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Medicinal-Pharmaceutical Chemistry Commons

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2011

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Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Activity Of Analogs Of Anticancer Drugs On The Serine Protease Enzymes Subtilisin And Chymotrypsin, Dhatri Ravipati Dec 2011

Activity Of Analogs Of Anticancer Drugs On The Serine Protease Enzymes Subtilisin And Chymotrypsin, Dhatri Ravipati

Masters Theses & Specialist Projects

The anticancer activity of several platinum compounds is due to the formation of complexes with DNA. We hypothesize that the size and shape of the platinum compounds would impact interaction with proteins, and these interactions may be partly responsible for the anticancer activity. Chymotrypsin and subtilisin are serine proteases that have a histidine residue in the active site. We are investigating the inhibition of the digestive enzymes chymotrypsin and subtilisin by analogs of the anticancer drug cisplatin and trying to discern trends in the inhibition as the active site residues vary. In our research, we found that the enzyme subtilisin ...


Inhibition Of Cysteine Protease By Platinum (Ii) Diamine Complexes, Chaitanya Rapolu Dec 2011

Inhibition Of Cysteine Protease By Platinum (Ii) Diamine Complexes, Chaitanya Rapolu

Masters Theses & Specialist Projects

Chemotherapy is the first line of treatment used in cancer. Chemotherapy drugs such as cisplatin, carboplatin and oxaliplatin are used in treatment. Cisplatin enters the cell through copper transporter CTR1 by passive diffusion and bind to DNA and proteins. Cisplatin is found to inhibit several enzymes targeting cysteine, histidine and methionine residues, which are expected to be responsible for its anticancer activity. A better understanding of how the size and shape and leaving ligands of platinum complexes affect cysteine protease, papain enzyme are studied. This could give new ways to optimize anticancer activity. The activity of papain enzyme was measured ...


The Tetrafluoroborate Salt Of 4-Methoxybenzyl N-2-(Dimethylamino)Ethyl-N-Nitrosocarbamate: Synthesis, Crystal Structure And Dft Calculations, Helene Hedian, Vladimir Benin Dec 2011

The Tetrafluoroborate Salt Of 4-Methoxybenzyl N-2-(Dimethylamino)Ethyl-N-Nitrosocarbamate: Synthesis, Crystal Structure And Dft Calculations, Helene Hedian, Vladimir Benin

Chemistry Faculty Publications

The tetrafluoroborate salt of 4-methoxybenzyl N-2-(dimethylamino)ethyl-N-nitrosocarbamate was prepared in two steps, via the corresponding carbamate. Its crystal structure is monoclinic, space group P21/c. The unit cell dimensions are: a = 19.499(8) Å, b = 5.877(3) Å, c = 15.757(7) Å, α = 90°, β = 110.019(7)°, γ = 90°, V = 1696.5(12) Å3, Z = 4. The structure exhibits an unexpected, pseudo-gauche conformation with respect to the C2–C3 bond, due to a stabilizing hydrogen bond between the carbonyl oxygen (O1) and the hydrogen atom at the trialkylammonium center (H3n ...


Analysis Of Binding Site Hot Spots On The Surface Of Ras Gtpase, Greg Buhrman, Casey O'Connor, Brandon Zerbe, Bradley M. Kearney, Raeanne Napoleon, Elizaveta A. Kovrigina, Sandor Vajda, Dima Kozakov, Evgueni Kovriguine, Carla Mattos Nov 2011

Analysis Of Binding Site Hot Spots On The Surface Of Ras Gtpase, Greg Buhrman, Casey O'Connor, Brandon Zerbe, Bradley M. Kearney, Raeanne Napoleon, Elizaveta A. Kovrigina, Sandor Vajda, Dima Kozakov, Evgueni Kovriguine, Carla Mattos

Chemistry Faculty Research and Publications

We have recently discovered an allosteric switch in Ras, bringing an additional level of complexity to this GTPase whose mutants are involved in nearly 30% of cancers. Upon activation of the allosteric switch, there is a shift in helix 3/loop 7 associated with a disorder to order transition in the active site. Here, we use a combination of multiple solvent crystal structures and computational solvent mapping (FTMap) to determine binding site hot spots in the “off” and “on” allosteric states of the GTP-bound form of H-Ras. Thirteen sites are revealed, expanding possible target sites for ligand binding well beyond ...


