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Analysis Of The Proposed Tpp-Related Patent Linkage System In Taiwan, Ping-Hsun Chen 2017 National Chengchi University

Analysis Of The Proposed Tpp-Related Patent Linkage System In Taiwan, Ping-Hsun Chen

Journal of Law and Health

The Trans-Pacific Partnership (TPP) Agreement mandates member states to implement a patent linkage system vested in Article 18.53. To successfully join the TPP Agreement, Taiwan has begun the legislation of a patent linkage system by proposing an amendment for the Pharmaceutical Affairs Act. Article 18.53 requires a member either to adopt a notification mechanism under Paragraph 1 or to stay the issuance of marketing approval under Paragraph 2. But, Taiwan’s proposal includes both measures. Taiwan’s patent linkage system allows a pioneer drug company to register patents claiming (a) a material, (b) a combination or formula, or ...


Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer 2017 University of Massachusetts Medical School

Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer

Celia A. Schiffer

Molecular recognition is a highly interdependent process. Subsite couplings within the active site of proteases are most often revealed through conditional amino acid preferences in substrate recognition. However, the potential effect of these couplings on inhibition and thus inhibitor design is largely unexplored. The present study examines the interdependency of subsites in HIV-1 protease using a focused library of protease inhibitors, to aid in future inhibitor design. Previously a series of darunavir (DRV) analogs was designed to systematically probe the S1' and S2' subsites. Co-crystal structures of these analogs with HIV-1 protease provide the ideal opportunity to probe subsite interdependency ...


Efficient Synthesis Of Cn2097 Using In Situ Activation Of Sulfhydryl Group, Shaban Darwish, Keykavous Parang, John Marshall, Dennis J. Goebel, Rakesh Tiwari 2017 Chapman University

Efficient Synthesis Of Cn2097 Using In Situ Activation Of Sulfhydryl Group, Shaban Darwish, Keykavous Parang, John Marshall, Dennis J. Goebel, Rakesh Tiwari

Pharmacy Faculty Articles and Research

CN2097 (R7Cs-sCYK[KTE(β-Ala)]V) is a rationally designed peptidomimetic that shows effectiveness in preclinical models for the treatment of neurological disorders, such as Angelman syndrome, traumatic brain injury (TBI), and stroke. Because of its potential therapeutic activity for the treatment of human CNS disorders, there was an urgent need to develop an efficient strategy for large-scale synthesis of CN2097. The synthesis of CN2097 was accomplished using Fmoc/tBu solid phase chemistry in multiple steps. Two different peptide fragments (activated polyarginine peptide Npys-sCR7 and CYK[KTE(β-Ala)]V) were synthesized, followed by solution phase coupling in water ...


Synthesis And Evaluation Of Antimicrobial Activity Of [R4w4k]-Levofloxacin And [R4w4k]-Levofloxacin-Q Conjugates, Neda Riahifard, Kathy Tavakoli, Jason Yamaki, Keykavous Parang, Rakesh Tiwari 2017 Chapman University

Synthesis And Evaluation Of Antimicrobial Activity Of [R4w4k]-Levofloxacin And [R4w4k]-Levofloxacin-Q Conjugates, Neda Riahifard, Kathy Tavakoli, Jason Yamaki, Keykavous Parang, Rakesh Tiwari

Pharmacy Faculty Articles and Research

The development of a new class of antibiotics to fight bacterial resistance is a time-consuming effort associated with high-cost and commercial risks. Thus, modification, conjugation or combination of existing antibiotics to enhance their efficacy is a suitable strategy. We have previously reported that the amphiphilic cyclic peptide [R4W4] had antibacterial activity with a minimum inhibitory concentration (MIC) of 2.97 g/mL against Methicillin-resistant Staphylococcus aureus (MRSA). Herein, we hypothesized that conjugation or combination of the amphiphilic cyclic peptide [R4W4] with levofloxacin or levofloxacin-Q could improve the antibacterial activity of levofloxacin and levofloxacin-Q. Fmoc/tBu solid-phase chemistry was employed to ...


