessuvium portulacastrum aqueous extract, indicating its potential to reduce glucose absorption and postprandial hyperglycemia. Moreover, the molecular docking analysis demonstrated strong binding interactions between active compounds in the extract and key proteins involved in diabetes-related pathways, namely apoptotic pathways, glycogen synthesis, and cell adhesion. The findings of this study highlight the promising antidiabetic potential of Sessuvium portulacastrum aqueous extract. Upcoming research should get an attention on isolating and characterizing the active compounds responsible for these effects on antidiabetic therapies from natural sources., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Pharmacy and Bioallied Sciences.)
- Published
- 2024
- Full Text
- View/download PDF
15. Molecular analysis to identify novel potential biomarkers as drug targets in colorectal cancer therapy: an integrated bioinformatics analysis.
- Author
-
Gatasheh MK, Natarajan SR, Krishnamoorthy R, Alsulami TS, Rajagopal P, Palanisamy CP, Veeraraghavan VP, and Jayaraman S
- Abstract
Colorectal cancer (CRC) is a heterogeneous disease that requires new diagnostic and prognostic markers. Integrated bioinformatics approach to identify novel therapeutic targets associated with CRC. Using GEO2R identified DEGs in CRC, and Funrich software facilitated the visualization of DEGs through Venn diagrams. From a total of 114 enhanced DEGs, potential hub genes were further filtered based on their nodal strength and edges using STRING database. To gain insights into the functional roles of these hub genes, gene ontology and pathway enrichment were conducted thorough g: profiler web server. Subsequently, overall survival plots from GEPIA and oncogenic predictive functions like mRNA expressions for stages and nodal metastasis were employed to identify hub genes in CRC patient samples. Additionally, the cBioPortal and HPA databases also revealed genetic alterations and expression levels in these hub genes in CRC patients, further supporting their involvement in colorectal cancer. Gene expression by RT-PCR shows upregulation of hub genes in HT-29 cells. Finally, our integrated bioinformatic analysis revealed that ABCE1, AURKA, HSPD1, PHKA1, CDK4, and YWHAE as hub genes with potential oncogenic roles in CRC. These genes hold promise as diagnostic and prognostic markers for colorectal tumorigenesis, providing insights into targeted therapies for improved patient outcomes., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)
- Published
- 2024
- Full Text
- View/download PDF
16. Exploring the therapeutic potential of curcumin in oral squamous cell carcinoma (HSC-3 cells): Molecular insights into hypoxia-mediated angiogenesis.
- Author
-
Jayaraman S, Veeraraghavan VP, Natarajan SR, and Jasmine S
- Subjects
- Humans, Squamous Cell Carcinoma of Head and Neck drug therapy, Angiogenesis, Molecular Docking Simulation, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic pathology, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Cell Line, Tumor, Curcumin pharmacology, Curcumin therapeutic use, Carcinoma, Squamous Cell drug therapy, Mouth Neoplasms drug therapy, Head and Neck Neoplasms
- Abstract
Background: Oral cancer represents a substantial global health burden, often associate with hypoxia-induced angiogenesis as a critical factor in its progression. Curcumin, a naturally occurring bioactive compounds, has gained increasing attention for its potential anticancer properties., Objective: To assess the impact of curcumin on oral cancer, particularly its role in modulating HIF-1α-mediated angiogenesis in HSC-3 cells., Methods: Our investigation involved multiple experimental approaches, including MTT assay, aerobic glycolysis by metabolic kit, cell cycle, and apoptosis assessment via flow cytometry. Furthermore, we employed molecular docking techniques to examine the interactions between curcumin and key angiogenesis related proteins, including HIF-1α, VEGF-B, MMP-3, and STAT3., Results: Our results demonstrate that curcumin exerts significant effects on the cell survivability, cell cycle regulation, and apoptosis induction in oral cancer cells. These effects were particularly pronounced under the conditions of HIF-1α mediated angiogenesis. Computational binding analysis revealed strong binding interactions with curcumin and the selected proteins, implying a plausible mechanism through which curcumin may modulate the angiogenic pathways in oral cancer., Conclusion: Our research sheds light on the diverse effects of curcumin on oral cancer cells, emphasizing its potential as a promising therapeutic tool for addressing hypoxia-induced angiogenesis. However, further investigation is essential to comprehensively understand the molecular mechanisms underlying these effects in in vitro models. This deeper comprehension is crucial for translating these findings into clinical applications aimed at improving oral cancer treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
17. Piperine modulates IR/Akt/GLUT4 pathways to mitigate insulin resistance: Evidence from animal and computational studies.
