Enlargement of a Modular System-Synthesis and Characterization of an s-Triazine-Based Carboxylic Acid Ester Bearing a Galactopyranosyl Moiety and an Enormous Boron Load

Abstract

The amount of boron accumulated in tumor tissue plays an important role regarding the success of the boron neutron capture therapy (BNCT). In this article, we report a modular system, combining readily available starting materials, like glycine, 1,3,5-triazine and the well-known 9-mercapto-1,7-dicarba-closo-dodecaborane(12), as well as α-d-galactopyranose for increased hydrophilicity, with a novel boron-rich tris-meta-carboranyl thiol.

Keywords: boron neutron capture therapy; cancer therapy; carborane; modular system; s-triazine.

Figure 1

Illustration of the modular system incorporating an α-d-galactopyranosyl moiety (yellow), protected glycine (blue), a tris-cluster derivative of 9-mercapto-1,7-dicarba-closo-dodecaborane(12) (pale red) and cyanuric chloride (green) as core; R = tert-butyl.

Scheme 1

Preparation of tert-butyl-N-{4,6-bis[(1,7-dicarba-closo-dodecaboran-9-ylmethyl)1,7-dicarba-closo-dodecaboran-9-ylthio]-1,3,5-triazin-2-yl}-N-(1′,2′:3′,4′-di-O-isopropylidene-6′-deoxy-α-d-galacto-pyranos-6′-yl)glycinate (7). a) I₂, AlCl₃, CH₂Cl₂, rt, 2 d, 92% [62,63]; b) paraformaldehyde, n-BuLi, tetrahydrofuran (THF), rt, overnight, 89%; c) Br₂, PPh₃, benzene, reflux, 46 h, 95% [64,65,66]; d) from 3—Mg, THF, reflux, 2 h; e) from 1—11 mol% CuI, 4 mol% [PdCl₂(PPh₃)₂], THF, reflux, 2 d, 30% [61,62,63,64,67,68]; f) S₂Cl₂, AlCl₃, CH₂Cl₂, reflux, 4 h, 67% [69]; g) Zn, HCl_conc., glacial acetic acid (HOAc), ethyl acetate, reflux, 4 h, 81% [69]; h) +8, K₂CO₃, MeCN, reflux, 2 d, 79%.

Figure 2

Comparison between 9-mercapto-1,7-dicarba-closo-dedecaboran(12) (left) and 1,7-bis(1,7-dicarba-closo-dodecaboran-9-ylmethyl)-1,7-dicarba-closo-dodecaboran-9-yl-thiol (6) (right) (altered fragments are drawn in red).

Figure 3

Molecular structure of 1,7-bis(1,7-dicarba-closo-dodecaboran-9-ylmethyl)-1,7-dicarba-closo-dodecaborane (4). Hydrogen atoms are omitted for clarity. Thermal ellipsoids are drawn at the 50% probability level. Selected bond lengths [pm] and bond angles [°]: C1–C3 153.5(2), C3–B20 160.1(3), C2–C6 153.0(2), C6–B30 159.6(3); C1–C3–B20 123.0(2), C2–C6–B30 124.2(2).

Figure 4

Mono-oxidized derivative of 1,2-bis[1,7-bis(1,7-dicarba-closo-dodecaboran-9-ylmethyl)-1,7-dicarba-closo-dodecaboran-9-yl]disulfane (5′).

Figure 5

Molecular structure of 1,7-bis(1,7-dicarba-closo-dodecaboran-9-ylmethyl)-1,7-dicarba-closo-dodecaboran-9-ylthiol (6). Thermal ellipsoids are drawn at the 50% probability level. Carbon/boron disorder in one of the carborane clusters in a ratio of 0.55(2):0.45(2) (shown) and the central carborane unit (ratio of 0.938(1):0.062(1), not shown) is observed. Hydrogen atoms (other than SH) are omitted for clarity. Selected bond lengths [pm] and bond angles [°]: S1–B7 187.0(4), C1–C7 152.9(3), C7–B20 159.9(4), C2–C8 152.5(4), C8–B30 160.3(4); C1–C7–B20 122.7(2), C2–C8–B30 124.2(2).

Figure 6

Comparison of the isotopic pattern of the calculated (top) and measured signal (bottom) of [7 + H]⁺ [41].

Figure 7

Numbering scheme of compound 7.