Modular Synthetic Approach to Carboranyl‒Biomolecules Conjugates

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.

Tumor Cell-Specific 2′-Fluoro RNA Aptamer Conjugated with Closo-Dodecaborate as A Potential Agent for Boron Neutron Capture Therapy

“…The only boron compounds clinically used for BNCT are boronophenylalanine (BPA) and sodium borocaptate (BSH), so-called second-generation boron delivery agents. In 2020, the Stella Pharma company marketed Steboronine ® drug (BPA as its D-sorbitol complex) for the treatment of head and neck cancer [ 6 , 7 ]. The pharmacokinetics and biodistribution of BSH and BPA are far from ideal, and one of their most prominent problems is the significant variability of tumor uptake [ 8 ].…”

New Boron Delivery Agents

“…1,2,37,38,39 They have devised efficient syntheses for novel boron compounds, which provide a combined tumour-targeting system: carborane-containing amino acids and carboxylic acids for incorporation in suitable peptides. 38,39,40,41,42 The first tumorselective peptide-carborane conjugates prepared comprised closo-carborane-modified neuropeptide Y analogs 43,44 or metallacarborane derivatives; 45 another approach was the incorporation of meta-carboranes in novel ghrelin receptor agonists. 37 However, a very high carborane loading (more than two carborane clusters attached to a peptide including 36 amino acids) resulted in loss of solubility or aggregation in aqueous media, resulting in decreased potency and higher EC50 values.…”

Sweet Boron: Boron-Containing Sugar Derivatives as Potential Agents for Boron Neutron Capture Therapy

“…The reaction of α-D-galactopyranose 6-triflate 36 with glycine t-butyl ester or with mono-Boc-ethylenediamine gave derivatives 40 and 43. Compounds 42 and 45 were further derivatized with 7-amino-4-methylcoumarin and with folic acid, respectively, which are two selected biomolecules that play roles in cancer treatment [52].…”

“…Starting from a previously proposed approach [53], the same group exploited cyanuric chloride 46 and 9-mercapto-meta-carborane 47, which has a highly nucleophilic thiol group, as a platform to quickly generate compounds with chemical diversity and high boron loading. Compounds 42 and 45 were further derivatized with 7-amino-4-methylcoumarin and with folic acid, respectively, which are two selected biomolecules that play roles in cancer treatment [52].…”

“…Synthesis of sugar-carborane building blocks for peptides conjugation. Alkylation of 40 and 43 with 1-(trifluoromethanesulfonylmethyl)-meta-carborane followed by removal of t-butyl groups eventually furnished carboxy-and amino-functionalized products 42 and 45.Compounds 42 and 45 were further derivatized with 7-amino-4-methylcoumarin and with folic acid, respectively, which are two selected biomolecules that play roles in cancer treatment[52].Starting from a previously proposed approach[53], the same group exploited cyanuric chloride 46 and 9-mercapto-meta-carborane 47, which has a highly nucleophilic thiol group, as a platform to quickly generate compounds with chemical diversity and high boron loading.After an initial demonstration of the synthetic feasibility, two units of 9-mercaptometa-carborane and some simple nucleophiles (Scheme 8) were introduced on a triazine core[54].…”