Boron-Substituted Pyrimidines

Liao, T. K.; Podrebarac, Eugene G.; Cheng, C.C.

doi:10.1021/ja01063a054

Cited by 47 publications

(23 citation statements)

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“…Several other classes of low molecular weight boron-containing drugs are under development, including porphyrins (16) and nucleosides. The rationale for the synthesis of the latter (17)(18)(19) is based on the fact that neoplastic cells have increased requirements for nucleic acid precursors. This is because of their higher proliferative rates compared with normal cells and the involvement of salvage pathways designed to reuse nucleosides, which are precursors of essential cellular biochemical building blocks such as DNA and RNA.…”

Section: Introductionmentioning

confidence: 99%

Boron-Containing Nucleosides as Potential Delivery Agents for Neutron Capture Therapy of Brain Tumors

Barth¹,

Yang²,

Madhoun³

et al. 2004

Cancer Research

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The purpose of the present study was to evaluate both in vitro and in vivo a series of boron-containing nucleosides that potentially could be used as delivery agents for neutron capture therapy. The rationale for their synthesis was based on the fact that proliferating neoplastic cells have increased requirements for nucleic acid precursors, and, therefore, they should preferentially localize in the tumor. A series of 3-carboranlyalkyl thymidine analogs has been synthesized and a subset, designated N4, N5, and N7, and the corresponding 3-dihydroxypropyl derivatives, designated N4 -2OH, N5-2OH, and N7-2OH, have been selected for evaluation. Using these compounds as substrates for recombinant human thymidine kinase-1 and the mitochondrial isoenzyme thymidine kinase-2, the highest phosphorylation levels relative to thymidine were seen with N5 and the corresponding dihydroxypropyl analog N5-2OH. In contrast, N4, N4-OH, N7, and N7-OH had substantially lower phosphorylation levels. To compare compounds with high and low thymidine kinase-1 substrate activity, N5 and N7 and the corresponding dihydroxypropyl derivatives were selected for evaluation of their cellular toxicity, uptake and retention by the F98 rat glioma, human MRA melanoma, and murine L929 cell lines, all of which are thymidine kinase-1(؉), and a mutant L929 cell line that is thymidine kinase-1(؊). N5-2OH was the least toxic (IC 50 , 43-70 M), and N7 and N7-2OH were the most toxic (IC 50 , 18 -49 M). The highest boron uptake was seen with N7-2OH by the MRA 27 melanoma and L929 wild-type (wt) cell lines. The highest retention was seen with L929 (wt) cells, and this ranged from 29% for N5-2OH to 46% for N7. Based on the in vitro toxicity and uptake data, N5-2OH was selected for in vivo biodistribution studies either in rats bearing intracerebral implants of the F98 glioma or in mice bearing either s.c. or intracerebral implants of L929 (wt) tumors. At 2.5 hours after convection-enhanced delivery, the boron values for the F98 glioma and normal brain were 16.2 ؎ 2.3 and 2.2 g/g, respectively, and the tumor to brain ratio was 8.5. Boron values at 4 hours after convection-enhanced delivery of N5-2OH to mice bearing intracerebral implants of L929 (wt) or L929 thymidine kinase-1(؊) tumors were 39.8 ؎ 10.8 and 12.4 ؎ 1.6 g/g, respectively, and the corresponding normal brain values were 4.4 and 1.6 g/g, thereby indicating that there was selective retention by the thymidine kinase-1(؉) tumors. Based on these favorable in vitro and in vivo data, neutron capture therapy studies will be initiated using N5-2OH in combination with two non-cell cycle dependent boron delivery agents, boronophenylalanine and sodium borocaptate.

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Section: Introductionmentioning

confidence: 99%

Boron-Containing Nucleosides as Potential Delivery Agents for Neutron Capture Therapy of Brain Tumors

Barth¹,

Yang²,

Madhoun³

et al. 2004

Cancer Research

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“…Liao et al [8] first synthesized 5-dihydroxyboryluracil 3, via a halogen-metal exchange reaction on 5-bromo-2,4-dibenzyloxypyrimidine by boration, however the product could not be isolated and it was converted directly to 3 by hydrogenation. Schinazi and Prusoff [9] resynthesized 3 by operating at -95°C -85°C (Scheme 2) via α-oxyalkylboranes 2 [1], and then used 3 for synthesis of boron nucleoside 4.…”

Section: Methodsmentioning

confidence: 99%

Boranes in Organic Chemistry 1. α-Carbonylalkyl- and β-Oxyalkylboranes in Organic Synthesis

Dembitsky

Толстиков

Srebnik

2017

Eurasian Chem. Tech. J.