- Author
-
Prasad M, Jayaraman S, Natarajan SR, Veeraraghavan VP, Krishnamoorthy R, Gatasheh MK, Palanisamy CP, and Elrobh M
- Subjects
- Humans, Rats, Animals, Proto-Oncogene Proteins c-akt metabolism, Molecular Docking Simulation, Antioxidants pharmacology, Quality of Life, Insulin metabolism, Diet, High-Fat adverse effects, Insulin Resistance, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Experimental metabolism
- Abstract
The global prevalence of diabetes mellitus is rising, especially in India. Medicinal herbs, whether used alone or in combination with conventional medicines, have shown promise in managing diabetes and improving overall well-being. Piperine (PIP), a major bioactive compound found in pepper, is gaining attention for its beneficial properties. This study aimed to assess whether PIP could alleviate diabetes by targeting insulin pathway-related molecules in the adipose tissue of rats on a high-fat diet (HFD). After 60 days on the HFD, rats received PIP at a dose of 40 mg/kg body weight for one month. The results showed that PIP significantly improved metabolic indicators, antioxidant enzymes, and carbohydrate metabolic enzymes. It also regulated the mRNA and protein expression of insulin signaling, which had been disrupted by the diet and sucrose intake. Molecular docking analysis also revealed strong binding of PIP to key diabetes-related regulatory proteins, including Akt (-6.2 kcal/mol), IR (-7.02 kcal/mol), IRS-1 (-6.86 kcal/mol), GLUT4 (-6.24 kcal/mol), AS160 (-6.28 kcal/mol), and β-arrestin (-6.01 kcal/mol). Hence, PIP may influence the regulation of glucose metabolism through effective interactions with these proteins, thereby controlling blood sugar levels due to its potent antilipidemic and antioxidant properties. In conclusion, our study provides in vivo experimental evidence against the HFD-induced T2DM model for the first time, making PIP a potential natural remedy to enhance the quality of life for diabetic patients and aid in their management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
18. Unveiling the anti-cancer mechanisms of calotropin: Insights into cell growth inhibition, cell cycle arrest, and metabolic regulation in human oral squamous carcinoma cells (HSC-3).
- Author
-
Jayaraman S, Natarajan SR, Veeraraghavan VP, and Jasmine S
- Abstract
Background: Calotropin, a cardiac glycoside obtained from the plant Calotropis gigantea , has demonstrated promising potential as an anti-tumorigenesis compound., Objective: The main objective of this study was to investigate the potential anti-cancer properties of calotropin against HSC-3 oral squamous cancer cells and to elucidate the underlying mechanisms involved in its action., Material and Method: Calotropin were treated in HSC-3 to evaluate cell viability by MTT assay. Flow cytometry analysis divulged that calotropin G0/G1 phase cell cycle arrest and apoptosis in HSC-3 cells. Calotropin displayed inhibitory properties against aerobic glycolysis, a metabolic alteration using glucose uptaken, lactose production and LDHA activity assays. Furthermore, migration and invasion assays help that calotropin has ability to reduce the migratory and invasive of HSC-3 cells, using transwell and Matrigel assay. Validation of mRNA expression through RT-PCR. Molecular docking was implemented to validate the binding association of calotropin with apoptosis and metastatic regulating targets., Result: The results exemplify that increasing doses of calotropin effectively hold back the HSC-3 cell progression. Migration and invasion assays help that calotropin has ability to reduce the migratory and invasive of HSC-3 cells, indicating its potential to inhibit cancer metastasis. These results imply that calotropin may influence genes linked to metastasis and apoptosis in order to achieve its beneficial effects on cancer. Docking results provided further support, showing a high binding energy between calotropin and metastasis-mediated pathways., Conclusion: Overall, our findings shed an experimental evidence on how calotropin inhibits the HSC-3 oral squamous cancer cell growth, highlighting the drug's potential as a treatment for oral cancer. Further, investigation on in-vivo experiment is warranted to explore its potential mechanism of action and to develop a novel drug towards clinical trial., Competing Interests: The authors declare no conflict of interest., (© 2023 Published by Elsevier B.V. on behalf of Craniofacial Research Foundation.)
