In vivo polymerization of the dopamine-borate melanin precursor: A proof-of-concept regarding boron neutron-capture therapy for melanoma

Abstract

The 10 boron neutron-capture therapy (BNCT) is an emerging antitumoral method that shows increasing biomedical interest. BNCT is based on the selective accumulation of the 10 boron isotope within the tumor, which is then irradiated with low-energy thermal neutrons, generating nuclear fission that produces 7 lithium, 4 helium, and γ rays. Simple catechol-borate esters have been rather overlooked as precursors of melanin biosynthesis, and therefore, a proof-of-concept approach for using dopamine-borate (DABO) as a suitable boron-containing candidate for potential BNCT is presented here. DABO can spontaneously oxidize and autopolymerize in vitro, giving a soluble, eumelaninlike brown-black poly-DABO product. Melanotic melanoma cell cultures treated with 1 mM DABO for 24 and 48 h were viable and showed no signs of damage or cell death. The stability and possible trans-esterification of DABO is shortly discussed. Chemical calculations and quantitative structure-activity relationships (QSAR) analysis of DABO and the BNCT agent BPA indicated that they should be cell permeant and accumulate within lysosomes and melanosomes. Molecular modeling allows visualization of both the DABO precursor and the structure of a borate derivative of the proposed catechol-porphycene model for eumelanin, showing interesting features from molecular orbital calculations. The main difference between DABO and other agents, such as BPA, is that it is not a boronic acid nor a boron cluster. This simple catechol-borate ester (protected from oxidation and blackening) could be administrated to living cells and organisms, in which biosynthesis of boron-melanin in melanoma melanocytes can lead to improved BNCT.

Diphenyl-Furanones and Diphenyl-Oxopyrrole Derivatives: From Analytical Reagents for Amino Groups to New Fluorochromes for Cytochemical Staining of Chromatin DNA and Chromosomes: Proposal for Intercalative Binding and Fluorescence Mechanism

“…Regarding molecular orbitals of diPOPy-H (Figure 7B), energy levels of higher occupied and lower unoccupied molecular orbitals (HOMO-0 and LUMO + 0, respectively) are well separated (LUMO + 0 subtracted from HOMO-0 = Eg = 6.01 eV), which is related to the large Stokes shift and a blue-green emission under UV excitation. As expected, the number of nodal planes is higher for LUMO + 0 than for HOMO-0 [36,40].…”

“…Regarding molecular orbitals of diPOPy-H (Figure 7B), energy levels of higher occupied and lower unoccupied molecular orbitals (HOMO-0 and LUMO + 0, respectively) are well separated (LUMO + 0 subtracted from HOMO-0 = Eg = 6.01 eV), which is related to the large Stokes shift and a blue-green emission under UV excitation. As expected, the number of nodal planes is higher for LUMO + 0 than for HOMO-0 [36,40]. Regarding molecular orbitals of diPOPy-H (Figure 7B), energy levels of higher occupied and lower unoccupied molecular orbitals (HOMO-0 and LUMO + 0, respectively) are well separated (LUMO + 0 subtracted from HOMO-0 = Eg = 6.01 eV), which is related to the large Stokes shift and a blue-green emission under UV excitation.…”

“…Amino derivatives from MDPF were prepared from the amino compounds BA, GA, and Sp using well-known synthetic procedures [2,7,13,29,38], yielding the corresponding 2,4-diphenyl-3-oxopyrrole products diPOPy-B, diPOPy-G, and bis-diPOPy-Sp, respectively (Figure 2). Other amines were found difficult to use: benzylamine was practically insoluble in water, and blackening of dopamine by autopolymerization [40] hindered the fluorescence of the reaction product, so no further studies were performed with these amines. The fluorescent reaction products were formed directly by mixing 1:4 (v/v) a solution of MDPF (2 mg/mL in acetone) with distilled water adjusted to pH 9 containing the solid amino compounds (GA, Sp, 1 mg/mL) or a 10% solution of BA.…”