Selective Synthesis of the <i>para</i>-Quinone Region of Geldanamycin

Andrus, Merritt B.; Hicken, Erik J.; Meredith, Erik; Simmons, Bryon; Cannon, John F.

doi:10.1021/ol035400g

Cited by 37 publications

(36 citation statements)

References 35 publications

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“…Most reported GDA derivatives are produced by nucleophilic displacement of the 17-methoxy substituent. [57,58] A complementary approach towards elucidation of structure-activity relationships for GDA was taken by researchers at Kosan Biosci- ences. Bioengineered derivatives of GDA were produced by performing site-directed mutagenesis on the polyketide synthase gene cluster encoded by gdmA1-A3.…”

Section: Geldanamycin and Derivativesmentioning

confidence: 99%

Hsp90 as a Target for Drug Development

2006

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Section: Geldanamycin and Derivativesmentioning

confidence: 99%

Hsp90 as a Target for Drug Development

2006

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“…94 More recent work by Andrus and co-workers 95 has led to the development of synthetic methodology that should afford both GDA and analogs for elucidation of structure-activity relationships. A complementary approach to the synthetic preparation of GDA was used by researchers at Kosan Biosciences to prepare bioengineered derivatives.…”

Section: Bioengineered Derivatives Of Geldanamycinmentioning

confidence: 99%

Hsp90 inhibitors: Small molecules that transform the Hsp90 protein folding machinery into a catalyst for protein degradation

Blagg

Kerr

2005

Medicinal Research Reviews

174

119

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The 90 kDa heat shock proteins (Hsp90) are responsible for the conformational maturation of nascent polypeptides and the renaturation of denatured proteins. In transformed cells, numerous mutated and overexpressed proteins rely on the Hsp90 protein folding machinery for tumor progression. The Hsp90-mediated protein folding process is dependent upon ATP, and when inhibitors of ATP are present, the Hsp90 machinery is unable to fold client proteins into their biologically active form, which results in the degradation of protein substrates via the ubiquitin-proteasome pathway. Consequently, Hsp90 has evolved into a promising anti-cancer target because multiple oncogenic proteins can be simultaneously degraded as a consequence of Hsp90 inhibition. This review serves to explain the Hsp90 protein folding process, the impact of Hsp90 inhibition, the identification of natural product inhibitors, and the development of rationally designed inhibitors of the Hsp90 protein folding machinery.

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“…Binding of ATP to the N-terminal domain is required in order for the C-terminal ATP site to become available for nucleotide binding. Based on previous studies, there is only a small therapeutic window for N-terminal inhibitors because of toxicity that is produced upon client protein degradation 11,12. Consequently, the development of such compounds to treat neurodegenerative diseases is limited.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective activity and evaluation of Hsp90 inhibitors in an immortalized neuronal cell line

Ansar

Michaelis

et al. 2009

Bioorganic & Medicinal Chemistry

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Alzheimer's disease (AD) neuropathology is characterized by loss of synapses and neurons, neuritic plaques consisting of β-amyloid (Aβ) peptides, and neurofibrillary tangles consisting of intracellular aggregates of hyperphosphorylated tau protein in susceptible brain regions. Aβ oligomers trigger a cascade of pathogenic events including tau hyperphosphorylation and aggregation, inflammatory reactions, and excitotoxicity that contribute to the progression of AD. The molecular chaperone Hsp90 facilitates the folding of newly synthesized and denatured proteins and is believed to play a role in neurodegenerative disorders in which the defining pathology results in misfolded proteins and the accumulation of protein aggregates. Some agents that inhibit Hsp90 protect neurons against Aβ toxicity and tau aggregation, and assays for rapidly screening potential Hsp90 inhibitors are of interest. We used the release of the soluble cytosolic enzyme lactate dehydrogenase (LDH) as an indicator of the loss of cell membrane integrity and cytotoxicity resulting from exposure to Aβ peptides to evaluate the neuroprotective properties of novel novobiocin analogues and established Hsp90 inhibitors. Compounds were assessed for potency in protecting proliferating and differentiated SH-SY5Y neuronal cells against Aβ-induced cell death; the potential of each agent alone was also determined. The data indicated that several of the compounds decreased Aβ toxicity even at low nanomolar concentrations and, unexpectedly, were more potent in protecting the undifferentiated cells against Aβ. The novobiocin analogues alone were not toxic even up to 10 μM concentrations whereas GDA and the parent compound, novobiocin, were toxic at 1 and 10 μM, respectively. The results suggest that novobiocin analogues may provide novel leads for the development of neuroprotective drugs.

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Selective Synthesis of the para-Quinone Region of Geldanamycin

Cited by 37 publications

References 35 publications

Hsp90 as a Target for Drug Development

Hsp90 as a Target for Drug Development

Hsp90 inhibitors: Small molecules that transform the Hsp90 protein folding machinery into a catalyst for protein degradation

Neuroprotective activity and evaluation of Hsp90 inhibitors in an immortalized neuronal cell line

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