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2016

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Articles 1 - 30 of 84

Full-Text Articles in Medicinal-Pharmaceutical Chemistry

Peptidylarginine Deiminase 1-Catalyzed Histone Citrullination Is Essential For Early Embryo Development, Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang Dec 2016

Peptidylarginine Deiminase 1-Catalyzed Histone Citrullination Is Essential For Early Embryo Development, Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang

Thompson Lab Publications

Peptidylarginine deiminase (PADI) enzymes are increasingly being associated with the regulation of chromatin structure and gene activity via histone citrullination. As one of the PADI family members, PADI1 has been mainly reported to be expressed in the epidermis and uterus, where the protein in keratinocytes is thought to promote differentiation by citrullinating filament proteins. However, the roles of PADI1 in preimplantation development have not been addressed. Using a PADI1-specific inhibitor and Padi1-morpholino knockdown, we found that citrullination of histone tails at H4R3 and H3R2/8/17 were markedly reduced in the 2- and 4-cell embryos. Consistent with this observation, early ...


Design, Synthesis, And Evaluation Of Dasatinib-Amino Acid And Dasatinib-Fatty Acid Conjugates As Protein Tyrosine Kinase Inhibitors, Rakesh Tiwari, Alex Brown, Neda Sadeghiani, Amir Nasrolahi Shirazi, Jared Bolton, Amanda Tse, Gennady M. Verkhivker, Keykavous Parang, Gongqin Sun Nov 2016

Design, Synthesis, And Evaluation Of Dasatinib-Amino Acid And Dasatinib-Fatty Acid Conjugates As Protein Tyrosine Kinase Inhibitors, Rakesh Tiwari, Alex Brown, Neda Sadeghiani, Amir Nasrolahi Shirazi, Jared Bolton, Amanda Tse, Gennady M. Verkhivker, Keykavous Parang, Gongqin Sun

Pharmacy Faculty Articles and Research

Derivatives of dasatinib were synthesized via esterification with 25 carboxylic acids including amino acids and fatty acids by extending the inhibitor to interact with more diverse sites and to improve specificity. Dasatinib-L-arginine derivative (Das-R, 7) was the most potent of the inhibitors tested with IC50 values of 4.4 nM, <0.25 nM, and <0.45 nM against Csk, Src, and Abl kinases, respectively. The highest selectivity ratio obtained in our study, 91.4 Csk/Src belonged to compound 18 (Das-C10) with an IC50 of 3.2 μM for Csk compared to 35 nM for Src. Furthermore, many compounds displayed increased selectivity toward Src, as compared with Abl. Compounds 15 (Das-E) and 13 (Das-C) demonstrated the largest gains (10.2 and 10.3 Abl/Src IC50 ratios). Das-R (IC50 = 2.06 μM) was significantly more potent than Das (IC50 = 26.3 μM) against Panc-1 cells while they both showed an IC50 < 51.2 pM against BV-173 and K562 cells. Molecular modeling and binding free energy simulations revealed a good agreement with the experimental results and rationalized differences in selectivity of the studied compounds. Integration of experimental and computational approaches in the design and biochemical screening of dasatinib derivatives facilitated rational engineering and diversification of dasatinib scaffold, providing useful insights into mechanisms of kinase selectivity.


Synthesis Of Orthogonally Protected Thioamide Dipeptides For Use In Solid-Phase Peptide Synthesis, Fintan Kelleher, Kim Manzor Nov 2016

Synthesis Of Orthogonally Protected Thioamide Dipeptides For Use In Solid-Phase Peptide Synthesis, Fintan Kelleher, Kim Manzor

Articles

Orthogonally protected thioamide-containing dipeptides were efficiently and cleanly prepared from the precursor dipeptides using Curphey’s method (P4S10, hexamethyldisiloxane (HMDO), reflux, DCM) in 67-96% isolated yield. This was in contrast to the use of Lawesson’s or Berzelius’ reagents where significant issues with reaction non-completion, decomposition and purification were observed. Subsequent clean removal of the dipeptides’ t-butyl ester protecting groups gave thioamide dipeptide acids which were suitable for use in solid-phase peptide synthesis (SPPS).


