CXCR4 is a chemokine receptor that has been linked to several disease related pathways including: HIV-1 proliferation, autoimmune disorders, inflammatory disease and cancer metastasis. The interaction of the C-X-C chemokine receptor type 4 (CXCR4) with C-X-C chemokine ligand 12 (CXCL12) plays a key role in triggering these disease related pathways. Various antagonists for these receptors have been synthesized and tested, but many are not useful clinically either because of toxicity or poor pharmacokinetics. Some of the most extensive CXCR4 antagonist libraries stem from a class of compounds, p-xylyl-enediamines, which all feature a benzene ring as the core of the compound. This work focuses on the design and synthesis of a new class of compounds that show potential as CXCR4 antagonists by using heterocyclic aromatic rings (2,6-pyridine, 2,5-furan, 2,5-pyrazine and 3,4-thiophene) as the core of the scaffold. After synthesis, these analogues were probed through a variety of assays and techniques by our collaborators in the Shim lab at Emory University including: preliminary binding assays, Matrigel invasion assays, carrageenan mouse paw edema tests, and in silico analysis. In silico analysis also probed 2,5-thiophene-based analogues previously synthesized. This work has produced the beginnings of a new library of CXCR4 antagonists and has identified fifteen hit compounds that are promising leads for further testing and modification.

Structure and functional study of glycans are highly challenging due to the difficulties in analyzing glycans and limited availability of samples for study. These limitations could be resolved by attaching DNA barcode to the glycan, which virtually represent glycan in further application, by increasing the sensitivity of detection by polymerase chain reaction (PCR), requiring minimal samples for analysis. Assuming bigger arena of DNA Encoded Glycan Libraries (DEGL) in future, we propose here a method for uniquely coding all glycans using computer program that can convert the structural information of glycans to DNA barcode. A unique and universal coding for glycans will benefit both synthesis and analysis of DEGLs. As a proof of principle study, a small DNA Encoded Glycan Library (DEGL) of blood and globo series glycan antigen and its application was demonstrated in detecting blood group and breast cancer from plasma.

Although the regulation of proteins functions by allosteric interactions has been identified in many subcellular processes, long-range conformational changes in proteins are also known to be induced by molecular switches. A molecular switch based on the cis-trans isomerization of a peptidyl-prolyl bond is capable of inducing a conformational change directly to the protein backbone, which is then propagated throughout the system. However, these switches are elusive and difficult to identify due to their intrinsic dynamics in the biomolecules where they are found. Herein, we explore the conformational dynamics and free energy landscape of the SH2 domain of Interleukin-2-inducible T-Cell Kinase (ITK) to fully understand the conformational coupling between the distal cis-trans molecular switch, and its phosphotyrosine binding pocket. Using multiple microsecond-long all-atom molecular dynamics simulations in explicit water for over a total of 60 μs, we show that the cis-trans isomerization of the Asn286-Pro287 peptidyl-prolyl bond is directly correlated to the dynamics of the phosphotyrosine binding pocket, in agreement with previous NMR studies. While the cis state is localized to a single free energy basin and less dynamic, the trans state samples two distinct conformations of its binding pocket – one that recognizes the phosphotyrosine motif, and another that is similar the cis state. These results provide an atomic-level description of a less-well understood allosteric regulation by a peptidyl-prolyl cis-trans molecular switch that could aid in the understanding of normal and aberrant sub-cellular process and the identification of these elusive molecular switches in other proteins.

Carbon monoxide (CO) is an endogenous signaling molecule and has therapeutic values. However, the application of CO in the development of therapeutic options is hampered by the lack of pharmaceutically acceptable delivery methods. Inhalation of CO is not an ideal option for wide-spread clinical applications. Existing CO releasing molecules (CORMs) are mostly metal complexes, which have toxicity concerns to overcome. Some metal free CORMs have been developed. However, they all require light as a trigger to release CO, which limits their applications in vivo. Herein, we describe a metal-free CO prodrug approach using an intramolecular inverse electron-demanded Diels-Alder reaction. Such prodrugs can release CO spontaneously under physiological conditions with tunable release rates with the concomitant formation of a fluorescent reporter after CO releases. This intramolecular “click and release” strategy represents a milestone in the development of CO based therapeutics.

Hypoxia Inducible Factors (HIFs) are very important transcription factors that can respond to low oxygen concentrations in the cellular environment. Inhibition of HIF’s transcriptional activity represents a promising approach to new anticancer compounds. Herein, we describe the design and synthesis of a series of HIF-1 inhibitors. Evaluation of these inhibitors using a cell-based luciferase assay led to the discovery compounds with sub-micromolar potency.

Thesis (M.S.)--Utah State University, 2010. / Title from title screen (viewed June 7, 2010). Department: Chemistry and Biochemistry. Includes bibliographical references. Archival copy available in print.

