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Synthesis Of Hydroxybenzylidene-Indolinones, Schiff Bases And N-Substituted Analogs And Their Effects On Bacterial Physiology., Catherine Eliana Cabrera, Neetu Dayal, Moloud Aflaki, Herman Sintim 2017 Universidad de Los Andes - Colombia

Synthesis Of Hydroxybenzylidene-Indolinones, Schiff Bases And N-Substituted Analogs And Their Effects On Bacterial Physiology., Catherine Eliana Cabrera, Neetu Dayal, Moloud Aflaki, Herman Sintim

The Summer Undergraduate Research Fellowship (SURF) Symposium

c-di-AMP is a global stress response regulator involved in some processes of biofilm formation and antibiotic resistance. It has become a candidate target for the development of new antibacterial treatments. Previous studies have shown that hydroxybenzylidene-indolinones can act as c-di-AMP synthase inhibitors. They also act as antibacterial and anti-biofilm inhibitors and re-sensitize resistant bacteria to methicillin and vancomycin. In this project, potent analogs of these compounds, including Schiff bases and N-substituted compounds, have been synthetized. The objective of this work is to explore the effect of these modifications on their biological activity. Base-catalyzed condensation and acid-catalyzed reactions were performed in ...


Synthesis Of Aza-Tetracyclic Indolines For The Treatment Of Methicillin-Resistant Staphylococcus Aureus, Kevin Xie 2017 University of Colorado, Boulder

Synthesis Of Aza-Tetracyclic Indolines For The Treatment Of Methicillin-Resistant Staphylococcus Aureus, Kevin Xie

Undergraduate Honors Theses

Antibiotic resistance is a major threat to public health. Currently new multi-drug resistant bacterial strains are appearing faster than new antibiotics can enter the clinic. Resistance modifying agents can potentially potentiate whole families of antibiotics and are one way to combat antibiotic resistance. Previously, our lab synthesized a library of polycyclic indolines which were found to potentiate β-lactams in MRSA in vitro but were poor candidates for in vivo testing due to their physical properties. To improve their physical properties, we synthesized a small library of aza-tetracyclic indolines. The nitrogen was functionalized with various functional groups to determine which modifications ...


Pioneering A Novel Class Of Tetrahydroimidazopyridines With Anti-Proliferative Property Study Against Prostate Cancer, Napoleon D'Cunha 2016 Clark Atlanta University

Pioneering A Novel Class Of Tetrahydroimidazopyridines With Anti-Proliferative Property Study Against Prostate Cancer, Napoleon D'Cunha

Electronic Theses & Dissertations Collection for Atlanta University & Clark Atlanta University

The synthesis of tetrahydroimidazo[1,5-a]pyridine (rIMP) through the transfer hydrogenation of imidazo[1,5-a]pyridine (IMP) was successfully developed. The simple two-step procedure is the most viable and efficient method that results in a unique conjugated system with pyridine at the 1-position and functionalized phenyl group at the 3-position.

In the synthesis of imidazo[1,5-a]pyridine, the reaction between di-2-pyridil ketone, substituted benzaldehyde and ammonium acetate in acetic acid under N2 was highly successful, resulting in yields ranging from 35-95%. Highest yields were obtained for compounds that had electron withdrawing group on them.

The transfer hydrogenation ...


Piperlongumine (Piplartine) And Analogues: Antiproliferative Microtubule-Destabilising Agents, Mary J. Meegan, Seema M. Nathwani, Brendan Twamley, Daniela M. Zisterer, Niamh O'Boyle 2016 Trinity College Dublin, Ireland

Piperlongumine (Piplartine) And Analogues: Antiproliferative Microtubule-Destabilising Agents, Mary J. Meegan, Seema M. Nathwani, Brendan Twamley, Daniela M. Zisterer, Niamh O'Boyle

Articles

Piperlongumine (piplartine, 1) is a small molecule alkaloid that is receiving intense interest due to its antiproliferative and anticancer activities. We investigated the effects of 1 on tubulin and microtubules. Using both an isolated tubulin assay, and a combination of sedimentation and Western blotting, we demonstrated that 1 is a tubulin-destabilising agent. This result was confirmed by immunofluorescence and confocal microscopy, which showed that microtubules in MCF-7 breast cancer cells were depolymerised when treated with 1. We synthesised a number of analogues of 1 to explore structure-activity relationships. Compound 13 had the best cytotoxic profile of this series, showing potent ...


