Chemical modulators of heat shock protein 70 (Hsp70) by sequential, microwave-accelerated reactions on solid phase.
Molecular chaperones, such as Hsp70 and Hsp90, are responsible for a variety of protective, anti-apoptotic functions. While inhibitors of Hsp90, such as geldanamycin and its derivative 17-AAG, are well known and important anti-cancer leads, Hsp70 has received less attention. Interesting lead candidates for Hsp70 share a dihydropyrimidine core; however, the preferred display of pendant functionality is still not clear. Here, we take advantage of the versatility of peptides to explore the requirements for activity. An exploratory compound collection was assembled by performing a Biginelli cyclocondensation at the terminus of a resin-bound beta-peptide. Liberation from solid support yielded peptide-modified dihydropyrimidines and, within this series, we uncovered compounds that alter the ATPase activity of Hsp70 and its bacterial ortholog, DnaK. Moreover, we identified important contributions made by aromatic, hydrophobic groups. These chemical probes could be used to study the roles of this molecular chaperone in disease.
University of Michigan, Department of Pathology and the Life Sciences Institute, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA.
Susanne
S
Wisén
John
J
Androsavich
Christopher G
CG
Evans
Lyra
L
Chang
Jason E
JE
Gestwicki
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D005449:Fluorenes / Q000737:chemistry; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008872:Microwaves; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000596:Amino Acids; D005449:Fluorenes; D018840:HSP70 Heat-Shock Proteins; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D009842:Oligopeptides; D011743:Pyrimidines