Identification Of A Nucleoside Analog Active Against Adenosine Kinase-Expressing Plasma Cell Malignancies, Utthara Nayar, Jouliana Sadek, Jonathan Reichel, Denise Hernandez-Hopkins, Gunkut Akar, Peter J. Barelli, Michelle A. Sahai, Hufeng Zhou, Jennifer Totonchy, David Jayabalan, Ruben Niesvizky, Ilaria Guasparri, Duane Hassane, Yifang Liu, Shizuko Sei, Robert H. Shoemaker, J. David Warren, Olivier Elemento, Kenneth M. Kaye, Ethel Cesarman 2017 Weill Cornell Medical College

Identification Of A Nucleoside Analog Active Against Adenosine Kinase-Expressing Plasma Cell Malignancies, Utthara Nayar, Jouliana Sadek, Jonathan Reichel, Denise Hernandez-Hopkins, Gunkut Akar, Peter J. Barelli, Michelle A. Sahai, Hufeng Zhou, Jennifer Totonchy, David Jayabalan, Ruben Niesvizky, Ilaria Guasparri, Duane Hassane, Yifang Liu, Shizuko Sei, Robert H. Shoemaker, J. David Warren, Olivier Elemento, Kenneth M. Kaye, Ethel Cesarman

Pharmacy Faculty Articles and Research

Primary effusion lymphoma (PEL) is a largely incurable malignancy of B cell origin with plasmacytic differentiation. Here, we report the identification of a highly effective inhibitor of PEL. This compound, 6-ethylthioinosine (6-ETI), is a nucleoside analog with toxicity to PEL in vitro and in vivo, but not to other lymphoma cell lines tested. We developed and performed resistome analysis, an unbiased approach based on RNA sequencing of resistant subclones, to discover the molecular mechanisms of sensitivity. We found different adenosine kinase–inactivating (ADK-inactivating) alterations in all resistant clones and determined that ADK is required to phosphorylate and activate 6-ETI. Further ...


Synthesis, Including Microwave Promotion, Of Selected Cyclopropyl Derivatives As Stereochemically Rigid Probes Of Certain Pharmalogical Receptors, Grace Hohn 2017 Olivet Nazarene University

Synthesis, Including Microwave Promotion, Of Selected Cyclopropyl Derivatives As Stereochemically Rigid Probes Of Certain Pharmalogical Receptors, Grace Hohn

Honors Program Projects

Pharmacologic intervention with stereochemical probes allows for the treatment of medical conditions by affecting receptors in the body and causing receptors to respond to the presence of the probe. Novel cyclopropyl derivatives were synthesized could serve as a stereochemically rigid probes of certain pharmacological receptors and could have potential use as a drug. A probe is a molecule or ligand that can bind to and interact with a receptor in the human body. This interaction triggers a desirable response by increasing or decreasing the presence of a compound (e.g. dopamine for depression) in order to repair a chemical imbalance ...


Companion Diagnostics For Breast Cancer Chemotherapeutics, Monica Tawadros, Michael Morin, Peter Gaines, Abiche H. Dewilde 2017 University of Massachusetts Medical School

Companion Diagnostics For Breast Cancer Chemotherapeutics, Monica Tawadros, Michael Morin, Peter Gaines, Abiche H. Dewilde

UMass Center for Clinical and Translational Science Research Retreat

Chemotherapy plays a major role in breast cancer treatment. However, not every chemotherapeutics is appropriate for each cancer due to the person’s individual cancer characteristics and whether the patient has developed chemoresistance to a particular drug. In this research, the InVitro-Q is used to detect subtle differences in tumor cell proliferation post-treatment with four-breast cancer chemotherapeutics used: paclitaxel, docetaxel, nocodazole, and cytochalasin B. Our multi-well cell-based sensor that can monitor real-time biological changes in living cells, such as mass redistribution, and viscoelasticity. This system provides unique kinetic information regarding the phenotypic change in the cells post treatment. Each drug ...


Effects Of Anandamide Administration On Components Of Reward Processing, Howard C. Cromwell 2017 Bowling Green State University

Effects Of Anandamide Administration On Components Of Reward Processing, Howard C. Cromwell

Howard Casey Cromwell

Previous research has implicated the positive modulation of anandamide, an endocannabinoid neurotransmitter,on feeding behavior. Anandamide is particularly noteworthy as it acts as an endogenous ligand of the CB1receptor, the same receptor that is activated by tetrahydrocannabinol, the primary psychoactive component in Cannabis sativa. Cannabis legalization in North America has presented with a need to study endocannabinoid agonists and their effects on behavior. Much has yet to be determined in terms of the role of the endocannabinoid system in decision-making scenarios. The research presented here tested the hypothesis that anandamide wouldaugment motivation and reward processing via appetitive and ...