Synthesis And Biochemical Evaluation Of 3-Phenoxy-1,4-Diarylazetidin-2-Ones As Tubulin-Targeting Antitumor Agents, Thomas F. Greene, Shu Wang, Lisa M. Greene, Seema M. Nathwani, Jade K. Pollock, Azizah M. Malebari, Thomas McCabe, Brendan Twamley, Niamh O'Boyle, Daniela M. Zisterer, Mary J. Meegan 2016 Trinity College Dublin

Synthesis And Biochemical Evaluation Of 3-Phenoxy-1,4-Diarylazetidin-2-Ones As Tubulin-Targeting Antitumor Agents, Thomas F. Greene, Shu Wang, Lisa M. Greene, Seema M. Nathwani, Jade K. Pollock, Azizah M. Malebari, Thomas Mccabe, Brendan Twamley, Niamh O'Boyle, Daniela M. Zisterer, Mary J. Meegan

Articles

Structure-activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated leading to the discovery of a number of potent antiproliferative compounds, including trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (78b) and trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (90b). X-ray crystallography studies indicate the potential importance of the torsional angle between the 1-phenyl ‘A’ ring and 4-phenyl ‘B’ ring for potent antiproliferative activity, and that a trans configuration between the 3-phenoxy and 4-phenyl rings is generally optimal. These compounds displayed IC50 values of 38 nM and 19 nM respectively in MCF-7 breast cancer cells, inhibited the polymerization ...


Synthesis Of Medicinally Relevant Thiazolyl Aryl Ketones Under Mild Conditions, Danielle M. Gardner 2015 dmgardne

Synthesis Of Medicinally Relevant Thiazolyl Aryl Ketones Under Mild Conditions, Danielle M. Gardner

Health, Human Performance and Recreation Undergraduate Honors Theses

Purpose: The growing amount of clinical resistance observed in current antifungal drugs and in anti-HIV pharmaceuticals is a concern in the medical community. The purpose of this study is to develop a mild synthetic process for biomedically relevant thiazolyl aryl ketones that can be used to develop antifungal and anti-HIV drugs. We hypothesized that the proposed synthetic technique would be more efficient, produce fewer unwanted byproducts, and be more tolerant of functional groups than existing methods.

Methods: Prior to each of the ketone reactions, the necessary salt was synthesized by mixing thiazole and 9-bromofluorene neat in a reaction tube heated ...


Design And Synthesis Of Novel Nucleoside Analogues: Oxidative And Reductive Approaches Toward Synthesis Of 2'-Fluoro Pyrimidine Nucleosides, Ramanjaneyulu Rayala 2015 Florida International University

Design And Synthesis Of Novel Nucleoside Analogues: Oxidative And Reductive Approaches Toward Synthesis Of 2'-Fluoro Pyrimidine Nucleosides, Ramanjaneyulu Rayala

FIU Electronic Theses and Dissertations

Fluorinated nucleosides, especially the analogues with fluorine atom(s) in the ribose ring, have been known to exert potent biological activities. The first part of this dissertation was aimed at developing oxidative desulfurization-fluorination and reductive desulfonylation-fluorination methodologies toward the synthesis of 2'-mono and/or 2',2'-difluoro pyrimidine nucleosides from the corresponding 2'-arylthiopyrimidine precursors. Novel oxidative desulfurization-difluorination methodology was developed for the synthesis of α,α-difluorinted esters from the corresponding α-arylthio esters, wherein the arylthio group is present on a secondary internal carbon. For the reductive desulfonylation studies, cyclic voltammetry was utilized to measure the reduction potentials at ...


