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Bandgar B.P.,University of Solapur | Bandgar B.P.,Swami Ramanand Teerth Marathwada University | Gawande S.S.,Swami Ramanand Teerth Marathwada University | Bodade R.G.,Swami Ramanand Teerth Marathwada University | And 2 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

Chalcones have been identified as interesting compounds with cytotoxicity, anti-inflammatory and antioxidant properties. In the present study, simple methoxychalcones were synthesized by Claisen-Schmidt condensation reaction and evaluated for above biological activities. The structures of the compounds were established by IR, 1H NMR and mass spectral analysis. The data revealed that compound 3s (99-100% at 10 μM concentration) completely inhibit the selected five human cancer cell lines as compared to standard flavopiridol and gemcitabine (70-90% at 700 nM and 500 nM concentrations, respectively), followed by 3a, 3n, 3o, 3p, 3q, 3r. Among the tested compounds 3l, 3m, 3r, and 3s exhibited promising anti-inflammatory activity against TNF-α and IL-6 with 90-100% inhibition at 10 μM concentration. DPPH free radical scavenging activity was given by the compounds 3o, 3n, 3l, 3r, 3m, 3a, 3p, 3c and 3s at 1 mM concentration. Overall, 3s was obtained as lead compound with promising anticancer, anti-inflammatory and antioxidant activities. Bioavailability of compounds were checked by in vitro cytotoxicity study and confirmed to be nontoxic. The structure activity relationship (SAR) and in silico drug relevant properties (HBDs, HBAs, PSA, c Log P, ionization potential, molecular weight, EHOMO and ELUMO) further confirmed that the compounds were potential candidates for future drug discovery study. © 2009 Elsevier Ltd. All rights reserved. Source

Bandgar B.P.,University of Solapur | Bandgar B.P.,Swami Ramanand Teerth Marathwada University | Gawande S.S.,Swami Ramanand Teerth Marathwada University | Warangkar S.C.,Swami Ramanand Teerth Marathwada University | Totre J.V.,Institute for Drug Research
Bioorganic and Medicinal Chemistry | Year: 2010

An efficient solvent-free procedure for the synthesis of thiomorpholides in the presence of a catalytic amount of solid-supported fluoroboric acid (HBF4-SiO2) is described. The advantages of this method are high yields, short reaction times, ease of product isolation, low cost, and the catalyst can be recycled for a number of times without significant loss of activity. Three thiomorpholides possessing electron-donating group (4c, 4g, and 4h) were exhibiting excellent stimulatory activities against Erwinia carotovora l-asparaginase. The most potent activator, compound 4h displayed the following kinetic parameters, Km = 75 μM and Vmax = 1000 μmol mg-1 min-1 and KA = 0.985 μM. Furthermore, these compounds (4g, 4h, 4c, 4f, 4a, and 4d) have also shown promising 2,2′-diphenyl-1-picrylhydrazyl (DPPH) reducing antioxidant activity (21-36%) at 1 mM concentration as compared to standard butylated hydroxyl anisole (72% at 1 mM). © 2010. Source

Merquiol E.,Hebrew University of Jerusalem | Uzi D.,Hebrew University of Jerusalem | Mueller T.,Charite - Medical University of Berlin | Goldenberg D.,Hebrew University of Jerusalem | And 4 more authors.
PLoS ONE | Year: 2011

Background: The endoplasmic reticulum (ER) is the cellular site for protein folding. ER stress occurs when protein folding capacity is exceeded. This stress induces a cyto-protective signaling cascades termed the unfolded protein response (UPR) aimed at restoring homeostasis. While acute ER stress is lethal, chronic sub-lethal ER stress causes cells to adapt by attenuation of UPR activation. Hepatitis C virus (HCV), a major human pathogen, was shown to cause ER stress, however it is unclear whether HCV induces chronic ER stress, and if so whether adaptation mechanisms are initiated. We wanted to characterize the kinetics of HCV-induced ER stress during infection and assess adaptation mechanisms and their significance. Methods and Findings: The HuH7.5.1 cellular system and HCV-transgenic (HCV-Tg) mice were used to characterize HCV-induced ER stress/UPR pathway activation and adaptation. HCV induced a wave of acute ER stress peaking 2-5 days post-infection, which rapidly subsided thereafter. UPR pathways were activated including IRE1 and EIF2α phosphorylation, ATF6 cleavage and XBP-1 splicing. Downstream target genes including GADD34, ERdj4, p58ipk, ATF3 and ATF4 were upregulated. CHOP, a UPR regulated protein was activated and translocated to the nucleus. Remarkably, UPR activity did not return to baseline but remained elevated for up to 14 days post infection suggesting that chronic ER stress is induced. At this time, cells adapted to ER stress and were less responsive to further drug-induced ER stress. Similar results were obtained in HCV-Tg mice. Suppression of HCV by Interferon-α 2a treatment, restored UPR responsiveness to ER stress tolerant cells. Conclusions: Our study shows, for the first time, that HCV induces adaptation to chronic ER stress which was reversed upon viral suppression. These finding represent a novel viral mechanism to manipulate cellular response pathways. © 2011 Merquiol et al. Source