Re-Engineering Drug Discovery And Development, Garret A. Fitzgerald Oct 2011

Re-Engineering Drug Discovery And Development, Garret A. Fitzgerald

Issue Briefs

The rate of new drug approvals in the US has remained essentially constant since 1950, while the costs of drug development have soared. Many commentators question the sustainability of the current model of drug development, in which large pharmaceutical companies incur markedly escalating costs to deliver the same number of products to market. This Issue Brief summarizes the problem, describes ongoing governmental efforts to influence the process, and suggests changes in regulatory science and translational medicine that may promote more successful development of safe and effective therapeutics.


High Yield Synthesis Of Positron Emission Tomography Ligands For Metabotropic Glutamate Receptor Imaging, Saraanne E. Hitchcock Aug 2011

High Yield Synthesis Of Positron Emission Tomography Ligands For Metabotropic Glutamate Receptor Imaging, Saraanne E. Hitchcock

Student Research Projects, Dissertations, and Theses - Chemistry Department

Positron Emission Tomography (PET) is a powerful and non-invasive imaging technique used for human and animal organ imaging. Currently, the market for PET is project to reach $5.4 billion per year by 2015.5 This research focuses on the direct incorporation of [18F]-fluoride into PET ligands. The widespread use of PET imaging is currently frustrated, in part, by the lack of efficient fluorination chemistry.

Glutamate, one of the 20 most abundant naturally occurring amino acids, serves as a neurotransmitter in the central nervous system. Glutamate functions in this capacity by binding to ionotropic and metabotropic receptors. Metabotropic receptors ...


Application Of Raman Spectroscopy To Lubricants, Lubricated Surfaces And Lubrication Phenomena, David W. Johnson Jul 2011

Application Of Raman Spectroscopy To Lubricants, Lubricated Surfaces And Lubrication Phenomena, David W. Johnson

Chemistry Faculty Publications

Recent advances in lasers and detector technologies and the development of low-cost instruments and fiber-optic probes have brought about an explosion in the lubrication systems being studied by Raman spectroscopy. This article provides examples of the use of Raman spectroscopy in the study of lubrication phenomena, including the characterization of liquid lubricants, lubricant additives, and solid lubricants; the study of vapor-phase lubrication; and the use of coated nanoparticles as lubricants.


Genome-Wide Analysis Reveals Padi4 Cooperates With Elk-1 To Activate C-Fos Expression In Breast Cancer Cells., Xuesen Zhang, Matthew J. Gamble, Sonja Stadler, Brian D. Cherrington, Corey P. Causey, Paul R. Thompson, Mark S. Roberson, W Lee Kraus, Scott A. Coonrod Jun 2011

Genome-Wide Analysis Reveals Padi4 Cooperates With Elk-1 To Activate C-Fos Expression In Breast Cancer Cells., Xuesen Zhang, Matthew J. Gamble, Sonja Stadler, Brian D. Cherrington, Corey P. Causey, Paul R. Thompson, Mark S. Roberson, W Lee Kraus, Scott A. Coonrod

Thompson Lab Publications

Peptidylarginine deiminase IV (PADI4) catalyzes the conversion of positively charged arginine and methylarginine residues to neutrally charged citrulline, and this activity has been linked to the repression of a limited number of target genes. To broaden our knowledge of the regulatory potential of PADI4, we utilized chromatin immunoprecipitation coupled with promoter tiling array (ChIP-chip) analysis to more comprehensively investigate the range of PADI4 target genes across the genome in MCF-7 breast cancer cells. Results showed that PADI4 is enriched in gene promoter regions near transcription start sites (TSSs); and, surprisingly, this pattern of binding is primarily associated with actively transcribed ...


