Design and synthesis of high affinity compounds for the Hsp60 expressioncontrol in carcinogenic processes

Risultato della ricerca: Other

Abstract

First observed in cells exposed to high temperatures, Heat shock proteins (Hsps) arenowadays considered the most important cell “chaperone” complexes over-expressedin response to a number of cell stress stimuli.1 The chaperone activity is the mainfunction of the eukaryotic Heat shock protein 60 kDa (Hsp60), involved in the captureand refold of unfolded or misfolded proteins. Additional roles in signal transduction,2senescence activation3 and apoptosis4 have been ascribed to cytosolic Hsp60. Duringthe carcinogenIc process, in vivo studies demonstrated increased levels of humanHsp60 in several organs, such as uterine exocervix,5 large bowel,6 and prostate.6In this context, our study aims to elucidate the structural details of the interactionbetween Hsp60 and novel designed antagonists able to specifically block thischaperonine. A preliminary virtual screening of 24 million molecules, available in theZinc database, was carried out on the ATP-binding site of a bacterial Hsp60 monomer,the coordinates of which were taken from Protein Data Bank (ID: 1WE3), figure 1.Compounds with high affinity were further refined by other in silico protocols previouslyand successfully applied by us in the study of several biological targets.7The analysis of virtual screening results highlights the N-{5-[1H-imidazol-4-yl-methyl)-amino]-benzofuran-3-yl}-benzamides of type 1 as interesting series for the inhibition ofHsp60 ATP-binding site. Selected compounds were prepared in excellent yields,following appropriate synthetic pathways. All compounds are currently tested in orderto proof they potential anticancer activity as modulator of Hsp60 function in tumor cells.
Lingua originaleEnglish
Numero di pagine1
Stato di pubblicazionePublished - 2013

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