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Chem 1AA3 - Chemical Biology.docx

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McMaster University
Jeff Landry

Chemical Biology Queen Phermone Blocks Aversive Learning in Young Worker Bees - Vergoz et al. Science (2007) 317: 384-386 - Queen mandibular pheromone (QMP) o Causes young workers to feed and groom her o Suppresses new queens, controls colony behaviour o HVA doesn’t allow them to respond negatively, don’t learn to sting when exposed o HVA has a selective effect; supresses negative memories in young bees o HVA doesn’t have any impact on aversion learning after 15 days o HVA is decreasing the concentration of dopamine in the bee brain The Biology of Brainwashing Bees - QMP contains homovanillyl alcohol (HVA) o HVA supresses bad memories, but not good ones - Biological role: o Mitigates unpleasant side effect of QMP - HVA interrupts negative memories / side effects - Significance: o HVA lowers [dopamine] o Dopamine is associated with learning - Therapeutic potential o High [dopamine] isn some psychoses & schitzophrenia o HVA-like molecules could be treatments BUT need high specificity  ADD and Parkinsons disease are linked to low [dopamine]  Global suppression of [dopamine] or suppression in the wrong part of the brain, could have undesired side effects Key Concepts - Queen bees control worker bees’ memories using HVA - Help understanding human learning - Develop new therapeutics - How do we go from a biological phenomenon to the development of a new therapeutic agent? - 1 new drug requires ~5000 failed compounds, therefore improving synthesis and accelerating assays facilitates drug discovery High-Throughput Screening - High-throughout screening (HTS) o Fast way to assay for a complex biological response - 2 components: 1) A fast assay 2) Massively parallel assays - Instead of doing experiments on live bees, use dopamine-producing bee neural cells growing in cell culture - A fast, colour-producing dopamine assay already exists o Bright green colour – dopamine still being produced, not desired effect?? - 96 well microtiter plates allow 96 simultaneous assays - Grow bee neural cells in wells of plates, test for dopamine production - Mix cells and test compound  no dopamine production.. means: o Test compound (analogue to HVA) is inhibiting production of dopamine o Maybe the assay doesn’t work / is failing o If all the cells died no dopamine would be produced Microtiter Control Wells - some wells are used for standard and controls, others are for test compounds - 6 wells: neural cells (+): dopamine & HVA, none, just HVA Neural cells (-): none, both, just HVA - Neural cells alone: high [dopamine] (positive control cells should produce dopamine) - Neural cells + both: high [dopamine] - Neural cells + HVA: no dopamine - No neural cells + none: no dopamine (negative control – no cells, no dopamine) - No neural cells + both: high [dopamine] o HVA cannot function on them but added dopamine is still there - No neural cells + HVA: no dopamine - HVA acts on neural cells not just simply on dopamine itself - Screening must be able to test thousands of compounds / day, therefore it must be automated using robots and microtiter plates - Grow neural cell cultures in 96-well plates, measure [dopamine] in response to test compounds - When blue colour showed up  no dopamine produced, potentially successful Key Concepts - High throughput assays that replicate complex biological phenomena, replicate what happens in bee brain - Require many compounds (more on this later) - Use microtiter plates - Highly automated Iclicker 1: if all the bee neural cells died which result would be observed? D) Aromaticity - One of the most noteable features of HVA is that it is an aromatic compound, like benzene - Benzene is flat so all the branching molecules are coplanar - Aromatic systems are very stable, less reactive than alkenes - Benzene looks like “cyclohexatriene” but it does not behave like an alkene - Typical alkene + Br2  antiaddition .. Br added to both carbons of the double bond - Diene + Br2  addition of Br to both carbons of double bond - Benzene + Br2  no reaction - Arenes behave different from alkenes - Addition: add something across both ends of a double bond and saturate it Recognizing aromatic compounds: - Cyclic - Planar - All sp (or sp) in ring o All the atoms (C, N, O) in the aromatic ring system must have a p orbital available to form a pi system; so they can all overlap with each other and created delocalization o NOT sp3 - Conjugation o Often see a pattern of alternating single and double bonds in line drawings o Not always completely followed for heteroaromatics or ions - Huckel 4n+2 rule (slide 19) - Benzene is planar, cyclohexane is bent Huckel 4n+2 rule - Aromatic systems have (4n+2) pi-electrons in a ring, n = 0,1,2,3… - A pi-electron is an electron engaged in a pi-bond, there are 2 pi-electrons per pi-bond - Eg. Benzene has 6 pi-electrons, so n = 1 - The p-orbitals of the conjugated atoms are all aligned perpednciular to the ring plane, and the total # of electrons in these p-oribtals meets the Huckel rule - Other examples of aromatic compounds: benzene, toluene, phenol, 4-chlorobenzaldehyde (6 pi electros) not necessarily considering the total number of pi electrons in the molecule.. just the ring? - Naphthalene (10 pi electrons) (2 benzene rings joined / side by side.. the two joining C/P’s count as one? Iclicker 2: which one of the following compounds does not satisfy the rules for aromatic? C) - Doesn’t follow the Huckel # of electrons.. it has 8 pi electrons which doesn’t work
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