Design, Synthesis and Biological Evaluation of Boron‐Containing Macrocyclic Polyamine Dimers and Their Zinc(II) Complexes for Boron Neutron Capture Therapy

Abstract

Boron neutron capture therapy (BNCT) is considered to have potential for cancer therapy based on the nuclear reaction between boron ( 10 B) atoms and thermal neutrons, yielding 4 He 2 + (α) and 7 Li 3 + ions. These heavy particles induce the destruction of biomolecules within short path length of 5-9 μm, resulting in a limited cytotoxic effect to 10 B-containing cells. Herein, we report on the design and synthesis of DNA-targeting BNCT agents equipped with homo-and hetero-dimeric macrocyclic polyamine units and their Zn 2 + complexes. It was hypothesized that the dizinc(II) complexes of these ligands would recognize two adjacent thymidines (thymidyl(3'-5')thymidine), resulting in an efficient contact with DNA and an efficient breakdown of DNA upon thermal neutron irradiation. To test this hypothesis, we performed a DNA interaction study and a biological evaluation such as cytotoxicity and intracellular uptake activity using cancer and normal cells. BNCT experiments utilizing the corresponding 10 B-enriched compounds were also conducted.

Advances in the synthesis and applications of macrocyclic polyamines

“…The synthesis of reactive 10 B derivatives plays a crucial role in boron neutron capture therapy, as it enables the nuclear reactions between 10 B-containing molecules and thermal neutrons, resulting in the release of α particles and lithium atoms that effectively eradicate tumour cells. In this context, Ueda et al [129] successfully designed and synthesized borate-modified [9]aneN 3 , [12]aneN 4 and [15]aneN 5 derivatives by linking the borate ester and polyamine through a benzene ring. Their studies demonstrate the high selectivity of single or dual-protonated [12]aneN 4 -and [15]aneN 5 -10 B derivatives for uptake by A549 cells, where they effectively induce cell death through reaction with thermal neutrons upon interaction with zinc ions.…”

“…In this context, Ueda et al . [ 129 ] successfully designed and synthesized borate-modified [9]aneN 3 , [12]aneN 4 and [15]aneN 5 derivatives by linking the borate ester and polyamine through a benzene ring. Their studies demonstrate the high selectivity of single or dual-protonated [12]aneN 4 - and [15]aneN 5 - 10 B derivatives for uptake by A549 cells, where they effectively induce cell death through reaction with thermal neutrons upon interaction with zinc ions.…”

Design, Synthesis, and Biological Applications of Boron-Containing Polyamine and Sugar Derivatives

“…In this context, we designed and synthesized some novel DNA-targeting BNCT agents containing macrocyclic polyamine scaffolds such as [9]aneN 3 , [12]aneN 4 , and [15] aneN 5 and their Zn 2+ complexes, which contain phenylboronic acid units, as shown in Figures 17 and 18 [55,56]. It was assumed that these boron-containing macrocyclic polyamine monomers 44-49 (L 6 -L 12 ) and their Zn 2+ complexes 50-52 (ZnL 6 -ZnL 12 ) would be efficiently transferred into cancer cells and that thermal neutron irradiation would induce effective DNA damage in cancer cells due the 10 B atoms being located in close proximity to DNA molecules (Figure 17).…”