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This review is devoted to the synthesis of α-carbonylalkyl-and β-hydroxy-alkyl boranes and their use in organic synthesis. α-Carbonyl-alkylboranes include several heteroatomic compounds, in particular, [1.2.3]-diazaborinines, uracyl boronic acids, and [1.2.3.4]diaza-diboretes. The latter type has been obtained by the ketene aminoborations. The reactions of halogenboranes with diazoesters and sulfur ylides resulting in formation of α-carbonyl alkylborates containing diazofunction or ylide structural fragment are described. Amino and halogen boration of acetylenic acid esters was also used for the synthesis of α-carbonyl alkyl boranes. Reactions involving Cr-carbene complexes and acetylenic borone esters were presented for the synthesis of naphthoquinone boronic acids. The formation of amidoboranes by boration of dichloroacetanilides was remined. Boration of 4,8-dimethoxy-2-quinolone with trimethylborates leading to 2-quinolone-3-boronic acid was described. The common synthetic method to α-carbonyl alkyl boranes based on the hydroboration of acrylic acid derivatives was discussed. The results of enhydrazones hydroboration, leading to stable cyclic complexes have been mentioned. The interaction of α-bromoketones with trialkyl or dialkylboranes represents as a general synthetic method to α-carbonyl alkyl boranes. Synthetic approaches to β-hydroxy alkyl boranes are performed. The wide spread hydroboration of vinyl and allyl esters received a well-described attention. The hydroboration of cyclanone enol acetates, 3-keto-and 17-keto-steroids and cyclic allyl alcohol acetates was discussed. The results of aliphatic and alicyclic vinyl esters (including dihydrofuran derivatives) boralylation leading to β-hydroxy alkyl boranes have been envisaged. The synthesis of optically active β-hydroxy alkyl boranes using chiral borane hydrides was discussed. The heterocyclic boran dihydrides are obtained by the hydroboration of dihydropyranes, chromenes and flavenes. Borosilylation of allyl allenylic esters was also been envisaged. The synthetic scheme to optically active boranes and further optically active alcohols were presented. The problems of selectivity regularities in hydroboration reaction by intermolecular complex formations have been discussed.

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“…This method was previously used [6] for preparation of phenol from phenylbromide and trimethylborate with formation of phenylboronic acid as intermediate and for preparation of boronic analogue of cho-line [7]. An alternative synthesis previously used for preparation of boronic analogues of nucleosides and nucleic bases [8][9][10][11] consist in treating the halogenated substrate with n-buthyllithium in THF followed by addition of trimethylborate at -86 o C. Trimethylborate was prepared by standard procedures [12] from 95% 10 B-enriched or natural isotope abundance boric acid and methanol and recovered from the formed azeotrope.…”

Section: Boronationmentioning

confidence: 99%

A Facile High-Yield Synthesis of [10 B]-8-Dihydroxyboryl Harmine, a Potential Agent for Boron Neutron Capture Therapy

Sintas¹,

Macareno²,

Vitale³

2000

Molecules

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The resurgence of interest in Boron Neutron Capture Therapy (BNCT) as a treatment for malignant lesions has resulted in the synthesis of numerous boron compounds as candidates for clinical use. BNCT is a selective radiotherapy using boron-10 which absorbs thermal neutrons and releases high Linear Energy Transfer (LET) alpha particles by 10 B (n, α) 7 Li reaction. The alpha radiation kills cells in the range of 5-9 µm from the site of the α generation. Therefore, it is theoretically possible to kill tumor cells without affecting adjacent healthy tissues, if 10 B-compounds could be selectively deliv- . They have a well know brain distribution, so these compounds, labeled with 10 B are potential agents for BNCT. A general synthetic method has been developed for the rapid and efficient production of boronated Harmine. Results And Discussion IodinationThe methods for iodination have been used previously for indolealkylamine [4] and phenethylamines [4] using thallium trifluoroacetate as specific oxidizing agent of molecular iodine for iodination of aromatic compounds [5]. BoronationWe used the condensation of the Grignard reagent from 8-I-Harmine with trimethylborate. This method was previously used [6] for preparation of phenol from phenylbromide and trimethylborate with formation of phenylboronic acid as intermediate and for preparation of boronic analogue of cho-

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Boron-Substituted Pyrimidines

Cited by 47 publications

References 1 publication

Boron-Containing Nucleosides as Potential Delivery Agents for Neutron Capture Therapy of Brain Tumors

Boron-Containing Nucleosides as Potential Delivery Agents for Neutron Capture Therapy of Brain Tumors

Boranes in Organic Chemistry 1. α-Carbonylalkyl- and β-Oxyalkylboranes in Organic Synthesis

A Facile High-Yield Synthesis of [10 B]-8-Dihydroxyboryl Harmine, a Potential Agent for Boron Neutron Capture Therapy

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