Dimeric and trimeric triazole based molecules as a new class of Hsp90 molecular chaperone inhibitors

• Design and synthesis of dimeric and trimeric triazole based molecules as Hsp90 inhibitors.
• Microwave-assisted one pot copper(I)-catalysed click chemistry reaction.
• Potential anti-tumour agents.

In the last decade Hsp90 inhibitors have emerged as attractive candidates for the development of new potent anticancer therapeutics. In order to identify novel agents able to block the chaperone activity, following a structure-based approach, we used in silico screening to direct the synthesis of potential inhibitors bearing the triazole scaffold, a widespread motif in drug-like molecules. Docking results, performed on a larger collection of dimeric and trimeric triazole derivatives, suggested the synthesis of some molecules showing different calculated binding energies and modes. Surface Plasmon Resonance Binding assay, performed on the synthesized compounds, allow to identify a series of molecules able to potently interact with the target enzyme and to disclose an interesting hit: compound 2b showed to interact with the ATP binding site in the N-terminus domain of Hsp90 and to efficiently inhibit the chaperone activity.

Figure optionsDownload as PowerPoint slide