Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 6; pp. 3291 - 3301
• Main Authors: Wright, Christine M., Chovatiya, Raj J., Jameson, Nora E., Turner, David M., Zhu, Guangyu, Werner, Stefan, Huryn, Donna M., Pipas, James M., Day, Billy W., Wipf, Peter, Brodsky, Jeffrey L.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.03.2008; Elsevier Science
• Subjects: Adenosine Triphosphatases - metabolism; Antineoplastic agents; Apoptosis; ATP; ATPase; Biginelli; Biological and medical sciences; Breast Neoplasms - drug therapy; Cell Proliferation - drug effects; Chaperone; Dihydropyrimidinone; Female; General aspects; Hsp40; Hsp70; HSP70 Heat-Shock Proteins - antagonists & inhibitors; Humans; J domain; Medical sciences; Molecular Chaperones - drug effects; Peptoids - chemistry; Peptoids - pharmacology; Pharmacology. Drug treatments; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; SK-BR-3; SV40; T antigen; Tetrahydropyrimidinone; Ugi; Tetrahydropyrimidinone; Biginelli; Chaperone; ATPase; J domain; Hsp40; SK-BR-3; Hsp70; Ugi; SV40; ATP; T antigen; Dihydropyrimidinone; Apoptosis; Antineoplastic agent; Nitrogen heterocycle; Ugi reaction; Molecular hybrid; Non peptide compound; Cytotoxicity; Benzoic acid derivatives; Ester; Structure activity relation; Six membered ring; Heat shock protein; Ureas; Biginelli reaction; Colon; Mammary gland; Chemical synthesis; Tumor cell; Human; Enzyme; Aminoamide; Adenosinetriphosphatase; Benzene derivatives; Enzyme inhibitor; Pyrimidone derivatives; In vitro; Cell line; Hydrolases; Carboxamide; Molecular domain
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.12.014

The Hsp70 molecular chaperones are ATPases that play critical roles in the pathogenesis of many human diseases, including breast cancer. Hsp70 ATP hydrolysis is relatively weak but is stimulated by J domain-containing proteins. We identified pyrimidinone-peptoid hybrid molecules that inhibit cell proliferation with greater potency than previously described Hsp70 modulators. In many cases, anti-proliferative activity correlated with inhibition of J domain stimulation of Hsp70.