- Published
- 2023
- Full Text
- View/download PDF
19. MARK2/4 promotes Warburg effect and cell growth in non-small cell lung carcinoma through the AMPKα1/mTOR/HIF-1α signaling pathway.
- Author
-
Natarajan SR, Ponnusamy L, and Manoharan R
- Subjects
- AMP-Activated Protein Kinases genetics, AMP-Activated Protein Kinases metabolism, Cell Line, Tumor, Humans, Protein Serine-Threonine Kinases, Signal Transduction, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases metabolism, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms metabolism
- Abstract
MARKs kinase belongs to an AMPK-related family kinase plays a critical role in tumor progression, but its exact role and contribution of four different isoforms remain largely ambiguous. In this study, we used a clinical dataset compiled by The Cancer Genome Atlas (TCGA) and GEO revealed that MARK2 and MARK4 expressions were significantly upregulated in non-small cell lung cancer (NSCLC) compared with normal tissues. Furthermore, expressions of MARK2/4 were highly appeared in advanced stages and associated with the low survival rate of NSCLC patients. Functional assays demonstrated that MARK2/4 deletion or MARKs inhibition significantly suppressed aerobic glycolysis and cell growth in NSCLC cells. Mechanistically, MARK2/4 stimulates the mTOR/HIF-1α pathway and subsequently alleviates AMPK activity via physically associate with Raptor and AMPKα1, thereby facilitating aerobic glycolysis and cell growth in NSCLC cells. However, these effects were markedly reversed by MARKs inhibitor 39621, or MARK2/4 deletion, mTOR inhibitor rapamycin, or AMPK activator AICAR. Together, the data demonstrated that MARK2/4 exerts its oncogenic effects by facilitating metabolic reprogramming in NSCLC cells. Therefore, MARK2/4 might be a potential therapeutic target for lung cancer., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
20. MARK2 potentiate aerobic glycolysis-mediated cell growth in breast cancer through regulating mTOR/HIF-1α and p53 pathways.
- Author
-
Ponnusamy L, Natarajan SR, and Manoharan R
- Subjects
- Cell Line, Tumor, Cell Proliferation, Female, Glycolysis, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Breast Neoplasms genetics, Breast Neoplasms metabolism, Protein Serine-Threonine Kinases genetics
- Abstract
The microtubule-affinity regulating kinases (MARKs) family plays a crucial role in regulating breast cancer development and progression. However, its precise function and the relevant molecular mechanism in breast cancer have not yet been elucidated. In this study, analysis of The Cancer Genome Atlas (TCGA) data revealed that MARK2 expression was markedly upregulated in breast cancer tissues, and high expression of MARK2 was correlated with poor survival. Functional assays showed that MARK2 deletion or inhibition suppressed aerobic glycolysis and cell growth as well as induced cell cycle arrest and apoptosis in breast cancer cells. Mechanistically, MARK2 stimulates mTOR-mediated hypoxia-inducible factor 1 alpha (HIF-1α) transcription activity and represses p53-transcription activity in breast cancer cells. TCGA data revealed that MARK2 expression was positively correlated with mTOR, Raptor, S6K1, glucose transporter 1, lactate dehydrogenase, HIF-1α, and 4E-BP1 expression, whereas negatively correlated with p53, p21, and Bax in breast cancer tissue. Conclusively, our study demonstrated that MARK2 promotes breast cancer aerobic glycolysis and cell proliferation, and inhibits apoptosis, in part, through regulating mTOR/HIF-1α and p53 signaling pathways. Overall, these findings point to the potential of targeting MARK2 for breast cancer treatment., (© 2022 Wiley Periodicals LLC.)
- Published
- 2022
- Full Text
- View/download PDF
21. MELK/MPK38 in cancer: from mechanistic aspects to therapeutic strategies.
- Author
-
Thangaraj K, Ponnusamy L, Natarajan SR, and Manoharan R
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Humans, Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases chemistry, Neoplasms metabolism, Protein Serine-Threonine Kinases metabolism
- Abstract
Maternal embryonic leucine zipper kinase (MELK)/Murine protein serine-threonine kinase 38 (MPK38) is a member of the AMP-related serine-threonine kinase family, which has been reported to be involved in the regulation of many cellular events, including cell proliferation, apoptosis, and metabolism, partly by phosphorylation and regulation of several signaling molecules. The abnormal expression of MELK has been associated with tumorigenesis and malignant progression in various types of cancer. Currently, several small-molecule inhibitors of MELK are under investigation although only OTS167 has entered clinical trials. In this review, we elaborate on the relative contributions of MELK pathways in the physiological process, their oncogenic role in carcinogenesis, and targeted agents under development for the treatment of cancer., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
