Enantioselective synthesis and biological evaluation of 5-o-carboranyl pyrimidine nucleosides

Mourier, Nicolas; Eleuteri, Anna Maria; Hurwitz, Selwyn J.; Tharnish, Phillip M.; Schinazi, Raymond F.

doi:10.1016/s0968-0896(99)00222-9

Cited by 14 publications

(6 citation statements)

References 26 publications

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“…Further conversion to the di- and triphosphates and possible subsequent incorporation into tumor cell DNA could result in the relocation of boron in close proximity to DNA, the most critical target of the α-particles and lithium nuclei . For these reasons, boronated nucleosides have been a focus of BNCT compound development and evaluation. − …”

Section: Introductionmentioning

confidence: 99%

“…4 For these reasons, boronated nucleosides have been a focus of BNCT compound development and evaluation. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] Previously, we have evaluated several C-5-substituted carboranyl 2′-deoxyuridine analogues and a small number of N-3-substituted carboranyl thymidines in phosphoryl transfer assays with recombinant human TK1 and recombinant human mitochondrial thymidine kinase (TK2), 23 the only two thymidine phosphorylating enzymes in animal cells. 3 The results indicated that the N-3-substituted carboranyl thymidines were good substrates for TK1 but not for TK2.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of a Small Library of 3-(Carboranylalkyl)thymidines and Their Biological Evaluation as Substrates for Human Thymidine Kinases 1 and 2

et al. 2002

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A small library consisting of two series of thymidine derivatives containing o-carboranylalkyl groups at the N-3 position was prepared. In both series, alkyl spacers of 2-7 methylene units were placed between the o-carborane cage and the thymidine scaffold. In one series, an additional dihydroxypropyl substituent was introduced at the second carbon atom of the carborane cage. In the series of N-3-substituted carboranyl thymidines without additional dihydroxypropyl substituent, three steps were required to obtain the target compounds in overall yields as high as 75%, while in the series of N-3-substituted carboranyl thymidines with additional dihydroxypropyl substituent, 9-10 steps were necessary with significantly lower overall yield. All target compounds were good substrates of human cytosolic thymidine kinase 1 while they were, if at all, poor substrates of the mitochondrial thymidine kinase 2. There was only a minor difference in phosphorylation rates between N-3-substituted carboranyl thymidines with additional dihydroxypropyl substituents with thymidine kinase 1 (range: 13-49% relative to thymidine) and their counterparts lacking this group (range: 11-57% relative to thymidine). Tether lengths of two and five methylene groups in both series gave the highest enzyme activities in the present study. A hypothesis for this result is presented.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis of a Small Library of 3-(Carboranylalkyl)thymidines and Their Biological Evaluation as Substrates for Human Thymidine Kinases 1 and 2

et al. 2002

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“…Carborane derivatives can be obtained through glycosylation of the appropriate heterocyclic units or directly from -D-or -L-nucleosides. 43 In particular, when the silylated 5-carboranyluracil 72-TMS was reacted with the protected dioxolane derivative 79 in the presence of tin chloride, the -protected carborane-containing nucleoside 80 was formed in low yield (10%). Deprotection of 80 with tetrabutylammonium fluoride in THF at room temperature led to carboranyl--D-1,3-dioxolanyluracil 81 in 56% yield (Scheme 28).…”

Section: Scheme 24 Synthesis Of Protected 2-o-carboranylinosinementioning

confidence: 99%

“…Based on the data of preliminary in vitro studies on cytotoxicity of the synthesized compounds for normal and tumor cell lines, it was concluded that compounds 1-(-Larabinofuranosyl)-5-o-carboranyluracil 84 and 1-(-L-ribofuranosyl)-5-o-carboranyluracil 87 could be regarded as promising agents for BNCT. 43…”

Section: Scheme 28 Synthesis Of Carboranyl--d-13-dioxolanyluracilmentioning

confidence: 99%

Azaheterocyclic Derivatives of ortho-Carborane: Synthetic Strategies and Application Opportunities

et al. 2019

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Azaheterocyclic derivatives of 1,2-dicarba-closo-dodecaborane (ortho-carborane) are known to be of particular interest due to numerous plausible applications, particularly, in medicine, materials science, and advanced technologies. Three principal synthetic strategies resulting in azaheterocyclic carboranes, in which boron-enriched and azaheterocyclic fragments are linked to each other, either directly by means of the C–C bonds or through a short spacer (CH2, CH2S, CH2O, etc.), have been outlined. These synthetic approaches are of general character and can be used both individually and in combination to afford promising organoboron clusters of diverse architectures.1 Introduction2 C–C Cross-Coupling Strategies in the Synthesis of Azaheterocyclic Carboranes3 Carboryne-Based Transformation Strategies4 Condensation Strategies: Reactions of Decaborane B10H14 with Substituted Acetylenes5 Conclusion and Outlook

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“…Nucleosides bearing a substituent at the 5-position (e.g. 5-iodo or 5-bromo-2´deoxyuridine) are very good substrates for enzymes involved in DNA synthesis, and are able to replace thymidine during this process[98].Schinazi et al[99] and Yamamoto et al[100] respectively synthesised compounds 14 and 22(Figure 4) and evaluated them in vitro and in vivo.Compounds 22 effected increased survival in mice, while studies involving enzymes suggested that the cellular uptake of 22 may be mediated by a nucleoside base transporter.…”

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confidence: 99%

Towards carborane-functionalised structures for the treatment of brain cancer

Calabrese

Daou

Barbu

et al. 2018

Drug Discovery Today

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Boron neutron capture therapy (BNCT) is a promising targeted chemoradiotherapeutic technique for the management of invasive brain tumors, such as glioblastoma multiforme (GBM). A prerequisite for effective BNCT is the selective targeting of tumour cells with B-rich therapeutic moieties. To this end, polyhedral boranes, especially carboranes, have received considerable attention because they combine a high boron content with relative low toxicity and metabolic inertness. Here, we review progress in the molecular design of recently investigated carborane derivatives in light of the widely accepted performance requirements for effective BNCT.

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Enantioselective synthesis and biological evaluation of 5-o-carboranyl pyrimidine nucleosides

Cited by 14 publications

References 26 publications

Synthesis of a Small Library of 3-(Carboranylalkyl)thymidines and Their Biological Evaluation as Substrates for Human Thymidine Kinases 1 and 2

Synthesis of a Small Library of 3-(Carboranylalkyl)thymidines and Their Biological Evaluation as Substrates for Human Thymidine Kinases 1 and 2

Azaheterocyclic Derivatives of ortho-Carborane: Synthetic Strategies and Application Opportunities

Towards carborane-functionalised structures for the treatment of brain cancer

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