? CHEMICAL SYNTHESIS SHARED RESOURCE The Chemical Synthesis Shared Resource, in development for several years, is proposed in this application as an established AECC shared resource. The objective of this facility is to design and synthesize novel small organic molecules in support of AECC research. The facility is staffed by a group of experienced chemists that have established a track-record of providing drugs and reagents in support of AECC research projects. These include novel first-in-class agents that are in the process of translation into novel cancer therapeutics. The facility provides: (i) Consultation in design/synthesis/compound verification. Investigators provide an overview of the target and the biological pathway following which staff research possible chemotypes previously reported by in silico or experimental screening. (ii) A synthetic route to the desired compound is designed along with alternative strategies. (iii) A small-scale (20-50 mg) ?proof-of-principle? synthesis is completed and validated chemically following which the biological or pharmacological effect is confirmed. (iv) The synthesis is then scaled-up and the large scale batch synthesis validated by analytical HPLC, UV-visible spectrophotometry, mass spectrometry and multinuclear (1H, 13C) NMR. Chemical stability (pH and temperature) and aqueous solubility or solubility in mixed solvents can be documented. The facility can assist investigators with more detailed SAR, when necessary, to further improve the properties of molecules once a synthesized compound has been shown to have the desired action. The additional chemical ?space? around the original compound can be probed and, since synthetic precursors to the original compound are often retained, substituent variations can made relatively quickly. In this way, an originally identified compound with activity can be ?built out? with resulting increases in potency. There are a number of examples in which this has been achieved. In other cases, a known chemotype has been modified to enhance stability and cell permeability. The facility has also purchased or synthesized a large number of alkynes and aliphatic and aromatic azides. When paired these ?click? reactants will react, catalyzed by Cu(I) by a cycloaddition to generate a triazole ring with excellent chemical and biological stability. The Facility has generated three novel chelators that enhance the reactivity of the copper catalyst and also reduce the inherent toxicity of copper in biological systems, allowing for these reactions to be performed on cells and tissues. These chelators are available to AECC investigators and frequently provided to the broader scientific community at modest cost. The facility provides AECC investigators with publication-quality details of the synthesis and analytical validation.
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