In Vitro Activities Of Synthetic Host Defense Propeptides Processed By Neutrophil Elastase Against Cystic Fibrosis Pathogens., Stephane Desgranges, Florie Le Prieult, Alan Daly, Marian Brennan, Dilip K. Rai, Anusha P. Subasinghage, Chandralal M. Hewage, Sally-Ann Cryan, Catherine M. Greene, Noel G. Mcelvaney, Timothy P. Smyth, Deirdre Fitzgerald-Hughes, Hilary Humphreys, Marc Devocelle May 2011

In Vitro Activities Of Synthetic Host Defense Propeptides Processed By Neutrophil Elastase Against Cystic Fibrosis Pathogens., Stephane Desgranges, Florie Le Prieult, Alan Daly, Marian Brennan, Dilip K. Rai, Anusha P. Subasinghage, Chandralal M. Hewage, Sally-Ann Cryan, Catherine M. Greene, Noel G. Mcelvaney, Timothy P. Smyth, Deirdre Fitzgerald-Hughes, Hilary Humphreys, Marc Devocelle

Chemistry Articles

The antimicrobial and hemolytic activities of a host defense peptide can be controlled by its modification as a propeptide of reduced net charge, which can then be processed by neutrophil elastase, a serine protease involved in chronic airway inflammation and infections associated with cystic fibrosis.


A Sodium Salt Of The Dimer Of Boronoterephthalic Acid Anhydride, Scott Simmons, Albert Fratini, Vladimir Benin Apr 2011

A Sodium Salt Of The Dimer Of Boronoterephthalic Acid Anhydride, Scott Simmons, Albert Fratini, Vladimir Benin

Chemistry Faculty Publications

The title compound, sodium bis­(6-carb­oxy-1-hy­droxy-3-oxo-1,3-dihydro-2,1-benzoxaborol-1-yl)oxidanium, Na+·C16H15B2O13-, was prepared in two steps from 2-bromo-p-xylene. Its crystal structure was determined at 140 K and has triclinic (P) symmetry. The compound presents a unique structural motif, including two units of the cyclic anhydride of boronoterephthalic acid, joined by a protonated, and thereby trivalent, oxonium center. Association in the crystal is realized by complementary hydrogen bonding of the carboxyl groups, as well as by coordination of the sodium cations to the oxygen centers on the five-membered rings.


Theoretical Investigation Of A Reported Antibiotic From The 'Miracle Tree' Moringa Oleifera, Michael Horwath, Vladimir Benin Apr 2011

Theoretical Investigation Of A Reported Antibiotic From The 'Miracle Tree' Moringa Oleifera, Michael Horwath, Vladimir Benin

Chemistry Faculty Publications

Moringa oleifera, sometimes called the “Miracle Tree,” has received international attention for its potential to improve health in impoverished tropical areas. In addition to high vitamin content in the leaves and pods, the tree contains compounds with antioxidant and antibacterial properties. This study focused on the theoretical investigation of the suggested structure of one antibacterial compound, “pterygospermin,” whose existence was proposed after some studies of the roots of M. oleifera. The structure of pterygospermin was first proposed by a research group working in the 1950s, but later studies have not found evidence of this compound and have instead attributed the ...


Organometallic Iron(Iii)-Salophene Exerts Cytotoxic Properties In Neuroblastoma Cells Via Mapk Activation And Ros Generation, Kyu Kwang Kim, Rakesh K. Singh, Robert M. Strongin, Richard G. Moore, Laurent Brard, Thilo S. Lange Apr 2011

Organometallic Iron(Iii)-Salophene Exerts Cytotoxic Properties In Neuroblastoma Cells Via Mapk Activation And Ros Generation, Kyu Kwang Kim, Rakesh K. Singh, Robert M. Strongin, Richard G. Moore, Laurent Brard, Thilo S. Lange

Chemistry Faculty Publications and Presentations

The objective of the present study was to investigate the specific effects of Iron(III)-salophene (Fe-SP) on viability, morphology, proliferation, cell cycle progression, ROS generation and pro-apoptotic MAPK activation in neuroblastoma (NB) cells. A NCI-DTP cancer screen revealed that Fe-SP displayed high toxicity against cell lines of different tumor origin but not tumor type-specificity. In a viability screen Fe-SP exhibited high cytotoxicity against all three NB cell lines tested. The compound caused cell cycle arrest in G1 phase, suppression of cells progressing through S phase, morphological changes, disruption of the mitochondrial membrane depolarization potential, induction of apoptotic markers as ...


