3-Carboranyl Thymidine Analogues (3CTAs) and Other Boronated Nucleosides for Boron Neutron Capture Therapy (original) (raw)
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Nucleosides, Nucleotides and Nucleic Acids, 2001
Several N-3 substituted carboranyl Thd analogs were synthesized. These agents as well as some non-boronated nucleosides were evaluated in phosphoryl transfer assays with recombinant human TK1 and TK2. For some carboranyl thymidine analogs, TK1 phosphorylation rates approached 38% that of thymidine. Their in vitro cytotoxicty appeared to correlate with the TK1 levels in the tested cells. In some cases increased uptake in tumor cell nuclei compared with the surrounding cytoplasm was detected in vitro.
European Journal of Medicinal Chemistry, 2015
A library of sixteen 2 nd generation amino-and amido-substituted carboranyl pyrimidine nucleoside analogues, designed as substrates and inhibitors of thymidine kinase 1 (TK1) for potential use in boron neutron capture therapy (BNCT) of cancer, was synthesized and evaluated in enzyme kinetic-, enzyme inhibition-, metabolomic-, and biodistribution studies. One of these 2 nd generation carboranyl pyrimidine nucleoside analogues (YB18A [3]), having an amino group directly attached to a meta-carborane cage tethered via ethylene spacer to the 3-position of thymidine, was approximately 3-4 times superior as a substrate and inhibitor of hTK1 than N5-2OH (2), a 1 st generation carboranyl pyrimidine nucleoside analogue. Both 2 and 3 appeared to be 5′-monophosphorylated in TK1(+) RG2 cells, both in vitro and in vivo. Biodistribution studies in rats bearing intracerebral RG2 glioma resulted in selective tumor uptake of 3 with an intratumoral concentration that was approximately 4 times higher than that of 2. The obtained results significantly advance the understanding of the binding interactions between TK1 and carboranyl pyrimidine nucleoside analogues and will profoundly impact future design strategies for these agents.
Journal of Organometallic Chemistry, 1999
The development of boron compounds with the capacity for selectively targeting tumor cells would offer the potential for specifically destroying such cells using the capture reaction of the nonradioactive 10 B nuclide and thermal neutrons. The key problem is the development of compounds with the ability to discriminate between tumor cells and contiguous normal cells and to concentrate in the former at suitable concentration levels. One category of agents that has been explored is boron-containing nucleosides. Such recent structures have been biochemically converted in vitro to their corresponding nucleotides by the action of human thymidine kinase. These studies have attempted to correlate a compound's physiochemical properties with its biochemical attributes. Since only a fraction of cells are undergoing replication at any one time, requiring the need for nucleic acid precursors, such boron compounds must be only one component of a cocktail of agents that are targeting malignant cells. This presentation is selective, focusing on those boron-containing nucleosides that have been designed for studies with kinases.
Bioorganic & Medicinal Chemistry, 2006
Five novel 3-carboranyl thymidine analogues (3CTAs) were designed and synthesized for boron neutron capture therapy (BNCT) of cancer. Phosphorylation of all five 3CTAs was catalyzed by recombinant human thymidine kinase (hTK1) using adenosine triphosphate (ATP) as the phosphate donor. The obtained phosphorylation rates ranged from 4% to 64.5% relative to that of thymidine. The compound with the most favorable hTK1 binding properties had a k cat /K M value of 57.4% relative to that of thymidine and an IC 50 of inhibition of thymidine phosphorylation by hTK1 of 92 lM. Among the five synthesized 3CTAs, this agent had also the overall most favorable physicochemical properties. Therefore, it may have the potential to replace N5-2OH, the current lead 3CTA, in preclinical studies. An in silico model for the binding of this compound to hTK1 was developed.
Cancer Research, 2004
Thymidine analogs containing o-carboranylalkyl groups at the 3-position were screened as potential substrates for human thymidine kinase 1 (TK1), an enzyme that is selectively expressed in a variety of rapidly proliferating cells, including tumor cells. On the basis of previous studies, 12 of these were identified as potential delivery agents for boron neutron capture therapy, a therapeutic method used for the treatment of highgrade brain tumors. Compound 4 with a pentylene spacer between the o-carborane cage and the thymidine scaffold and compound 10, which has an additional dihydroxypropyl substituent at the o-carborane cage, were the best substrates for TK1 with k cat /K m values of 27% and 36% relative to that of thymidine, respectively. These compounds showed partial competitive inhibition for thymidine phosphorylation by TK1. Neither compound was a substrate of recombinant human thymidine phosphorylase nor were their respective 5-monophosphates substrates of 5-deoxynucleotidase 1, thereby indicating potential in vivo stability. The octanol/water partition coefficient for compound 10 was 2.09, suggesting that it has excellent physiochemical properties for crossing the blood brain barrier and penetrating brain tissue. The in vitro cytotoxic effect of the 12 analogs was moderate to low in mammalian cell cultures with IC 50 values between 10 and 160 mol/L. Compounds 4 and 10 were taken up selectively and retained by the murine fibroblast L929 cell line, in contrast to its TK1deficient variant. These findings suggest that compound 10 is a promising candidate for selective delivery of boron-10 to malignant cells, and additional in vivo studies are planned to evaluate it for boron neutron capture therapy of brain tumors.