Discovery And Characterization Of A Potent And Selective Inhibitory Of Aedes Aegypti Inward Rectifier Potassium Channels, Matthew F. Rouhier, Rene Raphemot, Daniel R. Swale, Emily Days, C. David Weaver, Kimberly M. Lovell, Leah C. Konkel, Darren W. Engers, Sean F. Bollinger, Corey Hopkins, Peter M. Piermarini, Jerod S. Denton Oct 2016

Discovery And Characterization Of A Potent And Selective Inhibitory Of Aedes Aegypti Inward Rectifier Potassium Channels, Matthew F. Rouhier, Rene Raphemot, Daniel R. Swale, Emily Days, C. David Weaver, Kimberly M. Lovell, Leah C. Konkel, Darren W. Engers, Sean F. Bollinger, Corey Hopkins, Peter M. Piermarini, Jerod S. Denton

Matthew F Rouhier

Vector-borne diseases such as dengue fever and malaria, which are transmitted by infected female mosquitoes, affect nearly half of the world's population. The emergence of insecticide-resistant mosquito populations is reducing the effectiveness of conventional insecticides and threatening current vector control strategies, which has created an urgent need to identify new molecular targets against which novel classes of insecticides can be developed. We previously demonstrated that small molecule inhibitors of mammalian Kir channels represent promising chemicals for new mosquitocide development. In this study, high-throughput screening of approximately 30,000 chemically diverse small-molecules was employed to discover potent and selective inhibitors ...


Polymeric Prodrug Combination To Exploit The Therapeutic Potential Of Antimicrobial Peptides Against Cancer Cells., Graeme J. Kelly, A Foltyn-Arfa Kia, F Hassan, S O'Grady, Maria P. Morgan, B S. Creaven, S Mcclean, Judith H. Harmey, Marc Devocelle Oct 2016

Polymeric Prodrug Combination To Exploit The Therapeutic Potential Of Antimicrobial Peptides Against Cancer Cells., Graeme J. Kelly, A Foltyn-Arfa Kia, F Hassan, S O'Grady, Maria P. Morgan, B S. Creaven, S Mcclean, Judith H. Harmey, Marc Devocelle

Chemistry Articles

Antimicrobial Peptides (AMPs) have unique anticancer properties, but their clinical application is currently limited by an inadequate margin of safety. A prodrug strategy associated with a combination therapy approach could address this limitation by increasing their therapeutic index and their efficacy. Accordingly, the first targeted anticancer polymeric prodrug candidates of AMPs, intended for combination therapy with another polymeric prodrug of an approved antineoplastic agent (doxorubicin), were synthesized as either a PEG-based dual-release prodrug or two individual pegylated prodrugs. The latter are based on a cathepsin B-labile peptide linker and an acid-sensitive acyl hydrazone bond for the AMP and doxorubicin prodrugs ...


Synthesis, Self-Assembly, And Immunological Activity Of Α-Galactose-Functionalized Dendron–Lipid Amphiphiles, John Trant, Namrata Jain, D. M. Mazzuca, J Trevor Mcintosh, Bo Fan, S M Mansour Haeryfar, Sebastien Lecommandoux, Elizabeth Gillies Sep 2016

Synthesis, Self-Assembly, And Immunological Activity Of Α-Galactose-Functionalized Dendron–Lipid Amphiphiles, John Trant, Namrata Jain, D. M. Mazzuca, J Trevor Mcintosh, Bo Fan, S M Mansour Haeryfar, Sebastien Lecommandoux, Elizabeth Gillies

Chemistry Publications

Nanoassemblies presenting multivalent displays of biologically active carbohydrates are of significant interest for a wide array of biomedical applications ranging from drug delivery to immunotherapy. In this study, glycodendronlipid hybrids were developed as a new and tunable class of dendritic amphiphiles. A modular synthesis was used to prepare dendronlipid hybrids comprising distearylglycerol and 0 through 4th generation polyester dendrons with peripheral protected amines. Following deprotection of the amines, an isothiocyanate derivative of C-linked α-galactose (α-Gal) was conjugated to the dendron peripheries, affording amphiphiles with 1 to 16 α-Gal moieties. Self-assembly in water through a ...


Strained Alkyne Substituted Near Infrared Bf2 Azadipyrromethene Fluorochrome, Dan Wu, Shane Cheung, Corry James O'Sullivan, Yinghua Gao, Zhi-Long Chen, Donal F. O'Shea Sep 2016

Strained Alkyne Substituted Near Infrared Bf2 Azadipyrromethene Fluorochrome, Dan Wu, Shane Cheung, Corry James O'Sullivan, Yinghua Gao, Zhi-Long Chen, Donal F. O'Shea

Chemistry Articles

The contribution of imaging with near infrared (NIR) fluorophores to the elucidation of complex biological processes continues to rapidly expand. New tools for mild selective bioconjugation are strongly desirable for the construction of NIR labelled biomolecules. This work presents the synthesis and evaluation of a strained alkyne substituted NIR BF2-azadipyrromethene (NIR-AZA) which can conjugate in water with azido-homoalanine and cRGD peptide within 30 min at rt. Imaging analysis of the NIR-AZA–cRGD conjugate in vitro and in vivo showed efficient cellular uptake and good in vivo tumor targeting properties, illustrating the potential for translation to clinical imaging.


