Radiolabeled Cyclosaligenyl Monophosphates of 5-Iodo-2′-deoxyuridine, 5-Iodo-3′-fluoro-2′,3′-dideoxyuridine, and 3′-Fluorothymidine for Molecular Radiotherapy of Cancer: Synthesis and Biological Evaluation

Kortylewicz, Zbigniew P.; Kimura, Yu; Inoue, Kotaro; Mack, Elizabeth; Baranowska‐Kortylewicz, Janina

doi:10.1021/jm201482p

Cited by 19 publications

(32 citation statements)

References 73 publications

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“…The effect of AE-emitters on cell survival was first studied with molecules that can be incorporated in to the DNA, such as 125 I-UDR. These studies provided valuable knowledge that illuminated the inverse relationship between AE-emitter distance to the DNA and DNA damage and cell kill ( Kortylewicz et al, 2012 ). Since then, several small molecule DNA intercalators have been proposed as nuclear-targeting agents for AE-emitting radionuclides, such as radiolabeled derivatives of acridine orange ( Pereira et al, 2017 ), pyrene ( Häfliger et al, 2005 ; Reissig et al, 2016 ), doxorubicin ( Imstepf et al, 2015 ), and daunorubicin ( Fondell et al, 2011 ).…”

Section: Subcellular Targets For Radionuclide Therapymentioning

confidence: 99%

“…DeSombre and others subsequently evaluated various radiolabeled agents for the treatment of cancer, including 123 I- and 111 In-labeled analogs of estrogen and diethylstilboestrol, a non-steroid ER agonist ( DeSombre et al, 2000 ; Yasui et al, 2001 ; Fischer et al, 2008 ; Vultos et al, 2017 ). Kortylewicz et al (2012) developed an interesting hybrid molecule that exploits dual AR targeting and S-phase specific cell kill by linking 5α-dihydrotestosterone with 5-radioiodo-2′-deoxyuridine. They showed that this drug is initially trapped in the cytoplasm but associates exclusively with nuclear DNA after 24 h. A relatively low dose of radioactivity resulted in a reduction in clonogenic survival dependent on the expression of AR ( Kortylewicz et al, 2012 ; Han et al, 2014 ).…”

Section: Subcellular Targets For Radionuclide Therapymentioning

confidence: 99%

“… Kortylewicz et al (2012) developed an interesting hybrid molecule that exploits dual AR targeting and S-phase specific cell kill by linking 5α-dihydrotestosterone with 5-radioiodo-2′-deoxyuridine. They showed that this drug is initially trapped in the cytoplasm but associates exclusively with nuclear DNA after 24 h. A relatively low dose of radioactivity resulted in a reduction in clonogenic survival dependent on the expression of AR ( Kortylewicz et al, 2012 ; Han et al, 2014 ).…”

Section: Subcellular Targets For Radionuclide Therapymentioning

confidence: 99%

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Subcellular Targeting of Theranostic Radionuclides

et al. 2018

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The last decade has seen rapid growth in the use of theranostic radionuclides for the treatment and imaging of a wide range of cancers. Radionuclide therapy and imaging rely on a radiolabeled vector to specifically target cancer cells. Radionuclides that emit β particles have thus far dominated the field of targeted radionuclide therapy (TRT), mainly because the longer range (μm–mm track length) of these particles offsets the heterogeneous expression of the molecular target. Shorter range (nm–μm track length) α- and Auger electron (AE)-emitting radionuclides on the other hand provide high ionization densities at the site of decay which could overcome much of the toxicity associated with β-emitters. Given that there is a growing body of evidence that other sensitive sites besides the DNA, such as the cell membrane and mitochondria, could be critical targets in TRT, improved techniques in detecting the subcellular distribution of these radionuclides are necessary, especially since many β-emitting radionuclides also emit AE. The successful development of TRT agents capable of homing to targets with subcellular precision demands the parallel development of quantitative assays for evaluation of spatial distribution of radionuclides in the nm–μm range. In this review, the status of research directed at subcellular targeting of radionuclide theranostics and the methods for imaging and quantification of radionuclide localization at the nanoscale are described.

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Section: Subcellular Targets For Radionuclide Therapymentioning

confidence: 99%

Section: Subcellular Targets For Radionuclide Therapymentioning

confidence: 99%

Section: Subcellular Targets For Radionuclide Therapymentioning

confidence: 99%

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Subcellular Targeting of Theranostic Radionuclides

et al. 2018

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“…This target compound was obtained through the typical stannylation of the iodide by hexamethylditin in the presence of triethylamine catalyzed by bis-(triphenylphosphine) palladium(II) dichloride using our previously described procedures. [20][21][22][23] Stannylations were carried out under nitrogen in refluxed MeCN using crude iodide 2 contain-ing~7% of 1. The final purification of the stannane was accomplished on the HPLC system equipped with a semipreparative column after numerous injections of a crude product.…”

