Novel carboranyl C-glycosides for the treatment of cancer by boron neutron capture therapy

The synthesis of the novel unprotected carboranyl C-glycosides 2 and 20-24 starting from ethynyl C-glycosides 1, 5-8, 10, and 13 is described. The new compounds are highly water-soluble and display only a very low cytotoxicity, which makes them promising candidates for use in boron neutron capture therapy for the treatment of cancer.     

Synthesis of a porphyrin-labelled carboranyl phosphate diester: a potential new drug for boron neutron capture therapy of cancer

A boron-rich, water-soluble porphyrin conjugate was synthesized by coupling of two carboranyl alcohols with 2-chlorophenoxyphosphorus dichloride, followed by conjugation to an amine-functionalized tetraphenyl-porphyrin via an amide linkage.     

Depth dose evaluation for prostate cancer treatment using boron neutron capture therapy

Considering the advantages of boron neutron capture therapy (BNCT) in treating prostate cancer, the amount of dose delivered to tumour and healthy tissues must be determined. Therefore, in this study, Monte Carlo analyses were performed to evaluate physical doses of adjacent healthy tissues and prostate tumours located at different depths of reference phantom developed by International Commission on Radiological Protection. According to the results, when prostate depth decreases, the amount of physical dose in tumour increases but the physical doses of healthy organs around the tumour remain constant. As expected, lithium filter decreases the damages to normal tissues. The estimations of physical dose, dose uniformity and dose distribution suggested that using BNCT with a filtered neutron beam could be applicable for prostates locate at the depths less than 7 cm from the body surface, which occurs in 5 % of all subjects.     

Azanonaboranes containing imidazole derivatives for boron neutron capture therapy: synthesis, characterization, and in vitro toxicity evaluation

A number of azanonaboranes containing imidazole derivatives have been synthesized by a ligand-exchange reaction. The exo-NH(2)R group of the azanonaborane of the type [(RH(2)N)B(8)H(11)NHR] can be exchanged by one hetero-nitrogen atom of the imidazole ring. In the case of histamine, the exchange takes place on the aliphatic amino group, the hetero-nitrogen atom of the imidazole ring or both of them. The products were confirmed by NMR, IR spectroscopy, elemental analysis, and mass spectrometry. The electron-withdrawing effect of the nitro group in 2-nitroimidazole is the main hindrance to achieve the exchange reaction. In vitro experiments were performed with B16 melanoma cells. A comparison of the biological properties of the products in which the B(8)N cluster is connected to the hetero-nitrogen atom of imidazole ring or the aliphatic NH(2) group showed that incorporation of B(8)N cluster unit into primary amino group increases the compound's toxicity. In contrast, this specificity for cytotoxicity effect was not observed in the case of histamine containing two B(8)N clusters which was relatively nontoxic and did not inhibit colony formation up to concentrations of 2 mM.     

Novel glycosylated carboranylquinazolines for boron neutron capture therapy of tumors: synthesis,characterization, and in vitro toxicity studies

The synthesis of a series of N‐glycosyl caboranylquinazolines is described. The condensation reaction of nitro‐acetylanthranilic acid with aminophenylcarborane gave 3‐[(o‐carboran‐1‐yl)phenyl]‐2‐methyl‐6‐nitroquinazolin‐4(3H)‐one 1 followed by reduction with Na₂S to the corresponding 6‐amino‐3‐[(o‐carboran‐1‐yl)phenyl]‐2‐methylquinazolin‐4(3H)‐one 2 . Reaction of compound 2 with D‐glucose or D‐ribose in methanol in the presence of a catalytic amount of acetic acid affords boronated N‐glycosylaminoquinazolines namely: 2‐methyl‐3‐[4‐(o‐carboran‐1‐yl)phenyl]‐6‐[N‐β‐D‐glucopyranosyl)]aminoquinazolin‐4(3H)‐one 3 or 2‐methyl‐3‐[4‐(o‐carboran‐1‐yl)phenyl]‐6‐[N‐β‐D‐ribofuranosyl)]aminoquinazolin‐4(3H)‐one 4 , respectively. Degradation of the o‐caborane cage of compounds 3 and 4 yielded highly water‐soluble compounds of sodium 2‐methyl‐3‐[4‐( nido ‐undecarborate‐1‐yl)phenyl]‐6‐[N‐β‐D‐glucopyranosyl]aminoquinazolin‐4(3H)‐one 5 and sodium 2‐methyl‐3‐[4‐( nido ‐undecarborate‐1‐yl)phenyl]‐6‐[N‐β‐D‐ribofuranosyl)]aminoquinazolin‐4(3H)‐one 6 , respectively. The structures were established on the basis of elemental analysis, NMR, IR and mass spectrometry. The in vitro toxicity test using B16 melanoma cells showed that N‐glycosyl of nido ‐undecaboranylquinazolines ( 5 and 6 ), with higher water solubility, is not toxic at boron concentration of 3000 µg boron ml⁻¹, whereas, N‐glycosyl of closo ‐carboranylquinazolines ( 3 and 4 ) has LD₅₀ > 200 µg boron ml⁻¹. The compounds described here may be considered as potential agents for BNCT. Copyright © 2008 John Wiley & Sons, Ltd.     