Synthesis Of Polymeric Bismuth Chlorido Hydroxamato Complexes; X-Ray Crystal Structure And Antibacterial Activity Of A Novel Bi(Lll) Salicylhydroxamato Complex, Donal M. Keoghan, Lauren E. Fagan, Thayse Marques Passos, Helge Müller-Bunz, Bríd Quilty, Darren M. Griffith Sep 2016

Synthesis Of Polymeric Bismuth Chlorido Hydroxamato Complexes; X-Ray Crystal Structure And Antibacterial Activity Of A Novel Bi(Lll) Salicylhydroxamato Complex, Donal M. Keoghan, Lauren E. Fagan, Thayse Marques Passos, Helge Müller-Bunz, Bríd Quilty, Darren M. Griffith

Chemistry Articles

Reaction of salicylhydroxamic acid (Sha) and 2-aminophenyl hydroxamic acid (2-NH2-pha) with BiCl3 affords the corresponding novel polymeric bismuth chlorido hydroxamato complexes; [BiCl2(-Sha-1H)]∞ and [BiCl3(--Pha-1H)]∞ respectively. The X-ray crystal structure of the THF-solvated polymeric bismuth chlorido salicylhydroxamato complex, [BiCl2(-Sha-1H)(THF)]∞ was solved, confirming the polymeric structure of this class of compounds and the (O,μ-O’)-bidentate bridging coordination mode of the hydroxamato ligand. The antibacterial activity of the THF-free polymeric bismuth chlorido salicylhydroxamato complex, [BiCl2(-Sha-1H)]∞, was investigated against a broad panel of bacteria, further highlighting the antibacterial properties of Bi-based compounds against Gram-positive and Gram-negative pathogenic and ...


Peroxiredoxin Catalysis At Atomic Resolution, Arden Perkins, Derek Parsonage, Kimberly J. Nelson, O. Maduka Ogba, Paul Ha-Yeon Cheong, Leslie B. Poole, P. Andrew Karplus Sep 2016

Peroxiredoxin Catalysis At Atomic Resolution, Arden Perkins, Derek Parsonage, Kimberly J. Nelson, O. Maduka Ogba, Paul Ha-Yeon Cheong, Leslie B. Poole, P. Andrew Karplus

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Peroxiredoxins (Prxs) are ubiquitous cysteine-based peroxidases that guard cells against oxidative damage, are virulence factors for pathogens, and are involved in eukaryotic redox regulatory pathways. We have analyzed catalytically active crystals to capture atomic resolution snapshots of a PrxQ-subfamily enzyme (from Xanthomonas campestris) proceeding through thiolate, sulfenate, and sulfinate species. These analyses provide structures of unprecedented accuracy for seeding theoretical studies, and show novel conformational intermediates giving insight into the reaction pathway. Based on a highly non-standard geometry seen for the sulfenate intermediate, we infer that the sulfenate formation itself can strongly promote local unfolding of the active site to ...


Microfilariae Of Brugia Malayi Inhibit The Mtor Pathway And Induce Autophagy In Human Dendritic Cells, Prakash Babu Narasimhan, Sasisekhar Bennuru, Zhaojing Meng, Rachel N Cotton, Kathleen R Elliott, Sundar Ganesan, Renee Mcdonald-Fleming, Timothy Veenstra, Thomas B Nutman, Roshanak Tolouei Semnani Sep 2016

Microfilariae Of Brugia Malayi Inhibit The Mtor Pathway And Induce Autophagy In Human Dendritic Cells, Prakash Babu Narasimhan, Sasisekhar Bennuru, Zhaojing Meng, Rachel N Cotton, Kathleen R Elliott, Sundar Ganesan, Renee Mcdonald-Fleming, Timothy Veenstra, Thomas B Nutman, Roshanak Tolouei Semnani

Pharmaceutical Sciences Faculty Publications

Immune modulation is a hallmark of patent filarial infection, including suppression of antigen-presenting cell function and downmodulation of filarial antigen-specific T cell responses. The mammalian target of rapamycin (mTOR) signaling pathway has been implicated in immune regulation, not only by suppressing T cell responses but also by regulating autophagy (through mTOR sensing amino acid availability). Global proteomic analysis (liquid chromatography-tandem mass spectrometry) of microfilaria (mf)-exposed monocyte-derived dendritic cells (DC) indicated that multiple components of the mTOR signaling pathway, including mTOR, eIF4A, and eIF4E, are downregulated by mf, suggesting that mf target this pathway for immune modulation in DC. Utilizing ...