Synthesis And Characterization Of Imidazolium Salt Derivatives For Anti-Tumor Activity, Ryan W. Pearce 2015 University of Akron Main Campus

Synthesis And Characterization Of Imidazolium Salt Derivatives For Anti-Tumor Activity, Ryan W. Pearce

Honors Research Projects

Several aldehydes (butanal, pentanal, hexanal, 4-hydroxybenzaldehyde) were reacted with 1,3-bis(naphthalen-2-ylmethyl)-imidazolium bromide (1) to produce novel C2 substituted imidazolium salts for the potential use against non-small cell lung cancer in humans. Compounds 2-(1-hydroxypentyl)-1,3-bis(naphthalen-2-ylmethyl)-imidazolium bromide (3) and 2-(1-hydroxyhexyl)-1,3-bis(naphthalen-2-ylmethyl)-imidazolium bromide (5) were successfully synthesized with structures supported by NMR and mass spectrometry. Characterization by 1H NMR showed evidence of 1 in both compounds. The tumor cell growth inhibition of 3 against non-small cell lung cancer lines NCI-A549, NCI-H460, HCC827, and NCI-H1975 was tested and found to be comparable ...


Synthesis And Characterization Of Platinum (Ii) Complexes With Thiophene-Based Ligands, Julienne Aldeano Sarabia 2015 Bard College

Synthesis And Characterization Of Platinum (Ii) Complexes With Thiophene-Based Ligands, Julienne Aldeano Sarabia

Senior Projects Spring 2015

Multi-dentate thiophene-derived imine ligands, with a cyclohexyl backbone containing a variety of stereocenters, were synthesized and then subsequently reacted with the binuclear platinum compound, [Pt2Me4(µ-SMe2)2], to afford cyclometalated platinum(II) species with C^N^N pincer-type ligands. The complexes were characterized by NMR, IR, UV/vis, and emission spectroscopy. The complexes’ reactions with methyl iodide were explored to determine the stereospecificity of the oxidative addition reaction to form platinum(IV) species.


Target-Directed Biosynthetic Evolution: Redirecting Plant Evolution To Genomically Optimize A Plant’S Pharmacological Profile, Dustin Paul Brown 2015 University of Kentucky

Target-Directed Biosynthetic Evolution: Redirecting Plant Evolution To Genomically Optimize A Plant’S Pharmacological Profile, Dustin Paul Brown

Theses and Dissertations--Neuroscience

The dissertation describes a novel method for plant drug discovery based on mutation and selection of plant cells. Despite the industry focus on chemical synthesis, plants remain a source of potent and complex bioactive metabolites. Many of these have evolved as defensive compounds targeted on key proteins in the CNS of herbivorous insects, for example the insect dopamine transporter (DAT). Because of homology with the human DAT protein some of these metabolites have high abuse potential, but others may be valuable in treating drug dependence. This dissertation redirects the evolution of a native Lobelia species toward metabolites with greater activity ...


Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen 2015 University of Kentucky

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most ...


Design, Synthesis And Biological Evaluation Of Novel Compounds With Cns-Activity Targeting Cannabinoid And Biogenic Amine Receptors, Alexander M. Sherwood 2014 University of New Orleans

Design, Synthesis And Biological Evaluation Of Novel Compounds With Cns-Activity Targeting Cannabinoid And Biogenic Amine Receptors, Alexander M. Sherwood

University of New Orleans Theses and Dissertations

This work seeks to contribute to the discipline of neuropharmacology by way of structure activity relationship from the standpoint of an organic chemist. More specifically, we sought to develop robust synthetic methodology able to efficiently produce an array of compounds for the purpose of systematic evaluation of their interaction with specific sights within the central nervous system (CNS) in order to better understand the mind and to develop drugs that may have beneficial effects on neurological function.

The focus of these studies has been toward the development of novel molecules, using a structure-activity relationship approach, that exhibit binding affinity at ...