Design and synthesis of fluorescence-labeled closo-dodecaborate lipid: its liposome formation and in vivo imaging targeting of tumors for boron neutron capture therapy

The fluorescence-labeled closo-dodecaborane lipid (FL-SBL) was synthesized from (S)-(+)-1,2-isopropylideneglycerol as a chiral starting material. FL-SBL was readily accumulated into the PEGylated DSPC liposomes prepared from DSPC, CH, and DSPE-PEG-OMe by the post insertion protocol. The boron concentrations and the fluorescent intensities of the FL-SBL-labeled DSPC liposomes increased with the increase of the additive FL-SBL, and the maximum emission wavelength of the liposomes appeared at 531 nm. A preliminary in vivo imaging study of tumor-bearing mice revealed that the FL-SBL-labeled DSPC liposomes were delivered to the tumor tissue but not distributed to hypoxic regions.     

Dodecaborate cluster lipids with variable headgroups for boron neutron capture therapy: Synthesis, physical-chemical properties and toxicity

We have prepared two new boron-containing lipids with potential use in boron neutron capture therapy of tumors. These lipids consist of a diethanolamine frame with two myristoyl chains bonded as esters, and a butylene or ethyleneoxyethylene unit linking the doubly negatively charged dodecaborate cluster to the amino function of the frame, obtained by nucleophilic attack of the amino on the tetrahydrofurane and dioxane derivatives, respectively, of closo-dodecaborate. The latter cluster lipid can form liposomes at 25 °C whereas the former lipid at this temperature assembles into bilayer disks. Both lipids form stable liposomes when mixed with suitable helper lipids. The thermotropic behavior was found to be different for the two lipids, with the butylene lipid showing sharp melting transitions at surprisingly high temperatures. Toxicity in vitro and in vivo varies greatly, with the butylene derivative being more toxic than the ethyleneoxyethylene derivative.     

Synthesis of dodecaborate-conjugated cholesterols for efficient boron delivery in neutron capture therapy

Dodecaborate-conjugated cholesterols 3a-c were synthesized for liposomal boron delivery systems in neutron capture therapy. The current synthesis is based on the S-alkylation protocol of the cyanoethyl-protected BSH with alkyl halides. The dodecaborate-conjugated cholesterol 3a liposome, which was prepared from dimyristoylphosphatidylcholine (DMPC), cholesterol, dodecaborate-conjugated cholesterol 3a, and polyethyleneglycol-conjugated distearoylphosphatidylethanolamine (PEG-DSPE) (1:0.5:0.5:0.1), exhibited higher cytotoxicity than BSH at the same boron concentration and IC₅₀ values of the 3a liposome and BSH toward colon 26 cells were estimated as 25 and 78 ppm of boron concentration, respectively.     

Synthesis and characterization of a novel functionalized azanonaborane cluster for boron neutron capture therapy

The reactivity of an azanonaborane cluster containing free amino groups {H2N(CH2)4H2NB8H11NH(CH2)4NH2} towards ketones and aldehydes is investigated. In a one step reaction, the reductive amination of some ketones and aldehydes (namely acetone, benzaldehyde, 3-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 4-nitrobenzaldehyde, 4-acetoxybenzaldehyde, and 4-acetamidobenzaldehyde) with an azanonaborane cluster in the presence of H3BNH2(CH2)4NH2 gives monoalkylamino derivatives of the azanonaborane cluster {RHN(CH2)4H2NB8H11NH(CH2)4NHR} where (R =(Me)2CH-, C6H5CH2-, 3-OHC6H4CH2-, 4-OHC6H4CH2-, 4-NO2C6H4CH2-, 4-MeOCOC6H4CH2-, or 4-NH2COC6H4CH2-). The functionalized derivatives of the {B8N} cluster can be used in boron neutron capture therapy for tumors (BNCT). Similarly, the reductive amination of 5-(4"-formylphenyl)-10,15,20-triphenylporphyrin with the {B8N} cluster gave a porphyrin bearing azanonaborane cluster, while a porphyrin dimer linked by an azanonaborane moiety was obtained following the same method, starting with a 2:1 molar ratio of porphyrin:{B8N} cluster. 5,10,15,20-Tetraformylphenylporphyrin gave the chance to increase the percentage of boron in the resulting boronated porphyrin, which is considered an important factor for a BNCT delivery agent. With these compounds, the cell toxicity using V79 cells was carried out to determine whether these compounds would have favorable biological properties.     

