Synthesis and Solution Properties of Deferoxamine Amides

Ihnát, Peter; Vennerstrom, Jonathan L.; Robinson, Dennis H.

doi:10.1002/1520-6017(200012)89:12<1525::aid-jps3>3.0.co;2-t

Cited by 39 publications

(20 citation statements)

References 27 publications

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“…Similar to the iron chelator, deferasirox, both M-110 and OICR623 increased calcein fluorescence (Fig. 5B), whereas 21H7 yielded a more modest increase that was similar to that observed for desferioxamine, an iron chelator with poor cell-permeability properties (32). We next tested the effect of excess iron on compound activity in cells.…”

Section: Compounds Bind Iron In Vitro and In Cultured Cells And This mentioning

confidence: 56%

Wnt Inhibitor Screen Reveals Iron Dependence of β-Catenin Signaling in Cancers

et al. 2011

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Excessive signaling from the Wnt pathway is associated with numerous human cancers. Using a high throughput screen designed to detect inhibitors of Wnt/b-catenin signaling, we identified a series of acyl hydrazones that act downstream of the b-catenin destruction complex to inhibit both Wnt-induced and cancerassociated constitutive Wnt signaling via destabilization of b-catenin. We found that these acyl hydrazones bind iron in vitro and in intact cells and that chelating activity is required to abrogate Wnt signaling and block the growth of colorectal cancer cell lines with constitutive Wnt signaling. In addition, we found that multiple iron chelators, desferrioxamine, deferasirox, and ciclopirox olamine similarly blocked Wnt signaling and cell growth. Moreover, in patients with AML administered ciclopirox olamine, we observed decreased expression of the Wnt target gene AXIN2 in leukemic cells. The novel class of acyl hydrazones would thus be prime candidates for further development as chemotherapeutic agents. Taken together, our results reveal a critical requirement for iron in Wnt signaling and they show that iron chelation serves as an effective mechanism to inhibit Wnt signaling in humans. Cancer Res; 71(24); 7628-39. Ó2011 AACR.

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Section: Compounds Bind Iron In Vitro and In Cultured Cells And This mentioning

confidence: 56%

Wnt Inhibitor Screen Reveals Iron Dependence of β-Catenin Signaling in Cancers

et al. 2011

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“…While DXZ reduced mitochondrial iron levels in NRCMs after DOX treatment, the effect of DFO was minimal, as determined by the BPS ( Figure 8A) and RPA ( Figure 8B) assays. Failure of DFO to chelate mitochondrial iron is consistent with the poor mitochondrial permeability of the drug (27,28). Importantly, DXZ had no effect on the levels of nuclear and cytosolic iron in control NRCMs and led to only slight reduction in nuclear iron in DOX-treated cells, consistent with its low potency in chelating iron, while DFO reduced iron levels in both of these cellular compartments by 50% in the presence and absence of DOX (Supplemental Figure 8, A and B).…”

Section: Figurementioning

confidence: 77%

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

Ichikawa¹,

Ghanefar²,

Bayeva³

et al. 2014

J. Clin. Invest.

720

559

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Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.

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“…The drugs suitable for passive delivery are usually hydrophobic and have a molecular weight <500 Da, allowing them to pass through the hydrophobic stratum corneum (57). Unfortunately, DFO has a molecular weight of 560 Da and consists of three hydrophilic bidentate oxygen-containing groups, which reduces its lipid solubility (58). Collectively, these physical properties prevent it from penetrating intact stratum corneum.…”

Section: Discussionmentioning

confidence: 99%

Transdermal deferoxamine prevents pressure-induced diabetic ulcers

Duscher

Neofytou

Wong

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

173

174

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There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation.wound healing | diabetes | drug delivery | small molecule | angiogenesis D iabetes mellitus affects over 25 million people in the United States (1, 2) and costs nearly $250 billion per year (3). Chronic diabetic wounds and decubiti are important long-term sequalae of both diabetes mellitus types 1 and 2 (4). There is a high mortality in diabetic patients who develop decubiti (5-7), and owing to prolonged disability and the high rates of recurrence these wounds represent an especially severe complication of diabetes (8). This is further underscored by the fact that diabetic nonhealing wounds are the leading cause of nontraumatic amputations in the United States (3, 9-11). As such, there is a clear need for new approaches to effectively manage and treat diabetic ulcers.The propensity for wound development in diabetes is associated with a reduced capacity for ischemia-driven neovascularization (12, 13). Hypoxia inducible factor-1 (HIF-1), which consists of a highly regulated α-subunit and a constitutively expressed β-subunit, is a critical transcriptional regulator of the normal cellular response to hypoxia, promoting progenitor cell recruitment, proliferation, survival, and neovascularization (14, 15). In nondiabetics, hypoxia causes stabilization of HIF-1α protein by preventing the normal rapid proteasomal degradation of HIF-1α. It does this by inhibiting the prolyl hydroxylases (PHDs), which hydroxylate specific prolyl residues on HIF-1α. Without proline hydroxylation HIF-1α is not ...

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Synthesis and Solution Properties of Deferoxamine Amides

Cited by 39 publications

References 27 publications

Wnt Inhibitor Screen Reveals Iron Dependence of β-Catenin Signaling in Cancers

Wnt Inhibitor Screen Reveals Iron Dependence of β-Catenin Signaling in Cancers

Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation

Transdermal deferoxamine prevents pressure-induced diabetic ulcers

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