QSAR Study of p56lck Protein Tyrosine Kinase Inhibitory Activity of Flavonoid Derivatives Using MLR and GA-PLS

Quantitative relationships between molecular structure and p56lck protein tyrosine kinase inhibitory activity of 50 flavonoid derivatives are discovered by MLR and GA-PLS methods. Different QSAR models revealed that substituent electronic descriptors (SED) parameters have significant impact on protein tyrosine kinase inhibitory activity of the compounds. Between the two statistical methods employed, GA-PLS gave superior results. The resultant GA-PLS model had a high statistical quality (R2 = 0.74 and Q2 = 0.61) for predicting the activity of the inhibitors. The models proposed in the present work are more useful in describing QSAR of flavonoid derivatives as p56lck protein tyrosine kinase inhibitors than those provided previously

QSAR of Flavonoids: 4. Differential Inhibition of Aldose Reductase and p56lck Protein Tyrosine Kinase

Flavonoids are a group of low molecular weight plant products, based on the parent compound, flavone (2-phenylchromone) and have shown potential for application in a variety of pharmacological tar-gets. By using random screening techniques flavones have been proposed as inhibitors of aldose reductase, an enzyme crucial in the treatment of diabetic complications such as cataract formation. On the other hand, a large number of natural and synthetic flavonoids are being tested as specific inhibitors of protein tyrosine kinase (PTK). Kinetic analyses of the PTK inhibition indicate that flavonoids are competitive inhibitors with respect to the nucleotide ATP A thorough investigation of the available experimental data base by using both classical and quantum Chemical descriptors has been performed in order to develop quantitative structure-activity relationships for these enzyme systems. Relevance of the descriptors to binding properties of both enzyme receptors active site is proposed and the obtained results demonstrate in detail which specific electronic as well as the hydrophobic and steric properties of the substituents play a significant role in their differential binding

Methods to Improve Virtual Screening of Potential Drug Leads for Specific Pharmacodynamic and Toxicological Properties

Ph.DDOCTOR OF PHILOSOPH

EPIDERMAL GROWTH FACTOR RECEPTOR INDUCES FYN EXPRESSION VIA UP-REGULATION OF P47PHOX IN GLIOBLASTOMA MULTIFORME

Src family kinases (SFKs) are commonly over-expressed and/or activated in glioblastoma multiforme (GBM), where they serve as key mediators of GBM cell proliferation, survival, invasion and angiogenesis. Mechanisms of allosteric SFK activation are well described; however, the SFK Fyn is commonly up-regulated at the mRNA level in multiple human cancers, including GBM, where the mode of increased expression is poorly understood. Since activating mutations in the epidermal growth factor receptor (EGFR) are commonly occurring in GBM, we examined whether EGFR could induce Fyn expression. Here, we found that wild-type EGFR, and to a greater extent hyper-activating EGFR mutants, EGFRΔIII and R108K, induce a substantial up-regulation of Fyn expression. Furthermore, it was determined that Fyn expression is up-regulated across a panel of patient-derived GBM stem cells (GSCs) relative to normal progenitor controls. Inhibition of Fyn proved to be biologically relevant, as Fyn depletion significantly (p

In silico approaches in the study of traditional Chinese herbal medicine

Ph.DDOCTOR OF PHILOSOPH

Design, synthesis and biological evaluation of pyrazolo-pyrimidines and related isosteres as inhibitors of protein kinases, potential antineoplastic agents

Design, synthesis and biological evaluation of pyrazolo-pyrimidines and related isosteres as inhibitors of protein kinases, potential antineoplastic agent

Protein Kinases

Proteins are the work horses of the cell. As regulators of protein function, protein kinases are involved in the control of cellular functions via intricate signalling pathways, allowing for fine tuning of physiological functions. This book is a collaborative effort, with contribution from experts in their respective fields, reflecting the spirit of collaboration - across disciplines and borders - that exists in modern science. Here, we review the existing literature and, on occasions, provide novel data on the function of protein kinases in various systems. We also discuss the implications of these findings in the context of disease, treatment, and drug development

Bioactives and Functional Ingredients in Foods

The close relationship between food intake and health promotion is not new; it dates back to Hippocrates’s famous “let food be your medicine and medicine be your food”, which is still as timely as ever. In recent years, some scientific evidence has supported this statement, showing that dietary plant extracts, or bioactive compounds isolated therefrom, are able to prevent or slow down the progression of chronic and degenerative diseases, making them particularly interesting from a nutraceutical point of view. On the other hand, extensive chemical investigations of functional plant extracts’ constituents are needed to rationalize certain bioactivity, in terms of efficacy and safety

Purification of plant derived molecules that modulate sphingolipid enzymes in cancer and inflammation