Synthesis and vesicle formation of a nido-carborane cluster lipid for boron neutron capture therapy

The nido-carborane lipid, which has a double-tailed moiety, was synthesized from heptadecanol in 5 steps. Analysis in a transmission electron microscope by negative staining with uranyl acetate showed that the lipid formed a stable vesicle in which calcein was encapsulated. The lipid was incorporated into distearoylphosphatidylcholine (DSPC) liposomes at a very high concentration.     

Closomers of high boron content: synthesis, characterization, and potential application as unimolecular nanoparticle delivery vehicles for boron neutron capture therapy

Unique nanosized closomers of high boron content that may exhibit potential as boron neutron capture therapy target species have been synthesized. The design of these boron-rich nanospheres is based in part on previous work involving dodeca(carboranyl)-substituted closomers [Thomas, J.; Hawthorne, M. F. Chem. Commun. 2001, 1884-1885]. Coupling of ortho-carborane moieties through ester and ether linkages to the rigid [closo-B(12)(OH)(12)](2-) scaffold resulted in the development of a 12(12)-closomer-ester derivative, dodeca[6-(1,2-dicarba-closo-dodecaboran-1-yl)hexanoate]-closo-dodecaborate (2-), 6, and 12(12)-closomer-ether derivatives, dodeca[6-(2-methy1-1,2-dicarba-nido-dodecaboran-1-yl)hexyl]-closo-dodecaborane (14-), 14, and dodeca[6-(7,8-dicarba-nido-dodecaboran-7-yl)hexyl]-closo-dodecaborane (14-), 15. These closomers were investigated by UV-visible spectroscopy and cyclic voltammetry. Additionally, a deboronation method employing NaCN as the nucleophilic reagent was utilized to obtain sodium salts of the ether-linked nido-closomer polyanions, which were purified using a newly developed size-exclusion high pressure liquid chromatography method.     

10B quantitative determination in ppb range by particle tracks reading for boron neutron capture therapy

Quantitative determination of ppb-order ¹⁰B was carried out in a small number of cultured tumor cells by particle tracks by the ₁₀B(n,)⁷Li reactions using solid state nuclear track detector (SSNTD) for boron neutron capture therapy research. The detection limit of ¹⁰B concentration in tumor cells is less than 1·10^-3 ppm under our experimental conditions which permits the quantitative determination of ¹⁰B in a small number of boronated tumor cells (10⁵/ml = ca. 0.1 mg). Boron quantities in tumor cells determined were well compatible with the tumor cell killing effects of boron neutron capture therapy.     

Novel carboranylporphyrins for application in boron neutron capture therapy (BNCT) of tumors

Condensation of a new carboranylpyrrole 1 with benzaldehydes leads to β-carboranylporphyrins 2 and 3 in good yields. These new porphyrins of high boron content (32-43%) have potential as boron delivery agents for BNCT. The X-ray structures of one β-carboranylporphyrin, of a carboranylpyrrole, and of a side-product are presented.     

Liposomes loaded with lipophilic derivative of closo-carborane as a potential boron delivery system for boron neutron capture therapy of tumors

Liposomes encapsulated with lipophilic derivative of 1,2-dicarba-closo-dodecaborane have been obtained and tested for toxicity to glioblastoma U87 cells and biodistribution on a U87MG xenograft mouse model. The liposomes are able to penetrate the tumor and provide boron concentration up to 1.5 mmmmg g–1 with tumor-to-muscle ratio up to 2.4.     

硼中子俘获治疗肿瘤的研究 I. 合成硼化核酸的几种化学方法

本文以小牛胸腺DNA和酵母TRNA为载体, 对核酸与硼笼化物的几种偶联方法进行了研究结果表明, 活化后的核酸通过交联剂MBS和DCCI分别能与Na2B12H11SH和(Et4N)2B1OH9R相偶联, 找到了反应条件温和, 偶联程度较高的合成方法。     

Conjugates of polyhedral boron compounds with carbohydrates. 1. New approach to the design of selective agents for boron neutron capture therapy of cancer

Russian Chemical Bulletin -     

Design of multivalent galactosyl carborane as a targeting specific agent for potential application to boron neutron capture therapy

A multivalent galactosyl carborane derivative 10 (dendritic glyco-borane, DGB) was synthesized and demonstrated as a potential cell-targeting agent in BNCT with HepG2 cells. DGB 10 improved the delivery of boron to HepG2 cells and neutron irradiation data show DGB 10 with ten-fold improvement at killing the HepG2 cells over BSH.