Lavy T.,Institute for Drug Research | Harries D.,Hebrew University of Jerusalem | Goldblum A.,Institute for Drug Research
Journal of Physical Chemistry A | Year: 2011

We present a novel method for constructing the stable conformational space of small molecules with many rotatable bonds that uses our iterative stochastic elimination (ISE) algorithm, a robust stochastic search method capable of finding ensembles of best solutions for large combinatorial problems. To validate the method, we show that ISE reproduces the best conformers found in a fully exhaustive search, as well as compare computed dipole moments to experimental values, based on molecular ensembles and their Boltzmann distributions. Results were also compared to the alternative molecular dynamics and simulated annealing methods. Our results clarify that many low energy conformations may be required to reproduce molecular properties, while single low energy conformers or ensembles of low energy conformers cannot account for the experimental properties of flexible molecules. Whereas ISE well reproduces conformations that are not separated by very large energy barriers, it has not been successful in reproducing conformations of strained molecules. © 2010 American Chemical Society. Source

Home > Press > Nanotechnology delivery system offers new approach to skin disease therapies: Hebrew University formula that activates the body's natural defense against free radicals could control a variety of skin pathologies and disorders Abstract: Researchers at The Hebrew University of Jerusalem have developed a nanotechnology-based delivery system containing a protective cellular pathway inducer that activates the body's natural defense against free radicals efficiently, a development that could control a variety of skin pathologies and disorders. The human skin is constantly exposed to various pollutants, UV rays, radiation and other stressors that exist in our day-to-day environment. When they filter into the body they can create Reactive Oxygen Species (ROS) - oxygen molecules known as Free Radicals, which are able to damage and destroy cells, including lipids, proteins and DNA. In the skin - the largest organ of the body - an excess of ROS can lead to various skin conditions, including inflammatory diseases, pigmenting disorders, wrinkles and some types of skin cancer, and can also affect internal organs. This damage is known as Oxidative Stress. The body is naturally equipped with defense mechanisms to counter oxidative stress. It has anti-oxidants and, more importantly, anti-oxidant enzymes that attack the ROS before they cause damage. In a review article published in the journal Cosmetics, a PhD student from The Hebrew University of Jerusalem, working in collaboration with researchers at the Technion - Israel Institute of Technology, suggested an innovative way to invigorate the body to produce antioxidant enzymes, while maintaining skin cell redox balance - a gentle equilibrium between Reactive Oxygen Species and their detoxification. "The approach of using the body's own defense system is very effective. We showed that activation of the body's defense system with the aid of a unique delivery system is feasible, and may leverage dermal cure," said Hebrew University researcher Maya Ben-Yehuda Greenwald. Ben-Yehuda Greenwald showed that applying nano-size droplets of microemulsion liquids containing a cellular protective pathway inducer into the skin activates the natural skin defense systems. "Currently, there are many scientific studies supporting the activation of the body's defense mechanisms. However, none of these studies has demonstrated the use of a nanotechnology-based delivery system to do so," Ben-Yehuda Greenwald said. Production of antioxidant enzymes in the body is signaled in the DNA by activation of Nrf2 - a powerful protein that exists in every cell in our body. This Nrf2 cellular-protective signaling pathway is a major intersection of many other signaling pathways affecting each other and determining cell functionality and fate. Nrf2 is capable of coordinating the cellular response to internal as well as external stressors by tight regulation of phase-II protective enzymes, such as the antioxidant enzymes. Ben-Yehuda Greenwald has also discovered a new family of compounds capable of activating the Nrf2 pathway. Moreover, by incorporating them into the unique delivery system she has developed, she managed to efficiently stimulate the activation of the Nrf2 pathway and mimic the activity of the body's' natural way of coping with a variety of stress conditions. "The formula we have created could be used in topical medication for treating skin conditions. Our formula could be used both as preventive means and for treatment of various skin conditions, such as infections, over-exposure to UV irradiation, inflammatory conditions, and also internal disease," she said. While the researchers focused on the skin, the formulation could prove to be effective in enhancing the body's natural protection against the damaging effects of ROS in other parts of the body, such as inflammation in cardiovascular diseases, heart attack, cancer, multiple sclerosis and Alzheimer's. ### Ben-Yehuda Greenwald integrated several fields of research into her work and was guided by experts in their fields - Prof. Roni Kohen, the Director of the School of Pharmacy, The Institute of Drug Research in the Hebrew University's Faculty of Medicine; Prof. Shmuel Ben-Sasson from the Department of Developmental Biology and Cancer Research at The Institute for Medical Research Israel-Canada in the Hebrew University's Faculty of Medicine; and Prof. Havazelet Bianco-Peled from the Department of Chemical Engineering at the Technion-Israel Institute of Technology. She conducted her study at the David and Ines Myers Skin Research Laboratory at The Institute for Drug Research in the School of Pharmacy at The Hebrew University's Faculty of Medicine. For more information, please click If you have a comment, please us. Issuers of news releases, not 7th Wave, Inc. or Nanotechnology Now, are solely responsible for the accuracy of the content.

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