Modular Synthetic Approach to Carboranyl‒Biomolecules Conjugates

The development of novel, tumor-selective and boron-rich compounds as potential agents for use in boron neutron capture therapy (BNCT) represents a very important field in cancer treatment by radiation therapy. Here, we report the design and synthesis of two promising compounds that combine meta-carborane, a water-soluble monosaccharide and a linking unit, namely glycine or ethylenediamine, for facile coupling with various tumor-selective biomolecules bearing a free amino or carboxylic acid group. In this work, coupling experiments with two selected biomolecules, a coumarin derivative and folic acid, were included. The task of every component in this approach was carefully chosen: the carborane moiety supplies ten boron atoms, which is a tenfold increase in boron content compared to the l-boronophenylalanine (l-BPA) presently used in BNCT; the sugar moiety compensates for the hydrophobic character of the carborane; the linking unit, depending on the chosen biomolecule, acts as the connection between the tumor-selective component and the boron-rich moiety; and the respective tumor-selective biomolecule provides the necessary selectivity. This approach makes it possible to develop a modular and feasible strategy for the synthesis of readily obtainable boron-rich agents with optimized properties for potential applications in BNCT.     

BNCT蒙特卡洛剂量计算的混合网格算法研究

在硼中子俘获治疗(BNCT)的蒙特卡洛(MC)剂量计算中,通常使用单一的网格模式,如16mm,8mm,4mm.使用细网格计算资源太大,使用粗网格,计算精度不够,为此,根据粒子穿透深度和计数量的变化梯度,采用混合网格模拟计算,达到了细网格的精度,时间仅为细网格的37%.     

BNCT优化网格设计及相关算法研究

用MCNP蒙特卡罗程序模拟了硼中子俘获治疗(BNCT)3种国际基准网格模型, 并与 修正的Snyder椭球模型进行了比较. 在此基础上, 给出了一种保质量守恒、内存量少、易于产生输入文件的4种基本材料成分的BNCT网格模型. 计算结果表明, 在4mm网格下, 新模型可以达到基准模型的精度; 根据解析模型剂量随深度的变化规律, 研究构造了多网格组合模型, 在重要区域计算精度不损失的条件下, 计算时间大大缩短. 最后研究给出了一个既保证精度、又在可接受的时间内完成剂量计算的模型、样本数和相应的算法, 它基本上满足临床BNCT的要求.     

Synthesis and X-ray structural characterisation of the tetramethylene oxonium derivative of the hydrodecaborate anion. A versatile route for derivative chemistry of [B10H10]

The oxonium derivative P(C₆H₅)₄[2-B₁₀H₉O(CH₂)₄] (1) has been prepared from [B₁₀H₁₀]²⁻ by a solvent-addition reaction route, promoted by Et₂O · BF₃. Its structure has been confirmed by single crystal X-ray analysis. 1 is assumed to be a useful synthon for the derivative chemistry of [B₁₀H₁₀]²⁻. As an illustration, ring-opening reaction occurred in presence of the strong nucleophilic agent OH⁻, giving the monoanionic derivative [P(C₆H₅)₄]₂[2-B₁₀H₉O(CH₂)₄OH] (2).     

Nido-carborane encapsulated by BODIPY zwitterionic polymers: Synthesis,photophysical properties and cell imaging

Carborane encapsulation was visualized by using fluoroboropyrrole (BODIPY) zwitterionic polymer as fluorescence marker. Firstly, a water-soluble fluorescent probe carrier was prepared by combining the BODIPY derivatives with poly (carboxybetaine methacrylate) (p-CBMA). Two oil-in-water carborane polymers were self-assembled in organic solvents by means of dual ion hydrogen bonding. The ultraviolet and fluorescence spectra were measured with different organic solvents, and the spectra ranged from 531 to 555 nm. The dynamic self-assembly effect was tested by TEM, and the internal microscopic phenomena of the water-soluble polymer were further observed. It was confirmed that two kinds of BODIPY zwitterionic polymers were firmly encase the fat-soluble carborane, forming an oval shape. Carboranes are water-soluble, can achieve biocompatible expression, and can visualize the degree of aggregation in the targeted cells through its own fluorescence effect. Subsequent imaging of the cells showed that both polymers entered the targeted cells.     

Novel types of boronated chlorin e6 conjugates via ‘click chemistry’

Conjugates of chlorin e₆ with closo‐dodecaborate and cobalt bis(dicarbollide) anions were synthesized for the first time in high yields using the advanced ‘click’ methodology. In vitro study on A549 human lung adenocarcinoma cells revealed that the synthesized boronated conjugates are able to penetrate and accumulate in cancer cells, but their intracellular concentration is not sufficient for effective photodynamic and boron neutron capture therapy of cancer. Copyright © 2009 John Wiley & Sons, Ltd.     

Synthesis and properties of cobaltacarborane-functionalized Zn(II)-phthalocyanines

The syntheses of two new A₃B-type Zn(II)-phthalocyanines (Zn-Pcs) containing either one or two cobaltacarborane residues are reported, and the X-ray structure of a key phthalonitrile precursor is presented. The Zn-Pcs are highly soluble and exist as monomers in polar organic solvents.     

Water-soluble phosphonium salts containing 1,12-dicarba-closo-dodecaborane(12)

The preparation of new water-soluble phosphonium salts containing 1,12-dodeca-closo-dodecaborane(12) (closo-1,12-carborane) for potential use as tumor-targeting agents in Boron Neutron Capture Therapy (BNCT) is described.     

Nucleoside-boron cluster conjugates - Beyond pyrimidine nucleosides and carboranes

General methods for the synthesis of new purine and pyrimidine nucleosides modified with borane clusters and metallacarborane complexes are presented. They include: (1) attachment of carborane modification at 2′ position of nucleoside via formacetal linkage formation, (2) tethering of the metallacarborane group at nucleobase part of the nucleoside via dioxane ring opening in oxonium metallacarborane, carborane or dodecaborate derivatives, and (3) ‘‘click” chemistry approach based on Huisgen 1,3-dipolar cycloaddition. Proposed methodologies extend the range of nucleoside-boron cluster conjugates available and open new areas for their applications.     

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.