22. Therapeutic aspects of AMPK in breast cancer: Progress, challenges, and future directions.
- Author
-
Ponnusamy L, Natarajan SR, Thangaraj K, and Manoharan R
- Subjects
- Animals, Antineoplastic Agents pharmacology, Aspirin pharmacology, Aspirin therapeutic use, Biological Products pharmacology, Biological Products therapeutic use, Breast Neoplasms pathology, Carcinogenesis drug effects, Carcinogenesis pathology, Cell Line, Tumor, Clinical Trials as Topic, Disease Models, Animal, Disease Progression, Enzyme Activators pharmacology, Female, Humans, Metformin pharmacology, Metformin therapeutic use, Phosphorylation drug effects, Signal Transduction drug effects, Sorafenib pharmacology, Sorafenib therapeutic use, Treatment Outcome, AMP-Activated Protein Kinases metabolism, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Enzyme Activators therapeutic use
- Abstract
Breast cancer is the most ubiquitous type of neoplasms among women worldwide. Molecular aberrations associated with breast development and progressions have been extensively investigated in recent years. An AMP-activated kinase (AMPK) initially identified as a cellular energy sensor that plays a crucial role in cellular energy homeostasis. Intensive research over the last decade about the molecular mechanisms of AMPK has demonstrated that AMPK mediated diverse biological functions are achieved through phosphorylation and regulation of multiple downstream signaling molecules in normal tissue. Downregulation of AMPK activity or decreased level involved in the promotion of breast tumorigenesis, and thus activation of AMPK found to oppose tumor progression. In this review, we epitomize the recent advances in exploring the tumor suppressor function of AMPK pathways. Besides, we discuss the developments in the area of AMPK activator and its molecular mechanisms for breast cancer treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
23. C-H Oxidation of Ingenanes Enables Potent and Selective Protein Kinase C Isoform Activation.
- Author
-
Jin Y, Yeh CH, Kuttruff CA, Jørgensen L, Dünstl G, Felding J, Natarajan SR, and Baran PS
- Subjects
- Diterpenes metabolism, Enzyme Activation drug effects, Isoenzymes chemistry, Isoenzymes metabolism, Molecular Conformation, Oxidation-Reduction, Protein Kinase C chemistry, Diterpenes chemistry, Diterpenes pharmacology, Protein Kinase C metabolism
- Abstract
Ingenol derivatives with varying degrees of oxidation were prepared by two-phase terpene synthesis. This strategy has allowed access to analogues that cannot be prepared by semisynthesis from natural ingenol. Complex ingenanes resulting from divergent C-H oxidation of a common intermediate were found to interact with protein kinase C in a manner that correlates well with the oxidation state of the ingenane core. Even though previous work on ingenanes has suggested a strong correlation between potential to activate PKCδ and induction of neutrophil oxidative burst, the current study shows that the potential to activate PKCβII is of key importance while interaction with PKCδ is dispensable. Thus, key modifications of the ingenane core allowed PKC isoform selectivity wherein PKCδ-driven activation of keratinocytes is strongly reduced or even absent while PKCβII-driven activation of neutrophils is retained., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2015
- Full Text
- View/download PDF
24. Organic chemistry. Practical olefin hydroamination with nitroarenes.
- Author
-
Gui J, Pan CM, Jin Y, Qin T, Lo JC, Lee BJ, Spergel SH, Mertzman ME, Pitts WJ, La Cruz TE, Schmidt MA, Darvatkar N, Natarajan SR, and Baran PS
- Abstract
The synthesis and functionalization of amines are fundamentally important in a vast range of chemical contexts. We present an amine synthesis that repurposes two simple feedstock building blocks: olefins and nitro(hetero)arenes. Using readily available reactants in an operationally simple procedure, the protocol smoothly yields secondary amines in a formal olefin hydroamination. Because of the presumed radical nature of the process, hindered amines can easily be accessed in a highly chemoselective transformation. A screen of more than 100 substrate combinations showcases tolerance of numerous unprotected functional groups such as alcohols, amines, and even boronic acids. This process is orthogonal to other aryl amine syntheses, such as the Buchwald-Hartwig, Ullmann, and classical amine-carbonyl reductive aminations, as it tolerates aryl halides and carbonyl compounds., (Copyright © 2015, American Association for the Advancement of Science.)