Design And Synthesis Of 4-N-Alkanoyl And 4-N-Alkyl Gemcitabine Analogues Suitable For Positron Emission Tomography, Jesse E. Pulido 2014 Florida International University

Design And Synthesis Of 4-N-Alkanoyl And 4-N-Alkyl Gemcitabine Analogues Suitable For Positron Emission Tomography, Jesse E. Pulido

FIU Electronic Theses and Dissertations

Gemcitabine is a highly potent chemotherapeutic nucleoside agent used in the treatment of several cancers and solid tumors. However, it is therapeutically limitated because of toxicity to normal cells and its rapid intracellular deamination by cytidine deaminase into the inactive uracil derivative. Modification at the 4-(N) position of gemcitabine's exocyclic amine to an -amide functionality is a well reported prodrug strategy which has been that confers a resistance to intracellular deamination while also altering pharmacokinetics of the parent drug. Coupling of gemcitabine to carboxylic acids with varying terminal moieties afforded the 4-N-alkanoylgemcitabines whereas reaction of 4- ...


Ligand-Receptor Interactions For Supramolecular Disassembly With Applications In Screening And Drug Delivery, Diego Amado Torres 2014 University of Massachusetts - Amherst

Ligand-Receptor Interactions For Supramolecular Disassembly With Applications In Screening And Drug Delivery, Diego Amado Torres

Doctoral Dissertations

Proteins have the capacity to bind specific sets of compounds known as ligands, these are small molecules with a recurrent theme in their molecular design that is a characteristic exploited here to (i) identify particular affinities of small molecules for proteins with the aim of using them as ligands, inhibitors, or targeting moieties in more complex systems by means of a methodology that screens small molecules based on protein affinity; (ii) decorate a self-assembling supramolecular system at different positions, making it responsive to a complementary protein with the aim of exploring differences in disassembly and sensitivity of the release of ...


Β-Lactam Estrogen Receptor Antagonists And A Dual-Targeting Estrogen Receptor/Tubulin Ligand, Niamh O'Boyle, Jade K. Pollock, Miriam Carr, Andrew JS Knox, Seema M. Nathwani, Shu Wang, Laura Caboni, Daniela M. Zisterer, Mary Meegan 2014 Dublin Institute of Technology

Β-Lactam Estrogen Receptor Antagonists And A Dual-Targeting Estrogen Receptor/Tubulin Ligand, Niamh O'Boyle, Jade K. Pollock, Miriam Carr, Andrew Js Knox, Seema M. Nathwani, Shu Wang, Laura Caboni, Daniela M. Zisterer, Mary Meegan

Articles

Twelve novel β-lactams were synthesised and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ERα and ERβ, were determined. β-Lactams 23 and 26 had the strongest binding affinities for ERα (IC50 values: 40 and 8 nM respectively) and ERβ (IC50 values: 19 and 15 nM). β-Lactam 26 was the most potent in antiproliferative assays using MCF-7 breast cancer cells, and further biochemical analysis showed that it caused accumulation of cells in G2/M phase (mitotic blockade) and depolymerisation of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation ...


Integrating Phage Therapy Into Western Medicine, Jacob B. Jaminet 2014 Virginia Commonwealth University

Integrating Phage Therapy Into Western Medicine, Jacob B. Jaminet

Undergraduate Research Posters

The World Health Organization has described the rise of antibiotic use as a “global heath security emergency” (who.int). With the growing concern about antibiotic resistant bacteria, there has been an increased interest in bacteriophages. Bacteriophages are high-specific viruses that only infect bacteria. The use of bacteriophages medicinally to treat bacteria is called phage therapy. Research in phage therapy gained momentum until the introduction of antibiotics. While the USA and other Western countries accepted antibiotics, the Soviet Union and their satellite nations still continued to research phages. Since the funding for research was supplied by the Soviet military, the results ...