Antisense-Induced Suppression Of Taxoid 14Β-Hydroxylase Gene Expression In Transgenic Taxus × Media Cells, Feng-Lan Li, Xiao-Jun Ma, Angela Hoffman, Jun-Gui Dai, De-You Qui Jan 2011

Antisense-Induced Suppression Of Taxoid 14Β-Hydroxylase Gene Expression In Transgenic Taxus × Media Cells, Feng-Lan Li, Xiao-Jun Ma, Angela Hoffman, Jun-Gui Dai, De-You Qui

Chemistry Faculty Publications and Presentations

The enzyme taxoid 14β-hydroxylase (14OH) directs a side-route of taxol pathway to 14β-hydroxy taxoids. Suppression of this side-route could increase the production of taxol. To suppress taxoid 14β- hydroxylase gene (14OH) expression in theTaxus × media TM3 cell line, antisense RNA inhibition approach was used in this study. Following the construction of an antisense RNA expression vector of 14OH from Taxus chinensis, the antisense 14OH cDNA (as14OH) was introduced into TM3 cells by Agrobacterium tumefaciens-mediated transformation. Southern blot analysis of hygromycin phosphotransferase gene (HYG) revealed that this selection gene was integrated successfully into the genome of Taxus × media ...


Pharmacological Chaperoning In Fabry Disease, Jerome Rogich Jan 2011

Pharmacological Chaperoning In Fabry Disease, Jerome Rogich

Masters Theses 1911 - February 2014

Fabry Disease is an X-­‐linked lysosomal storage disorder characterized by a variety of symptoms including hypohydrosis, seizures, cardiac abnormalities, skin lesions, and chronic pain. These symptoms stem from a lack of functional endogenous α-­‐ Galactosidase A (α-­GAL), which leads to an accrual of its natural substrate. The severity of the disease symptoms can be directly correlated with the amount of residual enzyme activity. It has been shown that an imino sugar, 1-deoxygalactonojirimycin (DGJ), can increase enzymatic activity and clear excess substrate. This pH-­‐dependent chaperoning phenomenon is believed to arise from the presence of aspartic acid 170 in ...


Human Fatty Acid Transport Protein 2a/Very Long Chain Acyl-Coa Synthetase 1 (Fatp2a/Acsvl1) Has A Preference In Mediating The Channeling Of Exogenous N-3 Fatty Acids Into Phosphatidylinositol, Elaina M. Melton, Ronald Cerny, Paul A. Watkins, Concetta C. Dirusso, Paul N. Black Jan 2011

Human Fatty Acid Transport Protein 2a/Very Long Chain Acyl-Coa Synthetase 1 (Fatp2a/Acsvl1) Has A Preference In Mediating The Channeling Of Exogenous N-3 Fatty Acids Into Phosphatidylinositol, Elaina M. Melton, Ronald Cerny, Paul A. Watkins, Concetta C. Dirusso, Paul N. Black

Ronald Cerny Publications

The trafficking of fatty acids across the membrane and into downstream metabolic pathways requires their activation to CoA thioesters. Members of the fatty acid transport protein/ very long chain acyl-CoA synthetase (FATP/Acsvl) family are emerging as key players in the trafficking of exogenous fatty acids into the cell and in intracellular fatty acid homeostasis.We have expressed two naturally occurring splice variants of human FATP2 (Acsvl1) in yeast and 293T-REx cells and addressed their roles in fatty acid transport, activation, and intracellular trafficking. Although both forms (FATP2a (Mr 70,000) and FATP2b (Mr 65,000 and lacking exon3, which ...


