Synthesis and Biological Evaluation of Neutral and Zwitterionic 3-Carboranyl Thymidine Analogues for Boron Neutron Capture Therapy

Byun, Youngjoo; Yan, Junhua; Madhoun, Ashraf Al; Johnsamuel, Jayaseharan; Yang, Weilian; Barth, Rolf F.; Eriksson, Staffan; Tjarks, Werner

doi:10.1021/jm0491896

Cited by 64 publications

(70 citation statements)

References 52 publications

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“…[55] This has also been suggested as the major internalization route for carboranethymidine derivatives reported by Tjarks and colleagues. [56] Sufficient cell uptake of Re/Tc-labeled dThd complexes remains an obstacle that prevents their application in diagnosis and therapy at this point.…”

Section: Discussionmentioning

confidence: 99%

Synthesis, Cytotoxicity, and Insight into the Mode of Action of Re(CO)₃ Thymidine Complexes

Bartholomä¹,

Vortherms²,

Hillier³

et al. 2010

ChemMedChem

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Nucleoside analogues are extensively used in the treatment of cancer and viral diseases. The antiproliferative properties of organorhenium(I) complexes, however, have been scarcely explored to date. Herein we present the syntheses, characterization, and in vitro evaluation of Re(I)(CO)(3) core complexes of thymidine and uridine. For the binding of the Re(I)(CO)(3) core, a tridentate dipicolylamine metal chelate was introduced at positions C5', C2', N3, and C5 with spacers of various lengths. The corresponding organometallic thymidine complexes were fully characterized by IR and NMR spectroscopy and mass spectrometry. Their cytotoxicity was assessed against the A549 lung carcinoma cell line. Toxicity is dependent on the site and mode of conjugation as well as on the nature and the length of the tether. Moderate toxicity was observed for conjugates carrying the rhenium moiety at position C5' or N3 (IC(50)=124-160 microM). No toxicity was observed for complexes modified at C2' or C5. Complex 53, with a dodecylene spacer at C5', exhibits remarkable toxicity and is more potent than cisplatin, with an IC(50) value of 6.0 microM. To the best of our knowledge, this is the first report of the antiproliferative properties of [M(CO)(3)](+1)-nucleoside conjugates. In competitive inhibition experiments with A549 cell lysates and purified recombinant human thymidine kinase 1 (hTK-1), enzyme inhibition was observed for complexes modified at either N3 or C5', but our results suggest that the toxicity cannot be attributed solely to interaction with hTK-1.

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Section: Discussionmentioning

confidence: 99%

Synthesis, Cytotoxicity, and Insight into the Mode of Action of Re(CO)₃ Thymidine Complexes

Bartholomä¹,

Vortherms²,

Hillier³

et al. 2010

ChemMedChem

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“…28 Yields in this step were 80% for 6 and 85% for 7, respectively. Basic hydrolysis of the benzoate esters 6 and 7 produced 8 and 9 in 92% and 95% yields, respectively.…”

Section: Introductionmentioning

confidence: 95%

“…19,20 The nucleoside analogues radiolabeled in the 3 0 -position reported to date are 3 Recently a series of N-3(substituted)thymidine analogues carrying a carborane moiety at the N-3-position with various spacer length have drawn attention in boron neutron capture therapy. [24][25][26][27][28] It has been reported that some of the N-3(substituted)thymidine analogues are phosphorylated by TK1 with 50-89% efficiency as compared to thymidine, while being poor substrates for thymidine phosphorylase. [25][26][27] Furthermore, some simple N-3(substituted)thymidine derivatives such as ethyl, n-butyl, acetylenic, etc.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of [¹⁸F]‐labeled N‐3(substituted) thymidine analogues: N‐3([¹⁸F]fluorobutyl) thymidine ([¹⁸F]‐FBT) and N‐3([¹⁸F]fluoropentyl) thymidine ([¹⁸F]‐FPT) for PET