Ionophoric Polyphenols Selectively Bind Cu2+, Display Potent Antioxidant And Anti-Amyloidogenic Properties, And Are Non-Toxic Toward Tetrahymena Thermophila, Alberto Martinez, Ralph Alcendor, Tanzeen Rahman, Magdalena Podgorny, Ismaila Sanogo, Rebecca Mccurdy Aug 2016

Ionophoric Polyphenols Selectively Bind Cu2+, Display Potent Antioxidant And Anti-Amyloidogenic Properties, And Are Non-Toxic Toward Tetrahymena Thermophila, Alberto Martinez, Ralph Alcendor, Tanzeen Rahman, Magdalena Podgorny, Ismaila Sanogo, Rebecca Mccurdy

Publications and Research

Alzheimer’s disease (AD) is the most common form of dementia affecting more than 28 million people in the world. Only symptomatic treatments are currently available. Anticipated tri-fold increase of AD incidence in the next 50 years has established the need to explore new possible treatments. Accumulation of extracellular amyloid-b (Ab) plaques, intracellular tangles in the brain, and formation of reactive oxygen species (ROS) are the major hallmarks of the disease. The active role of some metal ions, especially Cu2+, in promoting both Ab aggregation and reactive oxygen species formation has rendered ionophoric drugs as a promising treatment strategy ...


The Synthesis Of Chemosensors For Toxic Analytes, Johnathan Hugh Broome Aug 2016

The Synthesis Of Chemosensors For Toxic Analytes, Johnathan Hugh Broome

Dissertations

A number of chemosensors have been designed and synthesized to target cations (Zn2+ions), neutral molecules (cathinones), charged molecules (aminoindanes), and anions. The Zn2+ ion sensor featured bistriazole designed binding unit and ferrocene signaling units. Characterization of Zn2+ ion binding was carried out with electrochemical techniques (CV and DPV), 1H-NMR, mass spectrometry, and molecular modelling. It exhibited a 1:1 binding stoichiometry with Zn2+ and had an affinity for ZnCl2 (Log K1:1 = 4.1 ± 0.02) over other Zn2+ salts.

The cathinone probe was designed to selectively bind mephedrone over common ...


Analysis Of The Intricacies Of Substrate Recognition Of High Mobility Group Proteins And Aminoacyl-Trna Synthetases Using Non-Cognate Substrates, Douglas Van Iverson Ii Aug 2016

Analysis Of The Intricacies Of Substrate Recognition Of High Mobility Group Proteins And Aminoacyl-Trna Synthetases Using Non-Cognate Substrates, Douglas Van Iverson Ii

Dissertations

The studies presented in section 1 (Chapters I-IV) focus on the design and development of nucleic acid four-way junctions (4WJs) to target a member of the high mobility group (HMG) proteins, the proinflammatory cytokine high mobility group box 1 protein (HMGB1). In the present study, hybrid PNA-DNA 4WJs based on a model DNA 4WJ were constructed to improve the thermal stability of 4WJs while maintaining strong binding affinity toward HMGB1. An electrophoretic mobility shift assay (EMSA) was used to examine the binding affinity of an isolated DNA binding domain of HMGB1, the HMGB1 b-box (HMGB1b), toward a set of PNA-DNA ...


Novel Improved Synthesis Of Hsp70 Inhibitor, Pifithrin-Μ. In Vitro Synergy Quantification Of Pifithrin-Μ Combined With Pt Drugs In Prostate And Colorectal Cancer Cells., Aoife M. Mckeon, Alan Egan, Jay Chandanshive, Helena Mcmahon, Darren M. Griffith Jul 2016

Novel Improved Synthesis Of Hsp70 Inhibitor, Pifithrin-Μ. In Vitro Synergy Quantification Of Pifithrin-Μ Combined With Pt Drugs In Prostate And Colorectal Cancer Cells., Aoife M. Mckeon, Alan Egan, Jay Chandanshive, Helena Mcmahon, Darren M. Griffith

Chemistry Articles

We describe a novel improved approach to the synthesis of the important and well-known heat shock protein 70 inhibitor (HSP70), pifithrin-μ, with corresponding and previously unreported characterisation. The first example of a combination study comprising HSP70 inhibitor pifithrin-μ and cisplatin or oxaliplatin is reported. We have determined, using the Chou-Talalay method, (i) moderate synergistic and synergistic effects in co-treating PC-3 prostate cancer cells with pifithrin-μ and cisplatin and (ii) significant synergistic effects including strong synergism in cotreating HT29 colorectal cancer cells with oxaliplatin and pifithrin-μ.