B7h6: A Cancer Biomarker For The Development Of Novel Immunotherapy Approaches, Mariana Phillips 2017 Seton Hall University

B7h6: A Cancer Biomarker For The Development Of Novel Immunotherapy Approaches, Mariana Phillips

Seton Hall University Dissertations and Theses (ETDs)

Cancer-based immunotherapy has led the evolution of biologics that can stimulate immune responses towards tumor eradication. The synthesis of small to intermediate size molecules with the targeting and effector functions of mAb may represent a novel class of immunotherapeutics that may overcome the limitations of their biological counterparts.Towards this objective, B7H6 has been identified as a protein ligand localized on the cell surface of transformed tumor cells. B7H6 binds specifically to the activating receptor NKp30, constitutively expressed on all resting and active NK cells. Upon ligand:receptor binding, B7H6 triggers NK cell activation and release of chemokines and pro-inflammatory ...


One-Pot Syntheses And Characterizations Of “Click-Able” Polyester Polymers For Potential Biomedical Applications, James F. Beach II 2017 Pittsburg State University

One-Pot Syntheses And Characterizations Of “Click-Able” Polyester Polymers For Potential Biomedical Applications, James F. Beach Ii

Electronic Thesis Collection

In this study, a synthetic polyester polymer was designed using polyethylene glycol, sorbitol, glutaric acid and 4-pentynoic acid as monomers. The synthesis was carried out using standard melt polymerization technique and catalyzed by Novozyme-435, an enzyme suitable for polyesterification of biocompatible compounds. The progress of the reaction was monitored with respect to time and vacuum exposure, with samples being subjected to standard characterization protocols. Polymers with high molecular weight and water solubility were chosen for further modification into folate-functionalized polymeric nanoparticles for targeted drug delivery to cancer cells. This was achieved by employing a solvent diffusion method, wherein the polymer ...


Structure Activity Relationship Studies Of Novel Diarylpentanoid Analogs Targeting The Androgen Receptor In Prostate Cancer Cells, Haili Coffin, Marco Bisoffi 2017 Chapman University

Structure Activity Relationship Studies Of Novel Diarylpentanoid Analogs Targeting The Androgen Receptor In Prostate Cancer Cells, Haili Coffin, Marco Bisoffi

Student Scholar Symposium Abstracts and Posters

The development of prostate cancer (PCa) relies strongly on the activation of the androgen receptor (AR) signaling pathway by its natural ligand dihydrotestosterone. Furthermore, PCa progression to metastatic disease represents oncogene addiction to AR activity. Androgen ablation therapy is thus a mainstay therapy against this disease, but the development of ligand-independent AR activation and persisting AR expression eventually leads to castration resistant PCa (CRPC). Therefore, down-regulation of AR expression in PCa cells may be an effective therapeutic modality. The diarylpentanoid ca27 has previously been shown to down-regulate AR expression by an unknown mechanism of action. The present work represents a ...


Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition Of Exosome And Microvesicle Release And Enhanced Efficacy Of Cancer Chemotherapy, Uchini S. Kosgodage, Rita P. Trindade, Paul R. Thompson, Jameel M. Inal, Sigrun Lange 2017 London Metropolitan University

Chloramidine/Bisindolylmaleimide-I-Mediated Inhibition Of Exosome And Microvesicle Release And Enhanced Efficacy Of Cancer Chemotherapy, Uchini S. Kosgodage, Rita P. Trindade, Paul R. Thompson, Jameel M. Inal, Sigrun Lange

Open Access Articles

Microvesicle (MV) release from tumour cells influences drug retention, contributing to cancer drug resistance. Strategically regulating MV release may increase drug retention within cancer cells and allow for lower doses of chemotherapeutic drugs. The contribution of exosomes to drug retention still remains unknown. Potential exosome and MV (EMV) biogenesis inhibitors, tested on human prostate cancer (PC3) cells for their capacity to inhibit EMV release, were also tested on PC3 and MCF-7 (breast cancer) cells for improving chemotherapy. Agents inhibiting EMV release most significantly, whilst maintaining cell viability, were chloramidine (Cl-amidine; 50 microM) and bisindolylmaleimide-I (10 microM). Apoptosis mediated by the ...


Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer 2017 University of Massachusetts Medical School

Interdependence Of Inhibitor Recognition In Hiv-1 Protease, Janet L. Paulsen, Florian Leidner, Debra A. Ragland, Nese Kurt Yilmaz, Celia A. Schiffer

University of Massachusetts Medical School Faculty Publications

Molecular recognition is a highly interdependent process. Subsite couplings within the active site of proteases are most often revealed through conditional amino acid preferences in substrate recognition. However, the potential effect of these couplings on inhibition and thus inhibitor design is largely unexplored. The present study examines the interdependency of subsites in HIV-1 protease using a focused library of protease inhibitors, to aid in future inhibitor design. Previously a series of darunavir (DRV) analogs was designed to systematically probe the S1' and S2' subsites. Co-crystal structures of these analogs with HIV-1 protease provide the ideal opportunity to probe subsite interdependency ...


