Modular triazine-based carborane-containing carboxylic acids – synthesis and characterisation of potential boron neutron capture therapy agents made of readily accessible building blocks

Abstract

Boron-rich carboxylic acid derivatives were synthesised as coupling partners for tumour-selective biomolecules with applications as selective BNCT agents.

Tuning a modular system – synthesis and characterisation of a boron-rich s-triazine-based carboxylic acid and amine bearing a galactopyranosyl moiety

“…Based on the synthetic procedures described in our previous work, [4,6-bis(1,7-dicarba-closo-dodecaboran-9-ylthio)-1,3,5triazin-2-yl]glycine (3) was prepared from glycine and 2-chloro-4,6-bis(1,7-dicarba-closo-dodecaboran-9-ylthio)-1,3,5-triazine (2), which was synthesised from 9-mercapto-(1,7-dicarba-closododecaborane) (12) (1) and cyanuric chloride. 27,35 The following step involved the base-assisted introduction of the monosaccharide moiety as 1,2:3,4-di-O-isopropylidene-6-deoxy-α-Dgalactopyranosyl-6-triflate (4), prepared from 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (Scheme 1, step c). 36 A protection strategy is required also to retain the monosaccharide as the α anomer.…”

“…The observation of hydrogen bonds was already described for compounds of this substance class. 27 Compound 11 crystallised from chloroform solution with two molecules in the asymmetric unit ( Fig. 3).…”

“…The necessity for increased hydrophilicity was concluded from previous studies concerning the introduction of meta-carboranes as single clusters 17 or s-triazine-based derivatives bearing no monosaccharide group. 27 Three different peptide conjugates were synthesised (Fig. 5A) by a combination of automated and manual solid phase peptide synthesis (SPPS).…”

“…13,[17][18][19]25,26 Recently, we reported the synthesis of s-triazine-based boron-rich carboxylic acids. 27 Preliminary studies showed that the incorporation of more than one s-triazine-based bis(carboranyl) derivative into the breast tumour-selective peptide [F 7 ,P 34 ]-neuropeptide Y leads to a decrease or even total loss of the hY 1 receptor activation potency. It was assumed that this was caused by the strong hydrophobic character of the carborane clusters attached to the peptide producing a hydrophobic collapse of the bioconjugate.…”

Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

“…[ 268 ] [F 7 ,P 34 ]‐NPY conjugates with a maximized boron loading were also developed. [ 269,270 ] A galactosyl‐ meta‐ carborane facilitated the generation of a peptide with eight incorporated carborane clusters, that is, 80 boron atoms per peptide molecule. The boron‐rich conjugate exhibited high activation and internalization of the hY 1 R, selectivity against the other hYR subtypes, and low intrinsic cytotoxicity.…”