Azadipyrromethenes: From Traditional Dye Chemistry To Leading Edge Applications., Yuan Ge, Donal F. O'Shea Jul 2016

Azadipyrromethenes: From Traditional Dye Chemistry To Leading Edge Applications., Yuan Ge, Donal F. O'Shea

Chemistry Articles

Azadipyrromethenes were first described over 70 years ago as blue pigments, but now are rapidly emerging as a compound class with highly desirable near infrared photophysical properties. Since the turn of the century several routes to azadipyrromethenes have been developed and numerous post-synthesis derivatizations have allowed for their exploitation in both biological and material sciences. The relative ease of access to specifically designed derivatives is now allowing their use in multiple technological formats from real-time fluorescence imaging, to solar energy materials, to optoelectronic devices and many more. In this review we have highlighted the synthetic component of this story as ...


Synthesis Of A Small Molecule Nitrosocysteine Inhibitor To Reduce The Activity Of Caspase-1, Catherine A. Shamblen, Caitlin E. Karver Jul 2016

Synthesis Of A Small Molecule Nitrosocysteine Inhibitor To Reduce The Activity Of Caspase-1, Catherine A. Shamblen, Caitlin E. Karver

DePaul Discoveries

Caspase-1 is an enzyme that is overactive in autoimmune and autoinflammatory diseases cleaving pro-interleukin-1β to the cytokine interleukin-1β (IL-1β), which leads to inflammatory symptoms. The inhibition of caspase-1 will cause a decrease in the concentration of interleukin-1β (IL-1β), resulting in the reduction of inflammatory symptoms. Recent research has revealed that the appending of a nitric oxide (NO) or nitroxyl (HNO) donating group to non-steroidal anti-inflammatory drugs (NSAIDs) reduced, or avoided, the side effects caused by currently available treatments. A small molecule based on a known caspase-1 inhibitor with a nitrosocysteine appended on was synthesized to look at the effect of ...


Novel Class Of Bi(Iii) Hydroxamato Complexes: Synthesis, Urease Inhibitory Activity And Activity Against H. Pylori., Donal M. Keogan, Brendan Twamley, Deirdre Fitzgerald-Hughes, Darren M. Griffith Jul 2016

Novel Class Of Bi(Iii) Hydroxamato Complexes: Synthesis, Urease Inhibitory Activity And Activity Against H. Pylori., Donal M. Keogan, Brendan Twamley, Deirdre Fitzgerald-Hughes, Darren M. Griffith

Chemistry Articles

Reaction of Bi(NO3)3 with benzohydroxamic acid (Bha) and salicylhydroxamic acid (Sha) gives the novel Bi(iii) complexes [Bi2(Bha-1H)2(μ-Bha-1H)2(η(2)-NO3)2] () and [Bi6(CH3OH)2(η(1)-NO3)2(η(2)-NO3)(OH2)2(Sha-1H)12](NO3)2 (). X-ray crystal structure of reveals two hydroxamato coordination modes; bidentate bridging (O, O') and bidentate non-bridging (O, O') and of reveals one coordination mode; bidentate bridging (O, O'). , specifically designed to and demonstrated to inhibit the activity of urease, exhibits excellent antibacterial activity against three strains of Helicobacter pylori with MIC ≥ 16 μg mL(-1).


Conformational Dynamics And Stability Associated With Magnesium Or Calcium Binding To Dream In The Regulation Of Interactions Between Dream And Dna Or Presenilins, Khoa Ngoc Pham Jun 2016

Conformational Dynamics And Stability Associated With Magnesium Or Calcium Binding To Dream In The Regulation Of Interactions Between Dream And Dna Or Presenilins, Khoa Ngoc Pham

FIU Electronic Theses and Dissertations

Downstream regulatory element antagonist modulator (DREAM) is involved in various interactions with targets both inside and outside of the nucleus. In the cytoplasm, DREAM interacts with the C-terminal fragments of presenilins to facilitate the production of β-amyloid plaques in Alzheimer’s disease. In the nucleus, Ca2+ free DREAM directly binds to specific downstream regulatory elements of prodynorphin/c-fos gene to repress the gene transcription in pain modulation. These interactions are regulated by Ca2+ and/or Mg2+ association at the EF-hands in DREAM. Therefore, understanding the conformational dynamics and stability associated with Ca2+ and/or Mg ...