- Published
- 2015
- Full Text
- View/download PDF
25. Synthesis and biological activity of pyridopyridazin-6-one p38α MAP kinase inhibitors. Part 2.
- Author
-
Tynebor RM, Chen MH, Natarajan SR, O'Neill EA, Thompson JE, Fitzgerald CE, O'Keefe SJ, and Doherty JB
- Subjects
- Animals, Dogs, Dose-Response Relationship, Drug, Haplorhini, Humans, Mitogen-Activated Protein Kinase 14 metabolism, Molecular Structure, Protein Kinase Inhibitors administration & dosage, Pyridazines administration & dosage, Pyridines administration & dosage, Rats, Structure-Activity Relationship, Mitogen-Activated Protein Kinase 14 antagonists & inhibitors, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Pyridazines chemical synthesis, Pyridazines pharmacology, Pyridines chemical synthesis, Pyridines pharmacology
- Abstract
This manuscript concludes the Structure Activity Relationship (SAR) on the pyridazinone scaffold and identifies a compound with subnanomolar p38α activity and 24h coverage in the rat arthritis efficacy model., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
26. Synthesis and biological activity of pyridopyridazin-6-one p38 MAP kinase inhibitors. Part 1.
- Author
-
Tynebor RM, Chen MH, Natarajan SR, O'Neill EA, Thompson JE, Fitzgerald CE, O'Keefe SJ, and Doherty JB
- Subjects
- Animals, Binding Sites, Catalytic Domain, Computer Simulation, Mitogen-Activated Protein Kinase 14 metabolism, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacokinetics, Protein Structure, Tertiary, Pyridazines chemical synthesis, Pyridazines pharmacokinetics, Rats, Structure-Activity Relationship, Mitogen-Activated Protein Kinase 14 antagonists & inhibitors, Protein Kinase Inhibitors chemical synthesis, Pyridazines chemistry
- Abstract
The development and synthesis of potent p38α MAP kinase inhibitors containing a pyridazinone platform is described. Evolution of the p38α selective pyridopyridazin-6-one series from the p38α/β dual inhibitor 2H-quinolizin-2-one series will be discussed in full detail., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
27. Synthesis and biological activity of 2H-quinolizin-2-one based p38alpha MAP kinase inhibitors.
- Author
-
Tynebor RM, Chen MH, Natarajan SR, O'Neill EA, Thompson JE, Fitzgerald CE, O'Keefe SJ, and Doherty JB
- Subjects
- Animals, Anti-Inflammatory Agents chemistry, Anti-Inflammatory Agents pharmacokinetics, Cell Line, Dogs, Haplorhini, Humans, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacokinetics, Quinolizines chemical synthesis, Quinolizines pharmacokinetics, Rats, Structure-Activity Relationship, Tumor Necrosis Factor-alpha metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Anti-Inflammatory Agents chemical synthesis, Protein Kinase Inhibitors chemical synthesis, Quinolizines chemistry, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
- Abstract
The development and synthesis of potent p38alpha MAP kinase inhibitors containing a 2H-quinolizin-2-one platform is described. Evolution of the 2H-quinolizin-2-one series from an early lead to solving off target activity and pharmacokinetic issues is also discussed., (2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
28. Rapid access to pyrazolo[3,4-c]pyridines via alkyne annulation: limitations of steric control in nickel-catalyzed alkyne insertions.
- Author
-
Heller ST and Natarajan SR
- Subjects
- Catalysis, Molecular Structure, Palladium chemistry, Stereoisomerism, Alkynes chemistry, Nickel chemistry, Pyrazoles chemistry, Pyridines chemistry
- Abstract
Polyfunctionalized pyrazolo[3,4-c]pyridines were readily prepared by the annulation of alkynes with tert-butyl 4-iodopyrazolocarboximines. The reaction was found to be catalyzed by both NiBr2(PPh3)2/Zn or PdCl2(PhCN)2 to yield complex heterocycles in good to moderate yields. Annulation using nickel catalysis was found to be regio-random, implying that steric control in nickel-catalyzed alkyne insertion has limitations based on the character of the Ni-C bond in the pre-insertion complex.