There is a constant need to discover new anticancer and anti-inflammatory compounds that can be developed as medicines. Sphingosine kinase 1 (SK1) and dihydroceramide desaturase (Des1) have been demonstrated to have a key role in sphingolipid metabolism and are potential targets for anticancer/anti-inflammatory therapeutics. This study aims to screen a plant library collected during field work in Egypt and then to isolate new anticancer and anti-inflammatory compounds with activity against SK1 and/ or Des1. This aim was achieved using plant extracts tested on breast cancer cell viability, proliferation and SK1 and/or Des1 protein expression. Bio-assay guided fractionation and isolation of compounds using flash column, silica gel column chromatography and preparative TLC techniques, followed by structure elucidation using 1D and 2D spectroscopic analysis enabled identification of compounds that met the criteria above. Cell proliferation was determined using [3H]-thymidine incorporation assay. Western blotting technique was used to determine the effect of isolated compounds on the targeted enzymes SK1/Des1 as well as the apoptotic pathway (PARP). There were three major findings. First, three plant species Gomphocarpus sinaicus, Urginea maritima and Pancratium tortuosum exhibited anticancer activity. Second, narciclasine was isolated for the first time from P. tortuosum and was demonstrated to inhibit cell proliferation (p<0.05) and to reduce SK1 and Des1 expression in MDA-MB-231 and MCF7-7L breast cancer cells. Narciclasine also induced PARP cleavage (a marker for apoptosis) and reduced expression of Ki67 and phosphorylated AKT levels (a marker for cell survival). The reduced expression of SK1 and Des1 in response to narciclasine was independent of the ubiquitin-proteasomal pathway, suggesting that this compound might affect the transcriptional/translational regulation of SK1 and Des1. Finally, narciclasine also exhibited ant-inflammatory activity as evidenced by its ability to prevent TNFα-stimulated degradation of IκB and to inhibit NFkB- and AP1-dependent transcriptional activity in keratinocytes. Third, a mixture of cardenolide glycosides were isolated from G. sinaicus and shown to inhibit cell proliferation (p<0.05), reduce expression of SK1 and Des1 and induce modest PARP cleavage in MDA-MB-231 and MCF-7L cells. This mixture contained humistratin and calactin and/or calotropin. These compounds reduced SK1 expression by inducing its proteasomal degradation, while the reduction in Des1 expression may be via a transcriptional/translational mechanism and is independent of ubiquitin-proteasomal degradation pathway. The mixture also exhibited anti-inflammatory activity in inhibiting NFkB- and AP-1-dependent transcriptional activity in keratinocytes. Narciclasine and the cardenolide glycoside mixture are potential anticancer/anti-inflammatory compounds require further studies in order to establish whether these compounds might be usefully exploited to treat cancer and inflammatory disease.There is a constant need to discover new anticancer and anti-inflammatory compounds that can be developed as medicines. Sphingosine kinase 1 (SK1) and dihydroceramide desaturase (Des1) have been demonstrated to have a key role in sphingolipid metabolism and are potential targets for anticancer/anti-inflammatory therapeutics. This study aims to screen a plant library collected during field work in Egypt and then to isolate new anticancer and anti-inflammatory compounds with activity against SK1 and/ or Des1. This aim was achieved using plant extracts tested on breast cancer cell viability, proliferation and SK1 and/or Des1 protein expression. Bio-assay guided fractionation and isolation of compounds using flash column, silica gel column chromatography and preparative TLC techniques, followed by structure elucidation using 1D and 2D spectroscopic analysis enabled identification of compounds that met the criteria above. Cell proliferation was determined using [3H]-thymidine incorporation assay. Western blotting technique was used to determine the effect of isolated compounds on the targeted enzymes SK1/Des1 as well as the apoptotic pathway (PARP). There were three major findings. First, three plant species Gomphocarpus sinaicus, Urginea maritima and Pancratium tortuosum exhibited anticancer activity. Second, narciclasine was isolated for the first time from P. tortuosum and was demonstrated to inhibit cell proliferation (p<0.05) and to reduce SK1 and Des1 expression in MDA-MB-231 and MCF7-7L breast cancer cells. Narciclasine also induced PARP cleavage (a marker for apoptosis) and reduced expression of Ki67 and phosphorylated AKT levels (a marker for cell survival). The reduced expression of SK1 and Des1 in response to narciclasine was independent of the ubiquitin-proteasomal pathway, suggesting that this compound might affect the transcriptional/translational regulation of SK1 and Des1. Finally, narciclasine also exhibited ant-inflammatory activity as evidenced by its ability to prevent TNFα-stimulated degradation of IκB and to inhibit NFkB- and AP1-dependent transcriptional activity in keratinocytes. Third, a mixture of cardenolide glycosides were isolated from G. sinaicus and shown to inhibit cell proliferation (p<0.05), reduce expression of SK1 and Des1 and induce modest PARP cleavage in MDA-MB-231 and MCF-7L cells. This mixture contained humistratin and calactin and/or calotropin. These compounds reduced SK1 expression by inducing its proteasomal degradation, while the reduction in Des1 expression may be via a transcriptional/translational mechanism and is independent of ubiquitin-proteasomal degradation pathway. The mixture also exhibited anti-inflammatory activity in inhibiting NFkB- and AP-1-dependent transcriptional activity in keratinocytes. Narciclasine and the cardenolide glycoside mixture are potential anticancer/anti-inflammatory compounds require further studies in order to establish whether these compounds might be usefully exploited to treat cancer and inflammatory disease