Management of Hsp90-Dependent Protein Folding by Small Molecules Targeting the Aha1 Co-Chaperone.

Hsp90 plays an important role in health and is a therapeutic target for managing misfolding disease. Compounds that disrupt co-chaperone delivery of clients to Hsp90 target a subset of Hsp90 activities, thereby minimizing the toxicity of pan-Hsp90 inhibitors. Here, we have identified SEW04784 as a first-in-class inhibitor of the Aha1-stimulated Hsp90 ATPase activity without inhibiting basal Hsp90 ATPase. Nuclear magnetic resonance analysis reveals that SEW84 binds to the C-terminal domain of Aha1 to weaken its asymmetric binding to Hsp90. Consistent with this observation, SEW84 blocks Aha1-dependent Hsp90 chaperoning activities, including the in vitro and in vivo refolding of firefly luciferase, and the transcriptional activity of the androgen receptor in cell-based models of prostate cancer and promotes the clearance of phosphorylated tau in cellular and tissue models of neurodegenerative tauopathy. We propose that SEW84 provides a novel lead scaffold for developing therapeutic approaches to treat proteostatic disease.

Anticancer and antimicrobial metallopharmaceutical agents based on palladium, gold, and silver N-heterocyclic carbene complexes.

Complete synthetic, structural, and biomedical studies of two Pd complexes as well as Au and Ag complexes of 1-benzyl-3-tert-butylimidazol-2-ylidene are reported. Specifically, trans-[1-benzyl-3-tert-butylimidazol-2-ylidene]Pd(pyridine)Cl2 (1a) was synthesized from the reaction of 1-benzyl-3-tert-butylimidazolium chloride (1) with PdCl2 in the presence of K2CO3 as a base. The other palladium complex, [1-benzyl-3-tert-butylimidazol-2-ylidene]2PdCl2 (1b), and a gold complex, [1-benzyl-3-tert-butylimidazol-2-ylidene]AuCl (1c), were synthesized by following a transmetallation route from the silver complex, [1-benzyl-3-tert-butylimidazol-2-ylidene]AgCl (1d), by treatment with (COD)PdCl2 and (SMe2)AuCl, respectively. The silver complex 1d in turn was synthesized by the reaction of 1 with Ag2O. The molecular structures of 1a-d have been determined by X-ray diffraction studies. Biomedical studies revealed that, while the palladium complexes 1a and 1b displayed potent anticancer activity, the gold (1c) and silver (1d) complexes exhibited significant antimicrobial properties. Specifically, 1b showed strong antiproliferative activity against three types of human tumor cells, namely, cervical cancer (HeLa), breast cancer (MCF-7), and colon adenocarcinoma (HCT 116), in culture. The antiproliferative activity of 1b was found to be considerably stronger than that of cisplatin. The 1b complex inhibited tumor cell proliferation by arresting the cell cycle progression at the G2 phase, preventing the mitotic entry of the cell. We present evidence suggesting that the treated cells underwent programmed cell death through a p53-dependent pathway. Though both the gold (1c) and silver (1d) complexes showed antimicrobial activity toward Bacillus subtilis, 1c was found to be ca. 2 times more potent than 1d.