Enzyme-Mediated And Mechanistic Investigations Of Tetrahydroisoquinoline Synthesis Through The Pictet-Spengler Reaction, Jordan Elise Fauser Jun 2016

Enzyme-Mediated And Mechanistic Investigations Of Tetrahydroisoquinoline Synthesis Through The Pictet-Spengler Reaction, Jordan Elise Fauser

College of Science and Health Theses and Dissertations

Tetrahydroisoquinolines (THI) are biologically active natural products with applications to a variety of diseases. These compounds also act as precursors for other pharmacologically active natural products. In this investigation, a new synthetic approach for generation of halogenated THIs was proposed. Using cross-linked tyrosinase aggregate, halogenated tyrosine and tyramine were oxidized to form halogenated catechols such as halogenated L-DOPA and dopamine. In a one-pot synthetic approach, the enzyme oxidation reaction was coupled to the Pictet-Spengler reaction, through the addition of an aldehyde, to generate halogenated THIs. The Pictet-Spengler reaction was catalyzed by the phosphate buffer in the reaction solution. The role ...


Novel Protein Disulfide Isomerase Inhibitor With Anticancer Activity In Multiple Myeloma, Sergei Vatolin, James G. Phillips, Babal K. Jha, Shravya Govindgari, Jennifer Hu, Dale Grabowski, Yvonne Parker, Daniel J. Lindner, Fei Zhong, Clark W. Distelhorst, Mitchell R. Smith, Claudiu Cotta, Yan Xu, Sujatha Chilakala, Rebecca R. Kuang, Samantha Tall, Frederic J. Reu Jun 2016

Novel Protein Disulfide Isomerase Inhibitor With Anticancer Activity In Multiple Myeloma, Sergei Vatolin, James G. Phillips, Babal K. Jha, Shravya Govindgari, Jennifer Hu, Dale Grabowski, Yvonne Parker, Daniel J. Lindner, Fei Zhong, Clark W. Distelhorst, Mitchell R. Smith, Claudiu Cotta, Yan Xu, Sujatha Chilakala, Rebecca R. Kuang, Samantha Tall, Frederic J. Reu

Chemistry Faculty Publications

Multiple myeloma cells secrete more disulfide bond–rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell–based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrow–sparing compound, exhibited a submicromolar IC50 in 10 of 10 multiple myeloma cell lines ...


Screening The Low Molecular Weight Fraction Of Human Serum Using Atr-Ir Spectroscopy, Franck Bonnier, Matthew J. Baker, Hugh J. Byrne Jun 2016

Screening The Low Molecular Weight Fraction Of Human Serum Using Atr-Ir Spectroscopy, Franck Bonnier, Matthew J. Baker, Hugh J. Byrne

Articles

Vibrational spectroscopic techniques can detect small variations in molecular content, linked with disease, showing promise for screening and early diagnosis. Biological fluids, particularly blood serum, are potentially valuable for diagnosis purposes. The so-called Low Molecular Weight Fraction (LMWF) contains the associated peptidome and metabolome and has been identified as potentially the most relevant molecular population for disease-associated biomarker research. Although vibrational spectroscopy can deliver a specific chemical fingerprint of the samples, the High Molecular Weight Fraction (HMWF), composed of the most abundant serum proteins, strongly dominates the response and ultimately makes the detection of minor spectral variations a challenging task ...


Multi-Functional Copper(Ii) Drug Candidates As Potential Anti-Cancer Agents, Tadhg James Patrick Mc Givern Jun 2016

Multi-Functional Copper(Ii) Drug Candidates As Potential Anti-Cancer Agents, Tadhg James Patrick Mc Givern

PhD theses

The development of metal complexes as therapeutic agents remains a focal point of modern medicinal inorganic chemistry. While platinum drugs are well established therapeutic agents, recent progress has shown that some copper complexes possess enhanced cytotoxic activity and in vivo cytotoxic tolerance owing to their DNA binding and DNA scission capabilities. In parallel, the design, synthesis and evaluation of enzyme inhibitors rationally chosen for their potential in suppressing tumour cell proliferation as well as possessing selective toxicity towards tumour over normal cells is another area receiving considerable attention of late.

To date, we have successfully synthesized a library of novel ...


