One-Step Synthesis, Crystallography, and Acute Toxicity of Two Boron-Carbohydrate Adducts That Induce Sedation in Mice

Abstract

Boronic acids form diester bonds with cis-hydroxyl groups in carbohydrates. The formation of these adducts could impair the physical and chemical properties of precursors, even their biological activity. Two carbohydrate derivatives from d-fructose and d-arabinose and phenylboronic acid were synthesized in a straightforward one-step procedure and chemically characterized via spectroscopy and X-ray diffraction crystallography. Additionally, an acute toxicity test was performed to determine their lethal dose 50 (LD₅₀) values by using Lorke's method. Analytical chemistry assays confirmed the formation of adducts by the generation of diester bonds with the β-d-pyranose of carbohydrates, including signals corresponding to the formation of new bonds, such as the stretching of B-O bonds. NMR spectra yielded information about the stereoselectivity in the synthesis reaction: Just one signal was found in the range for the anomeric carbon in the ¹³C NMR spectra of both adducts. The acute toxicity tests showed that the LD₅₀ value for both compounds was 1265 mg/kg, while the effective dose 50 (ED₅₀) for sedation was 531 mg/kg. However, differences were found in the onset and lapse of sedation. For example, the arabinose derivative induced sedation for more than 48 h at 600 mg/kg, while the fructose derivative induced sedation for less than 6 h at the same dose without the death of the mice. Thus, we report for the first time two boron-containing carbohydrate derivatives inducing sedation after intraperitoneal administration. They are bioactive and highly safe agents. Further biological evaluation is desirable to explore their medical applications.

Keywords: acute toxicity; adducts; boron; carbohydrate; mice; neurons; sedation.

Figure 1

Scheme of the synthesis reaction for the carbohydrate–boron adducts. Each carbohydrate ((1) d-fructose or (2) d-arabinose) equivalent requires two equivalents of (3) phenylboronic acid to generate two diester bonds for the new adducts.

Figure 2

ORTEP at a 30% probability level of β-d-fructopyranoborate (FB-1); the acetone molecule is omitted for clarity. Selected lengths (Å): B1–O3, 1.360(4); B1–O4, 1.365(4); B2–O6, 1.368(4); B2–O5, 1.373(4); C5–O5, 1.436(3); C6–O6, 1.439(3); C3–O3, 1.438(3); C4–O4, 1.436(3). Selected bond angles (°): O3–B1–O4, 113.4(3); O6–B2–O5, 112.7(2). Selected torsion angles (°): O3–C3–C4–O4, 12.6(3); O5–C5–C6–O6, 9.2(3).

Figure 3

ORTEP at a 30% probability level of β-d-arabinopyranoborate (AB-1). Selected lengths (Å): O1–B1, 1.370(8); O1–C6, 1.436(7); O2–B2, 1.371(7); O2–C7, 1.449(7); O3–B1, 1.353(8); O3–C13, 1.448(7); O5–B2, 1.369(8); O5–C15, 1.434(7). Selected bond angles (°): O3–B1–O1, 112.6(5); O5–B2–O2, 112.5(5). Selected torsion angles (°): O2–C7–C15–O5, 17.0(6); O1–C6–C13–O3, 11.4(5).

Figure 4

Motor performance in the open-field test. Motor activity that occurred within 5 min and the effect on locomotion after FB-1 administration. The markers represent the mean, while the bars represent the standard error of the mean. Asterisks indicate the lowest dose, which, at each measured time, reduced the total movements compared to the control group, p < 0.05; n ≥ 4.

Figure 5

Motor performance in the open-field test. Motor activity that occurred within 5 min and the effect on locomotion after AB-1 administration. The markers represent the mean, while the bars represent the standard error of the mean. Asterisks indicate the lowest dose, which, at each measured time, reduced the total movements compared with the control group, p < 0.05; n ≥ 4.

Figure 6

Motor performance in the open-field test. Illustrative reports of the effects of the administration of FB-1 or AB-1 (in the highest tested doses).