- Published
- 2007
- Full Text
- View/download PDF
29. p38 MAP kinase inhibitors. Part 6: 2-arylpyridazin-3-ones as templates for inhibitor design.
- Author
-
Natarajan SR, Heller ST, Nam K, Singh SB, Scapin G, Patel S, Thompson JE, Fitzgerald CE, and O'Keefe SJ
- Subjects
- Binding Sites, Drug Design, Glycine chemistry, Structure-Activity Relationship, Tyrosine chemistry, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Pyridazines chemical synthesis, Pyridazines pharmacology, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
- Abstract
p38 inhibitors based on 3,4-dihydropyrido[4,3-d]pyrimidazin-2-one template were synthesized and their SAR explored. Benchmark compounds 30, 35, and 36 were found to be potent against the enzyme. Crystal structure of p38 in complex with 30 indicated a key pi-stacking interaction with the pendant tyrosine residue-35 in the glycine-rich loop.
- Published
- 2006
- Full Text
- View/download PDF
30. p38 MAP kinase inhibitors. Part 5: discovery of an orally bio-available and highly efficacious compound based on the 7-amino-naphthyridone scaffold.
- Author
-
Natarajan SR, Liu L, Levorse M, Thompson JE, O'Neill EA, O'Keefe SJ, Vora KA, Cvetovich R, Chung JY, Carballo-Jane E, and Visco DM
- Subjects
- Administration, Oral, Animals, Binding Sites, Biological Availability, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Design, Drug Evaluation, Preclinical, Enzyme Activation drug effects, Enzyme Inhibitors chemistry, Humans, In Vitro Techniques, Lipopolysaccharides pharmacology, Macaca mulatta, Male, Mice, Mice, Inbred BALB C, Microsomes, Liver drug effects, Molecular Structure, Monocytes drug effects, Naphthyridines chemistry, Rats, Rats, Sprague-Dawley, Stereoisomerism, Structure-Activity Relationship, Tumor Necrosis Factor-alpha antagonists & inhibitors, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacokinetics, Naphthyridines administration & dosage, Naphthyridines pharmacokinetics, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
- Abstract
A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound 16 potently inhibited p38 in vitro, was functionally active, and displayed excellent pharmacokinetic profiles in two animal species. Compound 16 reduced inflammation in animal disease models at EC(50) doses as low as 0.2mpk.
- Published
- 2006
- Full Text
- View/download PDF
31. p38 MAP kinase inhibitors. Part 3: SAR on 3,4-dihydropyrimido[4,5-d]pyrimidin-2-ones and 3,4-dihydropyrido[4,3-d]pyrimidin-2-ones.
- Author
-
Natarajan SR, Wisnoski DD, Thompson JE, O'Neill EA, and O'Keefe SJ
- Subjects
- Chemistry, Pharmaceutical methods, Drug Design, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacology, Humans, Inhibitory Concentration 50, Models, Chemical, Pyridazines pharmacology, Pyridines chemistry, Pyrimidines pharmacology, Pyrimidinones pharmacology, Quinazolines chemistry, Structure-Activity Relationship, p38 Mitogen-Activated Protein Kinases chemistry, Enzyme Inhibitors chemistry, Pyridazines chemistry, Pyrimidines chemistry, Pyrimidinones chemistry, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
- Abstract
p38 inhibitors based on 3,4-dihydropyrimido[4,5-d]pyrimidin-2-one and 3,4-dihydropyrido[4,3-d]pyrimidin-2-one platforms were synthesized and preliminary SAR explored. Among the pyrimido-pyrimidones the emergence of two sub-types of analogs-C7-amino-pyrimidines such as 24 and C7-amino-piperidines such as 42-characterized with good p38 inhibition and better off-target profiles in terms of ion channel activities was significant. Representative compound 54 in the pyrido-pyrimidone class was found to be equipotent with corresponding analog in the quinazolinone series.
- Published
- 2006
- Full Text
- View/download PDF
32. 1,3-diketones from acid chlorides and ketones: a rapid and general one-pot synthesis of pyrazoles.
- Author
-
Heller ST and Natarajan SR
- Subjects
- Hydrazines chemistry, Molecular Structure, Chlorides chemistry, Combinatorial Chemistry Techniques, Ketones chemical synthesis, Ketones chemistry, Pyrazoles chemical synthesis
- Abstract
[reaction: see text] 1,3-Diketones were synthesized directly from ketones and acid chlorides and were then converted in situ into pyrazoles by the addition of hydrazine. This method is extremely fast, general, and chemoselective, allowing for the synthesis of previously inaccessible pyrazoles and synthetically demanding pyrazole-containing fused rings.