Optimizing Sequence Coverage For A Moderate Mass Protein In Nano-Electrospray Ionization Quadrupole Time-Of-Flight Mass Spectrometry, Ryan E. Matsuda, Venkata Kolli, Megan Woods, Eric D. Dodds, David S. Hage Jun 2016

Optimizing Sequence Coverage For A Moderate Mass Protein In Nano-Electrospray Ionization Quadrupole Time-Of-Flight Mass Spectrometry, Ryan E. Matsuda, Venkata Kolli, Megan Woods, Eric D. Dodds, David S. Hage

David Hage Publications

Sample pretreatment was optimized to obtain high sequence coverage for human serum albumin (HSA, 66.5 kDa) when using nano-electrospray ionization quadrupole time-of-flight mass spectrometry (nESI-Q-TOF-MS). Use of the final method with trypsin, Lys-C and Glu-C digests gave a combined coverage of 98.8%. The addition of peptide fractionation resulted in 99.7% coverage. These results were comparable to those obtained previously with matrixassisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The sample pretreatment/nESI-Q-TOF-MS method was also used with collision-induced dissociation to analyze HSA digests and to identify peptides that could be employed as internal mass calibrants in future ...


Abrogation Of Collagen-Induced Arthritis By A Peptidyl Arginine Deiminase Inhibitor Is Associated With Modulation Of T Cell-Mediated Immune Responses, Joanna Kawalkowska, Anne-Marie Quirke, Fatemeh Ghari, Simon Davis, Venkataraman Subramanian, Paul R. Thompson, Richard O. Williams, Roman Fischer, Nicholas B. La Thangue, Patrick J. Venables May 2016

Abrogation Of Collagen-Induced Arthritis By A Peptidyl Arginine Deiminase Inhibitor Is Associated With Modulation Of T Cell-Mediated Immune Responses, Joanna Kawalkowska, Anne-Marie Quirke, Fatemeh Ghari, Simon Davis, Venkataraman Subramanian, Paul R. Thompson, Richard O. Williams, Roman Fischer, Nicholas B. La Thangue, Patrick J. Venables

Open Access Articles

Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins have pro-inflammatory effects in both innate and adaptive immune responses. Here, we examine the therapeutic effects in collagen-induced arthritis of the second generation PAD inhibitor, BB-Cl-amidine. Treatment after disease onset resulted in the reversal of clinical and histological changes of arthritis, associated with a marked reduction in citrullinated proteins in lymph nodes. There was little overall change in antibodies to collagen or antibodies to citrullinated peptides, but a shift from pro-inflammatory Th1 and Th17-type responses to pro-resolution Th2-type responses was demonstrated by serum ...


Terpenes As ‘Resistance-Busting” Anthelmintic Drug, Zeynep Mirza, David Koch, Thanh-Thanh Nguyen, Yan Hu, Raffi V. Aroian, Gary R. Ostroff May 2016

Terpenes As ‘Resistance-Busting” Anthelmintic Drug, Zeynep Mirza, David Koch, Thanh-Thanh Nguyen, Yan Hu, Raffi V. Aroian, Gary R. Ostroff

UMass Center for Clinical and Translational Science Research Retreat

There is an urgent need for new therapies for parasitic helminthic diseases affecting 1.5-2 billion people worldwide due to the threat of wide-spread resistance development to existing treatments and due to problems of incomplete efficacies.

Terpenes are plant secondary metabolites and major essential oil constituents. Historically, the terpene thymol was successfully used to cure hookworm infections in the 1900’s. Although effective, large doses were needed and thymol treatment had significant side effects. Because free terpenes are absorbed in the stomach, less than 10% of oral terpenes entered the site where the parasites live. To overcome these problems we ...


Theoretical And Experimental Analysis Of The Antioxidant And Anti-Amyloid Features Of Synthetic Resveratrol Mimics, William Horton, Anne Kokel, Fanni Török, Chris Tran, Marianna Török, Bela Török May 2016

Theoretical And Experimental Analysis Of The Antioxidant And Anti-Amyloid Features Of Synthetic Resveratrol Mimics, William Horton, Anne Kokel, Fanni Török, Chris Tran, Marianna Török, Bela Török

UMass Center for Clinical and Translational Science Research Retreat

Diaryl hydrazones, possessing similar structure to the popular red wine antioxidant resveratrol, have been previously identified as multitarget compounds interfering with several processes associated with the pathogenesis of Alzheimer’s disease (AD). These compounds exhibited particularly strong inhibition of the amyloid beta (A) peptide self-assembly, including blocking the formation of fibrils and oligomers, species that are widely accepted to be neurotoxic. The molecules were also powerful free radical scavengers and thus have a potential to defend against oxidative stress.

In order to learn more about the mode of action of the compounds, theoretical and experimental studies have been carried out ...


