8-Triazolylpurines: Towards Fluorescent Inhibitors of the MDM2/p53 Interaction

Small molecule nonpeptidic mimics of alpha-helices are widely recognised as protein-protein interaction (PPIs) inhibitors. Protein-protein interactions mediate virtually all important regulatory pathways in a cell, and the ability to control and modulate PPIs is therefore of great significance to basic biology, where controlled disruption of protein networks is key to understanding network connectivity and function. We have designed and synthesised two series of 2,6,9-substituted 8-triazolylpurines as alpha-helix mimetics. The first series was designed based on low energy conformations but did not display any biological activity in a biochemical fluorescence polarisation assay targeting MDM2/p53. Although solution NMR conformation studies demonstrated that such molecules could mimic the topography of an alpha-helix, docking studies indicated that the same compounds were not optimal as inhibitors for the MDM2/p53 interaction. A new series of 8-triazolylpurines was designed based on a combination of docking studies and analysis of recently published inhibitors. The best compound displayed low micromolar inhibitory activity towards MDM2/p53 in a biochemical fluorescence polarisation assay. In order to evaluate the applicability of these compounds as biologically active and intrinsically fluorescent probes, their absorption/emission properties were measured. The compounds display fluorescent properties with quantum yields up to 50%

Entreprenören i servicebranschen

Sammanfattning (for english: scroll down) Titel: Entreprenören i servicebranschen Seminariedatum: 2007-05-31, 2007-06-01 Kurs: SMT302 Kandidatuppsats 10p Författare: Jimmy Heijel, Lars Jacobsson, Fredrik Svensson Handledare: Elin Bommenel, Carl R. Hellberg Nyckelord: Entreprenören, serviceentreprenören, servicebranschen, service management, kontrollens lokalisering, innovationsförmåga, riskhantering, prestationsbehov och intuition. Syfte: Att med utgångspunkt i entreprenörers vedertagna egenskaper identifiera beskriva och analysera egenskaper som särskiljer entreprenörer i serviceverksamheter. Metod: Arbetet genom uppsatsen har följt ett kvalitativt angreppssätt där en deduktiv ansats använts. Två intervjuer har gjorts med entreprenörer verksamma i näringslivet. Vidare görs en förklaring av servicebranschens särart för att sedan ställas mot entreprenörskapsteorier. Intervjuerna används som illustrationer för att levandegöra det teoretiska underlaget. Teoriskt perspektiv: De teorier som använts i uppsatsen r fokuserade på egenskaper och är hämtade från följande entreprenörskapsforskare; Fredrik Delmar, Scott Shane, David Kirby, Bengt Johannisson och Ingeman Arbnor. Fokus har legat på de egenskaper som författarna ansett lämpligast för ändamålet; individualism, innovationsförmåga, riskhantering, intuition och prestationsbehov. Dessa egenskaper är även de som varit ständigt återkommande hos forskarna. Empiri: Vårt empiriska material består av två semistrukturerade personliga intervjuer, som genomförts dels med Bicky Chakraborty och dels med Svante Paulsson. Vidare har även sekundärdata om bilbyggaren Christian von Koenigsegg använts. Slutsatser: Teorin säger att entreprenören är väldigt individuell och tar gärna inte hänsyn till andra människors idéer, ibland näst intill en avvikare. För en entreprenör att vara individuell inom servicesektorn lämpar sig inte så väl, då denne ständigt är i kontakt med människor, och måste ta hänsyn till människors önskemål. Det är människor som bygger verksamheten, och således entreprenörens framgång. För entreprenörer i servicebranschen handlar innovationer mer om att kontinuerligt utveckla sitt befintliga tjänsteerbjudande än om att komma med revolutionerade uppfinningar. Abstract Title: Entrepreneurship in the service industry Seminar date: 2007-05-31, 2007-06-01 Course: Bachelor thesis in Service Management, 10 Swedish credits (15 ECTC) Authors: Jimmy Heijel, Lars Jacobsson, Fredrik Svensson Supervisor/Advisor: Elin Bommenel, Carl R. Hellberg Key Words: Entrepreneur, hosptalityentrepreneur, Service Management, service entrepreneur, the service sector, independence, locus of control, innovation, risk-management, need for achievement and intuition. Purpose: To identify, describe and analyse the characteristics that distinguishes the entrepreneur within the hospitality industry weighing in to account the generally accepted characteristics of the entrepreneur. Methodology: In this thesis we use a qualitative approach. Two interviews have been conducted with entrepreneurs within the business world. We then describe the distinctive character of the hospitality industry, with which we compare the theories about the entrepreneur. We use the interviews to illustrate our theoretical perspective. Theoretical perspectives: The theories mainly focus on specific characteristics, which are collected from the fallowing entrepreneurship researchers; Fredrik Delmar, Scott Shane, David Kirby, Bengt Johannisson och Ingeman Arbnor. With our purpose in mind, we focus on the following characteristics; independence, locus of control, innovation, risk-management, need of achievement and intuition. Empirical perspectives: The empirical material consists of two semi structured personal interviews, the first with Bicky Chakraborty and the second with Svante Paulsson. Furthermore we have studied secondary sources around Christian von Koenigsegg. Conclusion: The theory describes an entrepreneur as very autonomous people who does not often consider other people’s ideas. In the hospitality industry individualism is not a favourable characteristic, since an entrepreneur in this industry has to consider peoples desires and interact with people on a daily basis. People are the cornerstone of this industry, which ultimately determines the success of the entrepreneur. Innovation within the hospitality industry consists of an ongoing development of ones established services, rather than implementing revolutional inventions