Alauddin¹,

Ghosh

Gelovani

2006

Labelled Comp Radiopharmac

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1,4-Butane diol and 1,5 pentane diol were converted to their tosyl derivatives 2 and 3 followed by conversion to benzoate esters 4 and 5, respectively. Protected thymidine 1 was coupled separately with 4 and 5 to produce 6 and 7, which were hydrolyzed to 8 and 9, then converted to their mesylates 10 and 11, respectively. Compounds 10 and 11 were fluorinated with n-Bu 4 N[18 F] to produce 12 and 13, which by acid hydrolysis yielded 14 and 15, respectively. The crude products were purified by HPLC to obtain [ 18 F]-FBT and [ 18 F]-FPT. The radiochemical yields were 58-65% decay corrected (d.c.) for 14 and 46-57% (d.c.) for 15 with an average of 56% in three runs per compound. Radiochemical purity was >99% and specific activity was >74 GBq/mmol at the end of synthesis (EOS). The synthesis time was 65-75 min from the end of bombardment (EOB).

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“…The first step is the simulation of the 3CTAs crossing of the membrane, which occurs by passive diffusion Byun et al, 2005). Free energy approaches such as metadynamics (Laio and Parrinello, 2002) could be used.…”

Section: Perspectivesmentioning

confidence: 99%

Computational molecular biology approaches to ligand‐target interactions

et al. 2009

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Binding of small molecules to their targets triggers complex pathways. Computational approaches are keys for predictions of the molecular events involved in such cascades. Here we review current efforts at characterizing the molecular determinants in the largest membrane-bound receptor family, the G-protein-coupled receptors "GPCRs…. We focus on odorant receptors, which constitute more than half GPCRs. The work presented in this review uncovers structural and energetic aspects of components of the cellular cascade. Finally, a computational approach in the context of radioactive boron-based antitumoral therapies is briefly described.

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Synthesis and Biological Evaluation of Neutral and Zwitterionic 3-Carboranyl Thymidine Analogues for Boron Neutron Capture Therapy

Cited by 64 publications

References 52 publications

Synthesis, Cytotoxicity, and Insight into the Mode of Action of Re(CO)₃ Thymidine Complexes

Synthesis, Cytotoxicity, and Insight into the Mode of Action of Re(CO)₃ Thymidine Complexes

Synthesis of [¹⁸F]‐labeled N‐3(substituted) thymidine analogues: N‐3([¹⁸F]fluorobutyl) thymidine ([¹⁸F]‐FBT) and N‐3([¹⁸F]fluoropentyl) thymidine ([¹⁸F]‐FPT) for PET

Computational molecular biology approaches to ligand‐target interactions

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Synthesis and Biological Evaluation of Neutral and Zwitterionic 3-Carboranyl Thymidine Analogues for Boron Neutron Capture Therapy

Cited by 64 publications

References 52 publications

Synthesis, Cytotoxicity, and Insight into the Mode of Action of Re(CO)3 Thymidine Complexes

Synthesis, Cytotoxicity, and Insight into the Mode of Action of Re(CO)3 Thymidine Complexes

Synthesis of [18F]‐labeled N‐3(substituted) thymidine analogues: N‐3([18F]fluorobutyl) thymidine ([18F]‐FBT) and N‐3([18F]fluoropentyl) thymidine ([18F]‐FPT) for PET

Computational molecular biology approaches to ligand‐target interactions

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Resources

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Synthesis, Cytotoxicity, and Insight into the Mode of Action of Re(CO)₃ Thymidine Complexes

Synthesis, Cytotoxicity, and Insight into the Mode of Action of Re(CO)₃ Thymidine Complexes

Synthesis of [¹⁸F]‐labeled N‐3(substituted) thymidine analogues: N‐3([¹⁸F]fluorobutyl) thymidine ([¹⁸F]‐FBT) and N‐3([¹⁸F]fluoropentyl) thymidine ([¹⁸F]‐FPT) for PET