Crystal Protein Cry5b As A Novel And Powerful Anthelmintic, David Koch, Zeynep Mirza, Yan Hu, Thanh-Thanh Nguyen, Gary R. Ostroff, Raffi V. Aroian May 2016

Crystal Protein Cry5b As A Novel And Powerful Anthelmintic, David Koch, Zeynep Mirza, Yan Hu, Thanh-Thanh Nguyen, Gary R. Ostroff, Raffi V. Aroian

UMass Center for Clinical and Translational Science Research Retreat

Soil-transmitted helminths (STHs), most notably, hookworms, whipworms, and Ascaris, are nematodes that infect more than 1.5 billion of the poorest people and are amongst the leading causes of morbidity worldwide. Only two classes of de-worming drugs (anthelmintics) are available for treatment, and only one is commonly used in mass drug administrations. New anthelmintics are urgently needed to overcome emerging resistance and to produce higher cure rates. Crystal (Cry) proteins, in particular Cry5B, made by Bacillus thuringiensis (Bt) are promising new candidates. Cry5B has excellent anthelmintic properties against many free-living and parasitic nematodes, including in vivo efficacy against multiple STH ...


Structural Activity Relationship Study On Dual Plk1 /Brd4 Inhibitor, Bi- 2536, Hailemichael Yosief, Shuai Liu, Dennis L. Buckley, Justin M. Roberts, Alex M. Muthengi, Francesca M. Corsini, James E. Bradner, Wei Zhang May 2016

Structural Activity Relationship Study On Dual Plk1 /Brd4 Inhibitor, Bi- 2536, Hailemichael Yosief, Shuai Liu, Dennis L. Buckley, Justin M. Roberts, Alex M. Muthengi, Francesca M. Corsini, James E. Bradner, Wei Zhang

UMass Center for Clinical and Translational Science Research Retreat

Polo-like kinase 1 (PLK1) and BRD4 are two different therapeutic targets in cancer drug discovery. Recently it has been reported that PLK1 inhibitor, BI-2536, is also a potent inhibitor of BRD4. The simultaneous inhibition of PLK1 and BRD4 by a single drug molecule is interesting because this could lead to the development of effective therapeutic strategy for different types of disease conditions in which PLK1 and BRD4 are implicated. Structural activity relationship studies has been carried out on BI-2536 to generate analogs with enhanced dual inhibitory activity against BRD4 and PLK1 as well as to render the molecule selective to ...


The Synthesis Of 1,3-Difluoro-2-Methyl-4-Phenylbenzene From A One-Pot Reaction Of Difluorocarbene And 1-Phenyl-2-Methylcyclobutene, Ruth Felicitas Menger May 2016

The Synthesis Of 1,3-Difluoro-2-Methyl-4-Phenylbenzene From A One-Pot Reaction Of Difluorocarbene And 1-Phenyl-2-Methylcyclobutene, Ruth Felicitas Menger

Senior Honors Projects, 2010-current

Previous studies show that 1,2-disubstituted cyclobutenes can be used in reaction with difluorocarbene to produce 1,3-difluorobenzenes. A pathway to the synthesis of these types of compounds is of interest due to their presence in fluoroquinolone antibacterials, resins, and insecticides. The synthesis is unique because the fluorine atoms from the difluorocarbene are not adjacent to each other when the ring expands to a benzene ring. This study focuses on the reaction of difluorocarbene with 1-phenyl-2-methylcyclobutene, which was synthesized in one-pot in 4 steps starting from 1-phenyl-1-propyne and zirconocene dichloride.


Zn(Ii), Cu(Ii), Sn(Ii), And Ni(Ii) And Other Metal Cations Do Not Prevent The Aggregation Of Hiapp, Charles Hoying May 2016

Zn(Ii), Cu(Ii), Sn(Ii), And Ni(Ii) And Other Metal Cations Do Not Prevent The Aggregation Of Hiapp, Charles Hoying

Honors Thesis

The Zn(II) metal ion has been shown to interact with Islet Amyloid Polypeptide (IAPP), a protein implicated in the progression of Type II Diabetes Mellitus, in such a way as to prevent the protein from aggregating into toxic fibers. We set out to find whether other metal ions might similarly prevent IAPP aggregation. Using Thioflavin T (ThT) spectroscopic assays, which measure fluorescence of ThT upon binding to aggregated IAPP, we observed a decrease in aggregation when incubated with Zn(II), Cu(II), Ni(II), and Sn(II). Atomic Force Microscopy (AFM), which can visualize fibril formation, revealed that the ...