- Published
- 2006
- Full Text
- View/download PDF
33. P38 MAP kinase inhibitors: evolution of imidazole-based and pyrido-pyrimidin-2-one lead classes.
- Author
-
Natarajan SR and Doherty JB
- Subjects
- Binding Sites, Imidazoles chemistry, Imidazoles pharmacology, Pyridazines chemistry, Pyridazines pharmacology, Pyrimidines chemistry, Pyrimidines pharmacology, Pyrimidinones chemical synthesis, Pyrimidinones pharmacology, Structure-Activity Relationship, Drug Design, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
- Abstract
The initial disclosure of tri-substituted imidazole-based drug molecules such as 1 for inhibition of p38 MAP kinase by SmithKline Beecham (SB) sparked an effort in this area at Merck and other pharmaceutical research establishments. Although analogs in this class have shown good inhibitory properties against p38 MAP kinase, their selectivity profile were modest and left much room for improvement. Attempts to discover newer compounds with improved selectivity over the prototypical SB compound 203580 (1), led to the discovery of a new sub-class of p38 inhibitors typified by compound 18 at Merck. Although this benchmark compound was potent, highly selective and orally efficacious it was burdened with compound related adverse effects in dogs that has delayed further development. In 1999, a new class of p38 inhibitors represented by clinical candidate VX-745 (26), was disclosed by Vertex Pharmaceuticals. This compound displayed unprecedented selectivity due to its unique mode of binding to the active site in p38 MAP kinase. Inspired by the exquisite selectivity profile of VX-745 [26] a scaffold re-design was initiated at Merck which resulted in the discovery of the quinazolinone, pyrimido-pyrimidone, pyrido-pyrimidone, quinolinone and naphthyridinone based p38 inhibitors.
- Published
- 2005
- Full Text
- View/download PDF
34. SAR of 3,4-dihydropyrido[3,2-d]pyrimidone p38 inhibitors.
- Author
-
Liu L, Stelmach JE, Natarajan SR, Chen MH, Singh SB, Schwartz CD, Fitzgerald CE, O'Keefe SJ, Zaller DM, Schmatz DM, and Doherty JB
- Subjects
- Enzyme Inhibitors pharmacology, Kinetics, Molecular Structure, Pyrimidinones pharmacology, Structure-Activity Relationship, p38 Mitogen-Activated Protein Kinases, Enzyme Inhibitors chemical synthesis, Mitogen-Activated Protein Kinases antagonists & inhibitors, Pyrimidinones chemical synthesis
- Abstract
Development for a class of potent 3,4-dihydropyrido(3,2-d)pyrimidone inhibitors of p38a MAP kinase is described. Modification of N-1 aryl and C-6 arylsulfide in 3,4-dihydropyrido(3,2-d)pyrimidone analogues for the interaction with the hydrophobic pockets in p38 active site is also discussed.
- Published
- 2003
- Full Text
- View/download PDF
35. p38MAP kinase inhibitors. Part 1: design and development of a new class of potent and highly selective inhibitors based on 3,4-dihydropyrido[3,2-d]pyrimidone scaffold.
- Author
-
Natarajan SR, Wisnoski DD, Singh SB, Stelmach JE, O'Neill EA, Schwartz CD, Thompson CM, Fitzgerald CE, O'Keefe SJ, Kumar S, Hop CE, Zaller DM, Schmatz DM, and Doherty JB
- Subjects
- Drug Design, Indicators and Reagents, Structure-Activity Relationship, p38 Mitogen-Activated Protein Kinases, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Mitogen-Activated Protein Kinases antagonists & inhibitors, Pyridines chemical synthesis, Pyridines pharmacology, Pyrimidinones chemical synthesis, Pyrimidinones pharmacology
- Abstract
A new class of p38 antagonists based on 3,4-dihydropyrido[3,2,-d]pyrimidine scaffold has been developed. These inhibitors exhibit unprecedented selectivity towards p38 over other very closely related kinases. Compounds 25, 33, and 34 were identified as benchmark analogues for follow-up studies. They show good potency for enzyme inhibition and excellent functional activity.
- Published
- 2003
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.