A New Methodology For The Synthesis Of 2-Alkyl-5,6-Bis(Alkylthio)Benzo[D]Thiazole-4,7-Dione, Jeena Foronda 2014 Southern Adventist Univeristy

A New Methodology For The Synthesis Of 2-Alkyl-5,6-Bis(Alkylthio)Benzo[D]Thiazole-4,7-Dione, Jeena Foronda

Senior Research Projects

Cancer is a rapidly growing fatal disease and with the various thiazole compounds being scientifically generated, possible treatment options can be implemented. Proper synthesis of 2,3-dimethoxy-1,4-benzoquinone allows for a variety of compounds to be made with further treatment of alkylthio reagents. Both thioacetamide and thiobenzamide are used to react with 2,3-dimethoxy-1,4-benzoquinone in order to build a library of thiazoles. Final compounds can be tested for the ability to inhibit recombinant enzyme activity and the capability to kill tumor cells. A basic oxidation procedure along with nucleophilic attack was used to create target products.


Design And Synthesis Of Novel Sultams As Non-Nucleoside Inhibitors Of Hiv Reverse Transcriptase, Brian Chadwick LeCroix 2013 University of Tennessee, Knoxville

Design And Synthesis Of Novel Sultams As Non-Nucleoside Inhibitors Of Hiv Reverse Transcriptase, Brian Chadwick Lecroix

Doctoral Dissertations

The compound 2-methyl-3-phenyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (NSC 108406) was identified as an HIV-1 reverse transcriptase inhibitor by the National Cancer Institute. Using this lead, the Baker group has developed a series of analogues with various groups at the 3-position that show a spectrum of biological activities. In the end, the substituents used could not compare to the biological activity of the inhibitor efavirenz (Sustiva® [trademark]), and so it was decided to synthesize sultams with alkylethynyl substituents at the 3-position of the sultams in an attempt to mimic the activity of efavirenz.

Previous research analyzed the proposed novel sultams in ...


Impact Of Pre-Injury Warfarin Use Among Medicare Beneficiaries With Head Trauma, Courtney E. Collins, Elan R. Witkowski, Julie M. Flahive, Timothy A. Emhoff, Frederick A. Anderson Jr., Heena P. Santry 2013 University of Massachusetts Medical School

Impact Of Pre-Injury Warfarin Use Among Medicare Beneficiaries With Head Trauma, Courtney E. Collins, Elan R. Witkowski, Julie M. Flahive, Timothy A. Emhoff, Frederick A. Anderson Jr., Heena P. Santry

UMass Center for Clinical and Translational Science Research Retreat

Introduction: The effect of warfarin on outcomes of head injured patients remains controversial. Yet more than 2 million Americans, many of them elderly, are started on warfarin annually. Meanwhile, with the aging US population, elderly Americans are becoming an increasingly large proportion of head injured patients. We studied a national cohort of Medicare beneficiaries with head injuries to determine the effects of pre-injury warfarin on outcomes.

Methods: A retrospective review of a 5% random sample of Medicare claims data (2009-2010) was performed for enrollees with at least 1 year of Medicare eligibility. Head injury cases were identified using ICD-9 codes ...


Design, Synthesis And Development Of Transporter Targeting Agents For Image-Guided Therapy And Drug Delivery, Ning Tsao 2013 The University of Texas Graduate School of Biomedical Sciences at Houston

Design, Synthesis And Development Of Transporter Targeting Agents For Image-Guided Therapy And Drug Delivery, Ning Tsao

UT GSBS Dissertations and Theses (Open Access)

The purpose of this study was to design, synthesize and develop novel transporter targeting agents for image-guided therapy and drug delivery. Two novel agents, N4-guanine (N4amG) and glycopeptide (GP) were synthesized for tumor cell proliferation assessment and cancer theranostic platform, respectively. N4amG and GP were synthesized and radiolabeled with 99mTc and 68Ga. The chemical and radiochemical purities as well as radiochemical stabilities of radiolabeled N4amG and GP were tested. In vitro stability assessment showed both 99mTc-N4amG and 99mTc-GP were stable up to 6 hours, whereas 68Ga-GP was stable up to 2 hours. Cell culture studies ...


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