Section: Resultsmentioning

confidence: 99%

Radiosynthesis of microtubule‐targeted theranostic methyl N‐[5‐(3’‐radiohalobenzoyl)‐1H‐benzimidazol‐2‐yl]carbamates

Kortylewicz

Baranowska‐Kortylewicz

2018

Labelled Comp Radiopharmac

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Microtubules are a target for a broad spectrum of drugs used as chemotherapeutics to treat hematological malignancies and solid tumors. Most of these drugs have significant dose-limiting toxicities including peripheral neuropathies that can be debilitating and permanent. In an ongoing effort to develop safer and more effective drugs, benzimidazole-based compounds are being developed as replacement for vincristine and similar agents. In this report, we describe radiosyntheses of novel microtubule-targeting methyl N-[5-(3'-radiohalobenzoyl)-1H-benzimidazol-2-yl]carbamates 4 that are intended as potential imaging agents and molecular radiotherapeutics. I- and I-radiolabeled derivatives were prepared either by direct radioiodination of methyl N-(6-benzoyl-1H-benzimidazol-2-yl)carbamate 1 or radioiododestannylation of the corresponding stannane precursor 3. The direct radioiodination was conducted in a solution of 1 in triflic acid and produced after ~1 hour at elevated temperatures and HPLC purification on average 62% of the no-carrier added products I-4 and I-4. Radioiododestannylation of 3'-trimethylstannane 3 proceeded with ease at room temperature in the presence of H O as the oxidant and produced no-carrier-added I-4 and I-4 in high isolated yields, on average 85%. The radiohalodestannylation protocol is universal and can be applied to other radiohalides including I to produce I-4, a positron emission tomography agent, and At to produce At-4, an α-particle emitting radiotherapeutic.

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“…Thymidine kinase 1 (TK1) and thymidine phosphorylase (TYMP) are key cytosolic thymidine salvage enzymes and targeted by anticancer thymidine therapeutics [ 1 - 5 ]. Two isoforms of TKs have been identified in cells, TK1 in cytosol and TK2 in mitochondria, which convert thymidine, 2’-deoxyuridine and 5-substiuted-2’-deoxyuridine or 2’-deoxycytidine (TK2) to the 5’-monophosphate form [ 2 - 4 ]. Low levels of TK1 are generally expressed in normal adult cells while high levels of TK1 are characteristic of cancer cells [ 6 - 9 ].…”

Section: Introductionmentioning

confidence: 99%

Anticancer activity of a thymidine quinoxaline conjugate is modulated by cytosolic thymidine pathways

et al. 2015

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BackgroundHigh levels of thymidine kinase 1 (TK1) and thymidine phosphorylase (TYMP) are key molecular targets by thymidine therapeutics in cancer treatment. The dual roles of TYMP as a tumor growth factor and a key activation enzyme of anticancer metabolites resulted in a mixed outcome in cancer patients. In this study, we investigated the roles of TK1 and TYMP on a thymidine quinoxaline conjugate to evaluate an alternative to circumvent the contradictive role of TYMP.MethodsTK1 and TYMP levels in multiple liver cell lines were assessed along with the cytotoxicity of the thymidine conjugate. Cellular accumulation of the thymidine conjugate was determined with organelle-specific dyes. The impacts of TK1 and TYMP were evaluated with siRNA/shRNA suppression and pseudoviral overexpression. Immunohistochemical analysis was performed on both normal and tumor tissues. In vivo study was carried out with a subcutaneous liver tumor model.ResultsWe found that the thymidine conjugate had varied activities in liver cancer cells with different levels of TK1 and TYMP. The conjugate mainly accumulated at endothelial reticulum and was consistent with cytosolic pathways. TK1 was responsible for the cytotoxicity yet high levels of TYMP counteracted such activities. Levels of TYMP and TK1 in the liver tumor tissues were significantly higher than those of normal liver tissues. Induced TK1 overexpression decreased the selectivity of dT-QX due to the concurring cytotoxicity in normal cells. In contrast, shRNA suppression of TYMP significantly enhanced the selective of the conjugate in vitro and reduced the tumor growth in vivo.ConclusionsTK1 was responsible for anticancer activity of dT-QX while levels of TYMP counteracted such an activity. The counteraction by TYMP could be overcome with RNA silencing to significantly enhance the dT-QX selectivity in cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1149-5) contains supplementary material, which is available to authorized users.

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Radiolabeled Cyclosaligenyl Monophosphates of 5-Iodo-2′-deoxyuridine, 5-Iodo-3′-fluoro-2′,3′-dideoxyuridine, and 3′-Fluorothymidine for Molecular Radiotherapy of Cancer: Synthesis and Biological Evaluation

Cited by 19 publications

References 73 publications

Subcellular Targeting of Theranostic Radionuclides

Subcellular Targeting of Theranostic Radionuclides

Radiosynthesis of microtubule‐targeted theranostic methyl N‐[5‐(3’‐radiohalobenzoyl)‐1H‐benzimidazol‐2‐yl]carbamates

Anticancer activity of a thymidine quinoxaline conjugate is modulated by cytosolic thymidine pathways

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