Synthesis and Study of Multifunctional Cyclodextrin–Deferasirox Hybrids

Gascon, Jose M.; Oliveri, Valentina; McGown, Andrew; Kaya, Ecem; Chen, Yu Lin; Austin, Carol; Walker, Martin; Platt, Frances M.; Vecchio, Graziella; Spencer, John

doi:10.1002/cmdc.201900334

Cited by 5 publications

(5 citation statements)

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“…Studies using a mouse model of NPC1 suggest that iron chelation with deferiprone (DFP) is ineffective in slowing the disease progression or in prolonging lifespan [ 43 ]. However, another study reported that DFP conjugated with β-cyclodextrin partially rescues the increase in lysosomal volume in NPC1-deficient cells [ 84 ]. Thus, more studies are required to evaluate the use of iron chelators as potential therapeutical strategies against NPC.…”

Section: Resultsmentioning

confidence: 99%

Iron Limitation Restores Autophagy and Increases Lifespan in the Yeast Model of Niemann–Pick Type C1

Martins

Costa

Vilaça

et al. 2023

IJMS

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Niemann–Pick type C1 (NPC1) is an endolysosomal transmembrane protein involved in the export of cholesterol and sphingolipids to other cellular compartments such as the endoplasmic reticulum and plasma membrane. NPC1 loss of function is the major cause of NPC disease, a rare lysosomal storage disorder characterized by an abnormal accumulation of lipids in the late endosomal/lysosomal network, mitochondrial dysfunction, and impaired autophagy. NPC phenotypes are conserved in yeast lacking Ncr1, an orthologue of human NPC1, leading to premature aging. Herein, we performed a phosphoproteomic analysis to investigate the effect of Ncr1 loss on cellular functions mediated by the yeast lysosome-like vacuoles. Our results revealed changes in vacuolar membrane proteins that are associated mostly with vesicle biology (fusion, transport, organization), autophagy, and ion homeostasis, including iron, manganese, and calcium. Consistently, the cytoplasm to vacuole targeting (Cvt) pathway was increased in ncr1∆ cells and autophagy was compromised despite TORC1 inhibition. Moreover, ncr1∆ cells exhibited iron overload mediated by the low-iron sensing transcription factor Aft1. Iron deprivation restored the autophagic flux of ncr1∆ cells and increased its chronological lifespan and oxidative stress resistance. These results implicate iron overload on autophagy impairment, oxidative stress sensitivity, and cell death in the yeast model of NPC1.

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Section: Resultsmentioning

confidence: 99%

Iron Limitation Restores Autophagy and Increases Lifespan in the Yeast Model of Niemann–Pick Type C1

Martins

Costa

Vilaça

et al. 2023

IJMS

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“…Finally, we evaluated the pharmacokinetic (PK) properties of (+)-JD1 vs (+)-JQ1 in selected standard assays (Table 1). 36 The mouse microsomal metabolism of (+)-JD1 was extremely high with a clearance value ca. 7 times that of (+)-JQ1.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor

et al. 2019

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+)-JD1, a rationally designed ferrocene analogue of the BET bromodomain (BRD) probe molecule (+)-JQ1, has been synthesized and evaluated in biophysical, cell-based assays as well as in pharmacokinetic studies. It displays nanomolar activity against BRD isoforms, and its cocrystal structure was determined in complex with the first bromodomain of BRD4 and compared with that of (+)-JQ1, a known BRD4 small-molecule probe. At 1 μM concentration, (+)-JD1 was able to inhibit c-Myc, a key driver in cancer and an indirect target of BRD4.

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“…After that, the βCD was allowed to react with the synthesized 1-(p-toluensulfonyl) imidazole to obtain the 6-O-mono (p toluenesulfonyl)-βCD (tosyl-βCD), in basic media. After one night, the reaction mixture was filtered and a white solid was collected [27,28] For the covalent linking of the activated β-CD (tosyl-βCD), it was added to 4 mL of the concentrated amine-functionalized ultraluminescent gold core-shell nano-emitter (Au@SiO 2 -RhB-NH 2 ) in DMF, or aqueous buffer colloidal dispersion. Thus, it was added to a 5 mM final concentration of tosylated CDs to have a large excess of the modified macrocycle within colloidal dispersions.…”

Section: General Proceduresmentioning

confidence: 99%

Multimodal Spectroscopy Assays for Advanced Nano-Optics Approaches by Tuning Nano-Tool Surface Chemistry and Metal-Enhanced Fluorescence

Romero,

Veglia,

Amé

et al. 2024

Crystals

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In this research work, different chemical modifications were applied to gold nanoparticles and their use in enhanced non-classical light emitters based on metal-enhanced fluorescence (MEF) was evaluated. In order to achieve this, gold core–shell nanoparticles with silica shells were modified via multilayered addition and the incorporation of a covalently linked laser dye to develop MEF. Their inter-nanoparticle interactions were evaluated by using additional silica shell multilayers and modified cyclodextrin macrocycles. In this manner, the sizes and chemical surface interactions on the multilayered nanoarchitectures were varied. These optical active nanoplatforms led to the development of different nanoassembly sizes and luminescence behaviors. Therefore, the interactions and nanoassembly properties were evaluated by using various spectroscopic and nanoimaging techniques. Highly dispersible gold core–shell nanoparticles with diameters of 50–60 nm showed improved colloidal dispersion that led to single ultraluminescent gold core–shell nanoparticles with MEF. Then, the addition of variable silica lengths produced increased interactions and consequent nanoaggregation. However, the silanized nanoparticles were easily dispersible after agitation or sonication. Thus, their sizes were proportional only to the diameter and the van de Waals interaction did not affect their sizes in bulk. Then, the covalent linking of different concentrations of modified cyclodextrins was applied to the chemical surfaces by incorporating additional hydroxyl groups from the glucose monomeric unities of cyclodextrins. In this manner, variable larger-sized and inter-branched grafted gold core–shell silica nanoparticles were generated. The ultraluminescent properties were conserved due to the non-optical activity of the cyclodextrins. However, they generated enhanced ultraluminescence phenomena. Laser fluorescence microscopy nanoimaging showed enhanced resolutions in comparison to non-grafted supramolecular gold core–shell nanoparticles. The differences in their interactions and the sizes of the nanoassemblies were explained by their single nanoparticle diameters and the interacting chemical groups on their nanosurfaces. While the varied luminescence emissions generated were tuned by plasmonics, enhanced plasmonic phenomena and light scattering properties were seen depending on the type of nanoassembly. Thus, optically active and non-optically active materials led to different optical properties in the bright field and enhanced the excited state within the electromagnetic near-field of the gold nanotemplates. In this manner, it was possible to achieve high sensitivity by varying the spacer lengths and optical properties. Therefore, further perspectives regarding the design of nano-tools composed of light for various applications were discussed.

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Synthesis and Study of Multifunctional Cyclodextrin–Deferasirox Hybrids

Cited by 5 publications

References 50 publications

Iron Limitation Restores Autophagy and Increases Lifespan in the Yeast Model of Niemann–Pick Type C1

Iron Limitation Restores Autophagy and Increases Lifespan in the Yeast Model of Niemann–Pick Type C1

Synthesis and Biological Investigation of (+)-JD1, an Organometallic BET Bromodomain Inhibitor

Multimodal Spectroscopy Assays for Advanced Nano-Optics Approaches by Tuning Nano-Tool Surface Chemistry and Metal-Enhanced Fluorescence

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