Dimeric Approaches to Anti-Cancer Chemotherapeutics

Hadden, M. Kyle; Blagg, Brian S. J.

doi:10.2174/187152008785914743

Cited by 50 publications

(36 citation statements)

References 84 publications

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“…Dimers of apigenin linked with ethylene glycol linker showed enhanced anticancer effect compared to apigenin in multidrug resistance breast cancer cells as well as in leukemia cell lines (Zhang et al 2004). It was suggested that dimeric molecules could bind to two distinct sites on a single molecule or a defined site on two separate molecules (Hadden and Blagg 2008). With respect to A" peptide aggregation and toxicity, a dimeric polyphenol, curcumin ( Fig.…”

Section: Beneficial Roles Of Naturally Occurring Polyphenolic Compounmentioning

confidence: 99%

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

Thapa

2015

Advances in Experimental Medicine and Biology

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Flavonoids are naturally occurring phytochemicals found in a variety of fruits and vegetables and offer color, flavor, aroma, nutritional and health benefits. Flavonoids have been found to play a neuroprotective role by inhibiting and/or modifying the self-assembly of the amyloid-β (Aβ) peptide into oligomers and fibrils, which are linked to the pathogenesis of Alzheimer's disease. The neuroprotective efficacy of flavonoids has been found to strongly depend on their structure and functional groups. Flavonoids may exist in monomeric, as well as di-, tri-, tetra- or polymeric form through C-C or C-O-C linkages. It has been shown that flavonoids containing two or more units, e.g., biflavonoids, exert greater biological activity than their respective monoflavonoids. For instance, biflavonoids have the ability to distinctly alter Aβ aggregation and more effectively reduce the toxicity of Aβ oligomers compared to the monoflavonoid moieties. Although the molecular mechanisms remain to be elucidated, flavonoids have been shown to alter the Aβ aggregation pathway to yield non-toxic, unstructured Aβ aggregates, as well as directly exerting a neuroprotective effect to cells. In this chapter, we review biflavonoid-mediated Aβ aggregation and toxicity, and highlight the beneficial roles biflavonoids can potentially play in the prevention and treatment of Alzheimer's disease.

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Section: Beneficial Roles Of Naturally Occurring Polyphenolic Compounmentioning

confidence: 99%

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

Thapa

2015

Advances in Experimental Medicine and Biology

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“…Polyvalent molecules have the potential to yield nonlinear, multifold potency against their respective targets compared to their corresponding monomers (18, 19). With the goal of generating new autophagy inhibitors with better potency, tolerability, and anticancer efficacy than HCQ, we used logical medicinal chemistry approaches to generate a series of new dimeric compounds containing modified core elements of HCQ, CQ and the anti-schistosomal drug lucanthone (Miracil D) (20).…”

Section: Introductionmentioning

confidence: 99%

Disruption of Autophagic Degradation with ROC-325 Antagonizes Renal Cell Carcinoma Pathogenesis

Carew

Espitia

Zhao

et al. 2017

Clinical Cancer Research

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Purpose Although autophagy plays important roles in malignant pathogenesis and drug resistance, there are few clinical agents that disrupt this pathway and the potential therapeutic benefit of autophagy inhibition remains undetermined. We used medicinal chemistry approaches to generate a series of novel agents that inhibit autophagic degradation. Experimental Design ROC-325 was selected as a lead compound for further evaluation. Comprehensive in vitro and in vivo studies were conducted to evaluate the selectivity, tolerability, and efficacy of ROC-325 in preclinical models of renal cell carcinoma (RCC) with HCQ serving as a comparator. Markers of autophagy inhibition and cell death were evaluated in tumor specimens. Results ROC-325 exhibited superior in vitro anticancer effects than the existing autophagy inhibitor hydroxychloroquine in 12 different cancer cell lines with diverse genetic backgrounds. Focused studies of the mechanism of action and efficacy of ROC-325 in RCC cells showed that drug treatment induced hallmark characteristics of autophagy inhibition including accumulation of autophagosomes with undegraded cargo, lysosomal deacidification, p62 stabilization, and disruption of autophagic flux. Subsequent experiments showed that ROC-325 antagonized RCC growth and survival in an ATG5/7-dependent manner, induced apoptosis, and exhibited favorable selectivity. Oral administration of ROC-325 to mice bearing 786-0 RCC xenografts was well tolerated, significantly more effective at inhibiting tumor progression than HCQ, and inhibited autophagy in vivo. Conclusions Our findings demonstrate that ROC-325 has superior preclinical anticancer activity compared to HCQ and support the clinical investigation of its safety and preliminary efficacy in patients with RCC and other autophagy-dependent malignancies.

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“…The most effective are coumermycin A1 (CA1) and its analogs (Figure 2). 20, 26, 27 There is currently no data on how the C-terminal hsp90 inhibitor CA1 controls the immunophilins. However, work done by Ratajczak and co-workers showed that a millimolar concentration of a structurally similar C-terminal inhibitor, novabiocin, disrupts immunophilins from binding to hsp90.…”

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confidence: 99%

A heat shock protein 90 inhibitor that modulates the immunophilins and regulates hormone receptors without inducing the heat shock response

McConnell

Alexander

McAlpine

2014

Bioorganic & Medicinal Chemistry Letters

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When a cell encounters external stressors, such as lack of nutrients, elevated temperatures, changes in pH or other stressful environments, a key set of evolutionarily conserved proteins, the heat shock proteins (hsps), become overexpressed. Hsps are classified into six major families with the hsp90 family being the best understood; an increase in cell stress leads to increased levels of hsp90, which leads to cellular protection. A hallmark of hsp90 inhibitors is that they induce a cell rescue mechanism, the heat shock response. We define the unique molecular profile of a compound (SM145) that regulates hormone receptor protein levels through hsp90 inhibition without inducing the heat shock response. Modulation of the binding event between heat shock protein 90 and the immunophilins/homologs using SM145, leads to a decrease in hormone receptor protein levels. Unlike N-terminal hsp90 inhibitors, this hsp90 inhibitor does not induce a heat shock response. This work is proof of principle that controlling hormone receptor expression can occur by inhibiting hsp90 without inducing pro-survival protein heat shock protein 70 (hsp70) or other proteins associated with the heat shock response. Innovatively, we show that blocking the heat shock response, in addition to hsp90, is key to regulating hsp90-associated pathways.

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Dimeric Approaches to Anti-Cancer Chemotherapeutics

Cited by 50 publications

References 84 publications

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

Disruption of Autophagic Degradation with ROC-325 Antagonizes Renal Cell Carcinoma Pathogenesis

A heat shock protein 90 inhibitor that modulates the immunophilins and regulates hormone receptors without inducing the heat shock response

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