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Target-guided synthesis, Fragment-based synthesis, NMR, Triazole, Azide


Protein-protein interactions are central to most biological processes. Although in the field of drug discovery there is a great interest in targeting protein-protein interactions, the discovery and development of small-molecules, which effect these interactions has been challenging. The purpose of this project is to determine if in situ click chemistry is a practical approach towards testing whether Bcl-XL is capable of assembling it's own inhibitory compounds. Abbott laboratories developed compound ABT-737, which binds with high affinity (Ki < 1 nM) to the binding sites of Bcl-XL.³⁶ Based on ABT-737, two acetylene anchor molecules AM3 and AM4 have been synthesized. These anchor molecules are distinguished by the reactivity of the their carbon-carbon triple bond. Compound AM3 contains an electron withdrawing carbonyl in the alpha-position to the acetylene resulting in an activating effect towards the [1,3]-dipolar cycloaddition compared to compound AM4.

To determine the reactivity of the activated system, ¹ H-NMR kinetic studies were performed to compare the relative rates of these two systems by reacting model alkynes 1,2,3, and 4 with azide AZ7. It was shown that the activated systems, 1 and 3, produce triazoles in an accelerated rate compared to the unactivated systems 2 and 3. To test for the self-assembly of inhibitory triazoles, the acetylenes AM3 and AM4 were incubated with Bcl-XL and 14 azide building blocks (AZ1-AZ12) for 12 hours at 37 degrees C. Subjecting these mixtures to LC/MS-SIM led to the discovery of two hit compounds, 35 and 36, of which 35 has been chemically synthesized confirming the hit. Future work includes the synthesis of all hit compounds. Since hit triazoles can be syn or anti, both need to be synthesized for each hit to investigate which regioisomer Bcl-XL generates. Tests to confirm if hit compounds are actually modulating Bcl-XL activity will be done using conventional bio-assays.

This will validate that Bcl-XL is capable of assembling its own inhibitor via the in situ click chemistry approach to drug discovery.