Age-Associated Expression Patterns Of Oatp 1b1 And Oatp 1b3 And Their Effect On The Disposition Of Fexofenadine, Margaret Mary Thomson 2017 University of Tennessee Health Science Center

Age-Associated Expression Patterns Of Oatp 1b1 And Oatp 1b3 And Their Effect On The Disposition Of Fexofenadine, Margaret Mary Thomson

Theses and Dissertations (ETD)

As part of the drug disposition process (absorption, distribution, metabolism, excretion), an often overlooked aspect is transport. In order for drugs to be metabolized and excreted from the body they go through the liver or other drug removal organs. For drugs that are polar or are large they must rely upon transport mechanisms to transport them across the biomembranes of the drug removal organs. OATP1B1 and OATP1B3 are transporters on the sinusoidal membrane of the liver which work in concert with the drug metabolizing enzymes as part of the drug removal process. It is known that the development of each ...


Kinetic Studies Of Dna Repair Enzyme Alkbh2, Michael R. Vittori 2017 University of Rhode Island

Kinetic Studies Of Dna Repair Enzyme Alkbh2, Michael R. Vittori

Senior Honors Projects

The genomes of living organisms are under constant bombardment from various sources, including chemical modification stemming from processes within the organisms themselves or from exogenous agents, and from radiation. These sources of genomic damage may induce structural changes in the genome’s most basic functional units, the nucleotides that comprise DNA. Damage to an organism’s DNA may result in the production of dysfunctional or nonfunctional proteins. Failure to repair such damage may result in the compounding of successive mutations within the organism’s genome, the pathogenesis of cancer and various genetic disorders in humans. To ensure their viability, organisms ...


Design, Synthesis, And Evaluation Of Novel Positron Emission Tomography Radiotracers, Christopher Philip Surdock 2017 University of Tennessee Health Science Center

Design, Synthesis, And Evaluation Of Novel Positron Emission Tomography Radiotracers, Christopher Philip Surdock

Theses and Dissertations (ETD)

Neuroblastoma (NB) is the most common extracranial tumor in patients under 1 year of age and it constitutes about 8-10% of all childhood cancer. It originates from neural crest cells that normally differentiate to form the sympathetic ganglia, adrenal medulla and other paraspinal sites where sympathetic nervous system tissue is present. Even with an extensive treatment regimen that typically includes surgery, chemotherapy, total body irradiation and autologous stem cell transplantation, the 5-year event-free survival is <50% for high risk patients, and there are numerous long-term side effects associated with treatment. This body of work investigated two projects for improving patient outcomes through the development of positron emission tomography (PET) radiotracers that could be used for therapy planning. The goal of the first project was to design, synthesize, and evaluate PET radiotracers that could measure the enzymatic activation of Irinotecan (CPT-11), a potent chemotherapeutic used in the treatment of colon cancer and several pediatric solid tumors. CPT-11 itself is a prodrug which is converted in vivo to SN-38, via metabolism by carboxylesterase (CE) enzymes. St. Jude Children’s Research Hospital researchers have designed a two-pronged protocol of tumor-targeted CPT-11 chemotherapy combining the complementary approaches of a) specific modulation of human CE in normal tissues to improve drug delivery, and b) tumor-targeted activation of prodrug using neural progenitor cells (NPC) transfected with a mutant human CE cDNA. The tumor-selective trafficking of NPC allows over-expression of CE within the tumor. This prodrug/activating enzyme therapeutic approach has shown extremely encouraging preclinical results in the treatment of NB (90% 1-year survival in mice). However, successful translation of this novel therapeutic approach into general clinical practice requires a better understanding of progenitor cell trafficking, duration and intensity of enzymatic activity and the ultimate biological fate of the therapeutic construct. Toward this end, PET radiotracers were developed based on extensive structure-activity relationship (SAR) studies of CE binding. The goal of the second project was to design, synthesize, and evaluate PET radiotracers that could identify the presence of the tropomyosin receptor kinase B (TrkB). TrkB is not normally found in sympathetic nervous tissue, which is the tissue NB develops from, and thus is a potential target for imaging and therapy. The presence of TrkB and its neurotrophin, brain derived neurotrophic factor (BDNF), have been reported to protect neuroblastoma tumor cells from chemotherapy-induced apoptosis via a phosphatidylinositol 3’-kinase pathway. Radiotracers were synthesized and evaluated for their ability to identify TrkB both in vitro and in vivo. PET radiosynthetic procedures were optimized to synthesize novel radiotracers for imaging targets that could help clinicians monitor therapy or identify markers that would aid in therapy planning for NB patients. The method development could be applied to future compounds that show improved chemical characteristics for synthesis and selectivity.