Consequently, specific parts or the whole plant can be used for various treatments. The aim of this study was to extract, isolate and characterize the biologically active volatile and non-volatile compounds from Tagetes minuta and Rauvolfia caffra respectively. Tagetes minuta plant was considered for extraction of essential oils using hydrodistillation method. Cis-β-ocimene (38.03%), caryophyllene oxide (18.04%), alloocimene (25.35 %), isopropyl tetradecanoate (17.02 %), cis-ocimene (38.14%) and trans-β-ocimene (37.03%) were the major components of essential oil analyzed from fresh stem, dried stem, fresh leaf, dried leaf, fresh flower and dried flower respectively. The volatile compounds were identified by Gas Chromatography-Mass Spectrometry (GC-MS) and Gas Chromatography (GC). Essential oil of dried stem leaf and flower parts of T. minuta exhibit antioxidant activity as demonstrated by the DPPH and FRAP bioassays. Crude extracts were extracted from R. caffra stem bark using sequence of solvents namely n-hexane, dichloromethane, ethyl acetate, methanol and ethanol. A white powder, a β-sitosterol (non-volatile compound) was isolated by column chromatography from ethyl acetate fractions of R. caffra stem bark and identified on various spectroscopic techniques such as FTIR and (1D and 2D) NMR. Melting point was also determined to be a sharp 129-130 ºC. DCM, EA, MetOH and EtOH fractions as well as β-Sitosterol (compound SM/01), showed antioxidant activity when tested on DPPH, FRAP, total phenolic and flavonoid bioassays. This antioxidant activity might be due to the presence of hydroxyl groups in the compound and crude fractions. On the other hand, T. minuta’s essential oil showed high antioxidant activity when evaluated on the DPPH and FRAP bioassays, which can be attributed to the presence of oxygenated monoterpenes and sesquiterpenes known to act as free radical scavenging and reducing agents. The use of R. caffra stem bark extracts against hypertension and other diseases by traditional healers could be attributed to the presence of phytochemicals (polyphenols and flavonoids) with known health benefits. Thus, it is recommended that the plant should be exploited further using modern techniques involving separation and purification of compounds that can be used for drug formulation. This study supports the use of T. minuta and R. caffra as the potential natural antioxidant source to manage various diseases including hypertension.

Särtryck ur Svensk kemisk tidskrift 70:2(1958). - Härtill 6 uppsatser. Uppsatserna saknas.

Dagens omgivning är full av osäkerhet, marknadssvängningar, geografiska förändringar i arbetskraft och den högteknologiska utvecklingen vilket utsätter nutidens organisationer för ständiga förändringar (Savery och Luks 2000). Detta innebär att företag på 2000-talet, genom att systematiskt förbättra verksamheten, oavbrutet måste hålla ner kvalitetsbristkostnader, minimera förluster och öka produktiviteten för att kunna bevara sin position på marknaden (Baghel, Bhuiyan och Wilson, 2005). I denna studie var syftet att skapa ett nytt arbetssätt och struktur för ett framgångsrikt förbättringsarbete på Akzo Nobel Surface Chemistry Stenungsund. Studien bestod dels av ett teoriavsnitt med en litteraturstudie utifrån nutida forskning och även en kvalitativ undersökning genom djupgående intervjuer med 19 medarbetare från olika ansvarsnivåer och via en enkätundersökning som gick ut till resterande medarbetare. Akzo Nobel Surface Chemistry är en del av Akzo Nobel koncernen som är en av världens ledande färgtillverkare. Koncernen har över 55 000 anställda i över 80 länder där ungefär 3600 anställda arbetar på ett 20-tal platser runt om i Sverige. Företaget bedriver förbättringsarbete genom daglig uppföljning ute i fabrikerna och på respektive avdelning. Dessutom samlas alla förbättringsförslag upp i en databas och en utvald styrgrupp analyserar och prioriterar dessa. Problemet är dock att det saknas struktur och systematik för hur förbättringsförslag och actionpunkter ska gå från idéer, till att genomföras och följas upp för att kunna driva igenom förbättringar. I detta projekt togs det fram en modell för hur företaget kan skapa förutsättningar för ettframgångsrikt förbättringsarbete genom att skapa en kreativ miljö för medarbetarna att arbeta i. Vidare poängterades vikten av att ledningen fokuserar på att generera kvalitet hos medarbetarna genom att fokusera på kärnvärden och emotionell kompetens. Därefter presenterades framtagen struktur med arbetssätt för att minimera ledtiden från förslag till genomförande och återkoppla detta genom givna forum och system. Vidare föreslogs att ledningen ska förbereda organisationen på att ett nytt förbättringsarbete är på väg och förklara varför detta är väsentligt för företagets framtida överlevnad. Detta kan skapa förutsättningar för att implementera förbättringsarbetet på ett framgångsrikt sätt med en positiv effekt på medarbetarna.

Lic.-avh. (sammanfattning) Stockholm : Tekn. högsk., 2005. / Härtill 3 uppsatser.