NEUTRON BEAM DYNAMIC THERAPY

Abstract

Provided is a new boron isotope (.sup.10B) tracing drug which can exhibit wide-area molecular-targeting function and stereotactic destructive power. The invented boron isotope (.sup.10B) tracing drug has higher selective tumor-targeting and tumor-accumulating pharmacokinetic functions appropriate for neutron beam dynamic therapy (NBDT) and boron neutron capture therapy (BNCT).

Claims

1-4. (canceled)

5. A drug for NBDT, comprising a compound represented by formula (1′) wherein “boron isotope (.sup.10B)” is introduced into a non-active site of (1,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, provided that boron isotope (.sup.11B) is not contained ##STR00006##

6. A drug for boron neutron capture therapy (BNCT) and a lead compound for NBDT, comprising the compound as claimed in claim 5.

7. The drug for NBDT as claimed in claim 5, wherein the compound of the formula (1′) incorporates a monosaccharide or an oligosaccharide therein to be a boron isotope (.sup.10B) glycoside represented by the following formula (2): ##STR00007## wherein a saccharide residue is a monosaccharide residue or a polysaccharide residue selected from the group consisting of glucosyl, galactosyl, mannosyl, furakutosyl, xylosyl, and arabinosyl groups.

8. A drug for NBDT or BNCT, comprising the boron isotope (10B)-containing curcumin compound according to claim 5.

9. A drug for NBDT or BNCT, comprising the boron isotope (.sup.10B)-containing curcumin glycoside according to claim 7.

Description

MODE FOR CARRYING OUT THE INVENTION

[0025] The present invention accomplished the preparation of the new drug for NBDT and BNCT from the lead compound 1 through boron isotope (.sup.10B) complex formation and then enhanced water solubility with the glycosylation reaction.

EXAMPLE 1

Synthesis of Curcumin-Boron Isotope (.SUP.10.B) Complex of [Compound 2]

[0026] Curcumin (50 mg) was suspended in diethylether (5.0 mL), and boron trifluoride ether (50 μL, 0.407 mmoL) was added dropwise. The reaction mixture was stirred at room temperature for 20 h. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (5% MeOH/CH.sub.2Cl.sub.2 eluent) to give curcumin-boron isotope (.sup.10B) complex (27 mg) [Chemical compound 2]: .sup.1H-NMR(400 MHz,CH.sub.2Cl.sub.2-d.sub.2): 7.99(d,J=15.4 Hz,2H),7.53-7.61(m,1H), 6.96-7.08 (m,H), 6.56(d.J=15.4 Hz, 2H), 6.02-6.03(s, 6H); HRMS(FAB+)

[0027] Calcd. for C.sub.21H.sub.19BF.sub.2O.sub.6(M+)m/z 416.1243, Found 416.1252.

##STR00004##

EXAMPLE 2

[0028] The curcumin-boron isotope (.sup.10B) complex obtained in Example 1 (20 mg) was suspended in dimethyl sulfoxide (1.0 mL) and then 0.1 M benzyl triethyl ammonium chloride (1.0 mL) was added under stirring followed by addition of 0.01 M sodium acetate buffer (10 mL). To the reaction mixture, glucose (85.5 mg) and beta-glucosidase (43.2 mg) were added and then incubated at 37.5-45.5+1.0° C. with shaking at 150 rpm for 35 hours. The resulting solution was heated in a boiled water bath for 5-10 minutes and cooled to room temperature. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layers were dried and concentrated under vacuum. The residue was purified by silica gel column chromatography to di-glucosylated curcumin-boron isotope (.sup.10B) complex [Chemical compound 3] in a 25% yield.

[0029] .sup.1H-NMR(400 MHz,DMSO-d.sub.6), 3.1-3.4(m, 8H), 3.6(m, 3H), 3.77(s, 6H, OCH.sub.3), 4.31(s, 1H), 4.5(t, 2H, J=5.5 Hz), 4.93(d, 2H J=7 Hz), 4.98(d,2H, J=5 Hz), 5.06(s, 2H), 5.25(d, 2H, J=4 Hz), 6.04(s,1H), 6.81(d, 2H),7.52(d, 2H, J=16 Hz); ESI-MS, m/z715 [M+N].sup.+.

##STR00005##