Conformational analysis of 8a.

<p>a) NOE correlations (green arrows) in proximity of the triazole ring observed for <b>8a</b>. b) Sideview and c) topview of one of the conformations found in the NAMFIS-analysis. (All 6 NAMFIS conformations can be found in Fig. D and E in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0124423#pone.0124423.s001" target="_blank">S1 File</a>).</p

Absorption and fluorescent properties of 8-(triazolyl)purine derivatives in methanol solution.

<p>λ_{abs, max} and λ_{em, max} are the wavelengths of absorption and emission maxima, respectively, and <i>Φ</i>_<i>F</i> is the fluorescence quantum yield</p><p>Absorption and fluorescent properties of 8-(triazolyl)purine derivatives in methanol solution.</p

Synthesis of 14a-l.

<p>Reaction conditions: (<b>a</b>) NaN₃, R₃-X, Cu(I)I, NaAsc, DMEDA, DMF.</p

Photophysical characterization of 14b, 14f, 14g, 14h and 14i.

<p>Normalised absorption (solid lines) and emission (dashed lines) spectra of a selection of the investigated compounds (the full set of absorption and emission spectra can be found in the SI).</p

8-(triazolyl)purine inhibitors of MDM2/p53.

<p>8-(triazolyl)purine inhibitors of MDM2/p53.</p

NOE correlations observed for 7a.

<p>NOE correlations in proximity of the triazole ring observed for <b>7a</b>.</p

Overview of 8-(triazolyl)purine design.

<p>Schematic representation of a) an α-helix with residues present on one face of the helix (<i>i</i>, <i>i</i>+4 and <i>i</i>+7) denoted as black spheres, and b) the 8-triazolyl scaffold with R-groups denoted as black spheres. c) Superimposition of Ala-helix (black), with low energy conformations of 8-(1,4-triazolyl)-purine (turquoise) and 8-(1,5-triazolyl)-purine (yellow).</p

Synthesis of compound 1–6.

<p>Reaction conditions: (<b>a</b>) R₁OH, DIAD, Ph₃P, THF. (<b>b</b>) R₂OH, ADDP, <i>n</i>Bu₃P, THF. (<b>c</b>) DMF, MW, 180°C. (<b>d</b>) PyBr₃, CH₂Cl₂. (<b>e</b>) (i) Pd(II)Cl₂(PPh₃)₂, Cu(I)I, Amberlite IRA-67, TMS-acetylene, MW, 110°C. (ii) PS-F, THF.</p