Boron-containing thiouracil derivatives for neutron-capture therapy of melanoma

Abstract

Boron-containing derivatives of 2-thiouracil and 2,4-dithiouracil and the corresponding 6-propyl compounds, containing a dihydroxyboryl group in the 5-position, have been prepared. These compounds accumulate in B16 melanoma in mice in concentrations up to 30 micrograms of boron per gram tissue. The uptake persists. The toxicity of both 2-thiouracil derivatives is low. These compounds are therefore good candidates for boron neutron-capture therapy of malignant melanoma.

Cellular Binding of Carboranylalanine and Some Effects of Boron Neutron Capture: Analysis of cultured melanoma B16 cells

“…This substance has been reported to be a melanin precursor (34) and one explanation for the lack of binding in our case is that the tested cells did not have enough melanin synthesis to allow for a measurable BTU-1 incorporation. If only small 0:A. PETTERSSON ET A 1 amounts were incorporated it might not have been detected with the method applied in the present study.…”

Pharmacokinetics in melanoma-bearing mice of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a candidate compound for boron neutron capture therapy

“…It was demonstrated, however, that the mechanism of BPA uptake is not unique for melanomas (Coderre et al, 1990). Melanoma-selective boronated thiouracils were synthesised by Tjarks and Gabel (1991) with the presumption that these compounds will be incorporated into melanin, giving long boron retention in melanoma cells, analogous to non-boronated thiouracils (Fairchild et al, 1982;Yamada et al, 1988;Tjarks & Gabel, 1991 and BPTU in vitro. After washing, it was observed that BPTU was better retained in the cells than BPA or BSH.…”

“…Although the uptake of BPA in melanoma cells is well accepted, incorporation of boron into melanin might not occur, resulting in poor retention. Boronated thiouracils that enter the melanogenesis pathway at a different point from BPA have been recently synthesised, aiming at boron incorporation into the melanin for better retention (Tjarks & Gabel, 1991). We have found previously that 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU) and not boronthiouracil (BTU) was retained in vitro in melanotic B16 cells, while BPTU failed to be retained in the non-pigmented B16.013 subclone (R. Verrijk et al, 1991, unpublished data).…”

Crystal structure of tert-butyl-3-(4-oxo-2-thioxo-3,4-dihydropyrimidin- 1(2H)-yl)propanoate, C11H15N2O3S

“…, an established antithyroid drug and melanomaseeker [1], hasshown therapeuticproperties, especially antiviral, antithyroid [2][3][4], and antitumor activities was found to selectively inhibit neuronal nitric oxide synthase (nNOS) in acompetitive manner (Ki =20WM) [5].Therefore many derivatives of 2-thiouracil have been developed to improve its topical delivery and reduce the side effects. On the other hand, compounds containing thiophene aromatic ring are ubiquitous in nature, thiophene oligomers and polymers have received great attention due to their potential anti-cancer and anti-inflammatory properties [6].Inrecent years, more and more attention has been focused on synthesis and properties of thiophene carboxylic acid derivatives, which not only play an important role in constructing coordination polymers with attractive topological structures but which also have been found application in alarge number of organic reactions and are widely employed in organic synthesis [7][8][9].…”