Discovery Of Natural Product-Based Antimycobacterial Agents Effective Against Non-Replicating Bacilli, Shajila Siricilla 2017 University of Tennessee Health Science Center

Discovery Of Natural Product-Based Antimycobacterial Agents Effective Against Non-Replicating Bacilli, Shajila Siricilla

Theses and Dissertations (ETD)

New antimycobacterial molecules that kill non-replicating Mycobacterium tuberculosis (Mtb) were identified by screening libraries of synthetic natural products. De novo screening of a 400-membered library of aurachin RE analogs resulted in discovery of UT-317 ((R)-20). UT-317 is a selective vitamin K2 biosynthesis (MenA) inhibitor that killed replicating and non-replicating Mtb at 2.31 μg/mL (MIC) and 0.85 μg/mL, respectively. A 50-membered library of capuramycin analogs was evaluated in their enzymatic inhibitory activities against translocase I (MraY/MurX) and prenyl-phosphate-GlcNAc-1-phosphate transferase (WecA). UT-01320 (45) is identified as a selective WecA inhibitor that kills both replicating and non-replicating ...


Synthesis Of 20s-Hydroxyvitamin D3 Analogs And Their 1Α-Hydroxyl Derivatives As Potent Anti-Inflammatory Agents, Zongtao Lin 2017 University of Tennessee Health Science Center

Synthesis Of 20s-Hydroxyvitamin D3 Analogs And Their 1Α-Hydroxyl Derivatives As Potent Anti-Inflammatory Agents, Zongtao Lin

Theses and Dissertations (ETD)

Rheumatoid arthritis (RA) is one of the autoimmune diseases, and is affecting 2.5 million Americans in total. Among the treatment options of RA, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is the only steroidal drug used clinically for anti-inflammatory and immune diseases. However, long-term use of 1,25(OH)2D3 (625 µg/day) in human would result in hypercalcemia (toxicity), and 1,25(OH)2D3 has substantial hypercalcemic effects (toxicity) in mice at a dose as low as only 2 µg/kg. Fortunately, during the investigation of novel metabolic pathway of vitamin D3 by cytochrome P450 enzymes, we found ...


Simplified Reversed Chloroquines To Overcome Malaria Resistance To Quinoline-Based Drugs, Bornface Gunsaru, Steven J. Burgess, Westin Morrill, Jane X. Kelly, Shawheen Shomloo, Martin J. Smilkstein, Katherine May Liebman, David H. Peyton 2017 Portland State University

Simplified Reversed Chloroquines To Overcome Malaria Resistance To Quinoline-Based Drugs, Bornface Gunsaru, Steven J. Burgess, Westin Morrill, Jane X. Kelly, Shawheen Shomloo, Martin J. Smilkstein, Katherine May Liebman, David H. Peyton

Chemistry Faculty Publications and Presentations

Building on our earlier work of attaching a chemosensitizer (reversal agent) to a known drug pharmacophore, we have now expanded the structure-activity relationship study to include simplified versions of the chemosensitizer. The change from two aromatic rings in this head group to a single ring does not appear to detrimentally affect the antimalarial activity of the compounds. Data from in vitro heme binding and beta-hematin inhibition assays suggest that the single aromatic RCQ compounds retain activities against Plasmodium falciparum similar to those of CQ, although other mechanisms of action may be relevant to their activities.


Characterization Of Novel Cannabinoid Receptor 2-Selective Agonists At The Biochemical And Cellular Levels: Leads For Therapeutic Agents, Ashley M. Hine 2017 University of Connecticut - Storrs

Characterization Of Novel Cannabinoid Receptor 2-Selective Agonists At The Biochemical And Cellular Levels: Leads For Therapeutic Agents, Ashley M. Hine

Honors Scholar Theses

Putative cannabinoid receptor 2 (CB2)-selective agonists were identified from a library of commercially available compounds via inhibition of cAMP accumulation in high throughput screening. Binding affinity and receptor subtype selectivity were assessed using heterologous competition binding assays against the known cannabinoid orthosteric ligand CP55940. Test compounds ASX0152383 and CSC003141 preferentially bound to CB2, with no detection of binding to CB1 up to 1 mM. CMB038865 exhibited nearly 100-fold selectivity for CB1 over CB2, while CZ000026 bound non-preferentially to both receptors in the low micromolar range. To determine the extent of G protein coupling, GTPγS ...


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