Abstract
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.
Highlights
Since boron neutron capture therapy (BNCT) was ascertained to be a very promising binary cancer treatment [1,2,3,4], research has focused on the development of potent and selective boron-containing drugs [5,6]
The synthetic procedures of Goto and co-workers for the synthesis of 1-(hydroxymethyl)-1,7-dicarba-closo-dodecaborane(12) [57]. Those of Kalinin and co-workers for the preparation of 1-(trifluoromethanesulfonylmeth yl)-1,7-dicarba-closo-dodecaborane(12) [58] were employed. 1,2:3,4-Di-O-isopropylidene-αD-galactopyranose is commercially available or can be prepared in quantitative yield according to a procedure described by Saltan and co-workers [59]. 1,2:3,4-Di-O-isopropylideneα-D-galactopyranose was converted to the triflate 1,2:3,4-di-O-isopropylidene-6-deoxyα-D-galactopyranosyl-6-triflate following a procedure described by Brackhagen and coworkers [60]
The reaction with the galactopyranosyl moiety was conducted under basic conditions using N,N-diisopropylethylamine (DIPEA) as a base in acetonitrile (MeCN) at elevated temperature (Scheme 1a,b)
Summary
Since boron neutron capture therapy (BNCT) was ascertained to be a very promising binary cancer treatment [1,2,3,4], research has focused on the development of potent and selective boron-containing drugs [5,6]. Activation of the BNCT agents is caused by irradiation with thermal neutrons [13,14] for which 10 B exhibits a large capture cross section (3835 barn, 1 barn = 1 × 10−24 cm2 ) [9] This renders BNCT a promising strategy to treat malignant tissue with tumor-selective boron-containing drugs [6,15,16,17,18,19,20], as the thermal neutron beam can be focused on the affected area [21,22,23,24], generating therapeutic particles only upon neutron irradiation. Normal tissue can be spared and severe side effects, as known from pure radiotherapy or systemic effective chemotherapy, can be reduced
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