Overexpression Of Galnac-Transferase Galnac-T3 Promotes Pancreatic Cancer Cell Growth, Keisuke Taniuchi, Ronald Cerny, Aki Tanouchi, Kimitoshi Kohno, Norihiro Kotani, Koichi Honke, Toshiji Saibara, Michael A. Hollingsworth Jan 2011

Overexpression Of Galnac-Transferase Galnac-T3 Promotes Pancreatic Cancer Cell Growth, Keisuke Taniuchi, Ronald Cerny, Aki Tanouchi, Kimitoshi Kohno, Norihiro Kotani, Koichi Honke, Toshiji Saibara, Michael A. Hollingsworth

Ronald Cerny Publications

O-linked glycans of secreted and membrane bound proteins play an important role in the pathogenesis of pancreatic cancer by modulating immune responses, inflammation, and tumorigenesis. A critical aspect of O-glycosylation, the position at which proteins are glycosylated with N-acetyl-galactosamine on serine and threonine residues, is regulated by the substrate specificity of UDP-GalNAc: polypeptide N-acetylgalactosaminyl-transferases (GalNAc-Ts). Thus, GalNAc-Ts regulate the first committed step in O-glycosylated protein biosynthesis, determine sites of O-glycosylation on proteins, and are important for understanding normal and carcinoma-associated O-glycosylation. We have found that one of these enzymes, GalNAc-T3, is overexpressed in ...


Structure Function Analysis Of An Adp-Ribosyltransferase Type Iii Effector And Its Rna-Binding Target In Plant Immunity, Byeong-Ryool Jeong, Yan Lin, Anna Joe, Ming Guo, Christin Korneli, Huirong Yang, Ping Wang, Min Yu, Ronald Cerny, Dorothee Staiger, James R. Alfano, Yanhui Xu Jan 2011

Structure Function Analysis Of An Adp-Ribosyltransferase Type Iii Effector And Its Rna-Binding Target In Plant Immunity, Byeong-Ryool Jeong, Yan Lin, Anna Joe, Ming Guo, Christin Korneli, Huirong Yang, Ping Wang, Min Yu, Ronald Cerny, Dorothee Staiger, James R. Alfano, Yanhui Xu

Ronald Cerny Publications

Background: HopU1 ADP-ribosylates GRP7, suppressing plant immunity.

Results: The HopU1 structure has two novel loops required for GRP7 recognition, and HopU1 ribosylates GRP7 at an arginine in position 49 disrupting its function.

Conclusion: HopU1 targets a conserved arginine in GRP7, disabling its ability to bind immunity-related RNA.

Significance: The mechanistic details of how HopU1 recognizes its substrate reveal how HopU1 contributes to pathogenesis.


Identification And Characterization Of The Anti-Methicillin-Resistant Staphylococcus Aureus Wap-8294a2 Biosynthetic Gene Cluster From Lysobacter Enzymogenes Oh11, Wei Zhang, Yaoyao Li, Guoliang Qian, Yan Wang, Haotong Chen, Yue-Zhong Li, Fengquan Liu, Yuemao Shen, Liangcheng Du Jan 2011

Identification And Characterization Of The Anti-Methicillin-Resistant Staphylococcus Aureus Wap-8294a2 Biosynthetic Gene Cluster From Lysobacter Enzymogenes Oh11, Wei Zhang, Yaoyao Li, Guoliang Qian, Yan Wang, Haotong Chen, Yue-Zhong Li, Fengquan Liu, Yuemao Shen, Liangcheng Du

Faculty Publications -- Chemistry Department

Lysobactor enzymogenes strain OH11 is an emerging biological control agent of fungal and bacterial diseases. We recently completed its genome sequence and found it contains a large number of gene clusters putatively responsible for the biosynthesis of nonribosomal peptides and polyketides, including the previously identified antifungal dihydromaltophilin (HSAF). One of the gene clusters contains two huge open reading frames, together encoding 12 modules of nonribosomal peptide synthetases (NRPS). Gene disruption of one of the NRPS led to the disappearance of a metabolite produced in the wild type and the elimination of its antibacterial activity. The metabolite and antibacterial activity were ...