Journal of Pharmacology and Experimental Therapeutics, 2013
3-[5-{2-(2,3-Dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5-2OH) is a first generation 3-carboranyl thymidine analog (3CTA) that has been intensively studied as a boron-10 (10 B) delivery agent for neutron capture therapy (NCT). N5-2OH is an excellent substrate of thymidine kinase 1 and its favorable biodistribution profile in rodents led to successful preclinical NCT of rats bearing intracerebral RG2 glioma. The present study explored cellular influx and efflux mechanisms of N5-2OH, as well as its intracellular anabolism beyond the monophosphate level. N5-2OH entered cultured human CCRF-CEM cells via passive diffusion, whereas the multidrug resistance-associated protein 4 appeared to be a major mediator of N5-2OH monophosphate efflux. N5-2OH was effectively monophosphorylated in cultured murine L929 [thymidine kinase 1 (TK1 1)] cells whereas formation of N5-2OH monophosphate was markedly lower in L929 (TK1-) cell variants. Further metabolism to the di-and triphosphate forms was not observed in any of the cell lines. Regardless of monophosphorylation, parental N5-2OH was the major intracellular component in both TK1 1 and TK1cells. Phosphate transfer experiments with enzyme preparations showed that N5-2OH monophosphate, as well as the monophosphate of a second 3-carboranyl thymidine analog [3-[5-(o-carboran-1yl)pentan-1-yl]thymidine (N5)], were not substrates of thymidine monophosphate kinase. Surprisingly, N5-diphosphate was phosphorylated by nucleoside diphosphate kinase although N5-triphosphate apparently was not a substrate of DNA polymerase. Our results provide valuable information on the cellular metabolism and pharmacokinetic profile of 3-carboranyl thymidine analogs.
Carboranyl thymidine analogues for neutron capture therapy
Chemical Communications, 2007
Neutron capture therapy (NCT) is a binary radio-chemotherapeutic modality for the treatment of cancer. A major focus of NCT-related research is the development of novel tumor-selective agents that serve as the chemical component in NCT. Thymidine analogues substituted with a boroncontaining carborane cluster at the N3 position, designated 3CTAs (3-carboranyl thymidine analogues), constitute one class of these new improved NCT agents. Their chemical, structural and biological properties are discussed in this Feature Article.
Synthesis and biological evaluation of 3′-Carboranyl thymidine analogues
Bioorganic & Medicinal Chemistry Letters, 2002
Boron neutron capture therapy (BNCT) is a chemoradio-therapeutic method for the treatment of cancer. It depends on the selective targeting of tumor cells by boron-containing compounds. One category of BNCT agents with potential to selectively target tumor cells may be thymidine derivatives substituted at the 3'-position with appropriate boron moieties. Thus, several thymidine analogues were synthesized with a carborane cluster bound to the 3'-position either trough an ether-or a carbon linkage. The latter are the first reported carborane-containing nucleosides in which the carboranyl entity is directly linked to the carbohydrate portion of the nucleoside by a carbon-carbon bond. Low but significant phosphorylation rates in the range of 0.1 -8 % that of thymidine were observed for the carbon-linked 3'-carboranyl thymidine analogues in phosphoryl transfer assays using recombinant preparations of thymidine kinases 1 (TK1) and thymidine kinases 2 (TK2). Some of the ether-linked 3'-carboranyl thymidine analogues appeared to be slightly unstable under acidic as well as phosphoryl transfer assay conditions and were, if at all, poor substrates for TK1.
Thymidine conjugates containing metallacarborane, {8-[5-(N3-thymidine)-3-oxa-pentoxy]-3-cobalt bis(1,2-dicarbollide)} (5) and {8-[5-(O4-thymidine)-3-oxa-pentoxy]-3-cobalt bis(1,2-dicarbollide)} (6) ions and several simple [3-cobalt bis(1,2- dicarbollide)] ion (1) derivatives have been studied as potential boron carriers for BNCT. Compound 6 and some nonnucleoside derivatives of 1 were not toxic above 100 lM. The partition coefficient for both metallacarborane bearing thymidine conjugates 5 and 6 was more than 500 times higher than that of unmodified nucleoside. The cellular uptake studies showed accumulation of compounds 6 in V79 Chinese hamster cells but not of compound 5. The low toxicity of conjugate type of 6 together with its high partition coefficient suggest that judicially designed derivatives of metallacarboranes can be considered as potential boron carriers for BNCT.
The formulation of polyhedral boranes for the boron neutron capture therapy of cancer
Drug Discovery Today
The early promise of boron neutron capture therapy as a method for the treatment of cancer has been inhibited by the inherent toxicity associated with therapeutically useful doses of 10 B-containing pharmacophores, the need for target-tissue specificity and the challenges imposed by biological barriers. Although developments in the synthetic chemistry of polyhedral boranes have addressed issues of toxicity to a considerable extent, the optimisation of the transport and the delivery of boronated agents to the site of action -the subject of this review -is a challenge that is addressed by the development of innovative formulation strategies.