Preparation of Apoptotic Inducers, 2,2-Diphenyl-1,3,2-oxazaborolidin-5-ones, Under Alkaline Conditions

Abstract

An efficient and high-yielding procedure has been developed for the synthesis of a set of fifteen 2,2-diphenyl-1,3,2-oxazaborolidin-5-ones, through the reaction of the corresponding α-amino acid with diphenyl borinic acid under alkaline conditions (pH 7.5-8). It is of note that these compounds showed potent cytotoxic activity on K-562 and HCT-15 cell lines.

α-amino acids - diphenyloxazaborolidinones - boron complexes - apoptosis - diphenylborinic acid

References and Notes

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<A NAME="RS14606ST-16">16</A>

Typical procedure (Table 1, entry 1, 3a): Glycine (0.5g, 6.6 mmol) was dissolved in H₂O (3 mL) and the pH was ad-justed to 8 with NaOH (5%, 2 mL). A solution of diphenyl-borinic acid was prepared from 2-aminoethyl-diphenyl-borinate (1.59 g, 6.6 mmol) as described in the literature.¹⁴ The solutions were mixed together and heated at reflux for 4 h. The solvent was evaporated slowly and the product was filtered and washed with cold H₂O and n-hexane, yielding 1.49 g of 3a (6.26 mmol, 94%).

<A NAME="RS14606ST-17">17</A>

Cytotoxicity in K-562 and HCT-15 cell lines, using the sulforhodamine B assay: Skehan P., Storeng R., Scudiero D., Monks A., McMahon J., Vistica D., Warren J. T., Bokesh H., Kenney S., Boyd M.R.; J. Natl. Cancer Inst.; 1990, 82: 1107; 24 h after treatment, the treated and control cell cultures were fixed with ice-cold 10% CCl₃COOH for 30 min. The 96-well plates were washed in H₂O and then sulforhodamine (SRB, 100 µL, 0.4%) dissolved in AcOH (1%) was added to each well and left for 15 min. The SRB was removed, washed in AcOH (1%) and allowed to air-dry. Then aqueous Tris base [tris(hydroxymethyl)aminoethane] (100 µL, 10 mM) was added to each well to solubilize the cell-bound dye and the absorbance at 550 nm was measured. The results are expressed as a percentage of control cell growth.

<A NAME="RS14606ST-18">18</A>

2,2-Diphenyl-1,3,2-oxazaborolidin-5-one (3a): White solid; mp 241-243 °C (Lit. 242-245 °C); IR (KBr): 3428, 3243, 3074, 1720, 1604, 1434, 1302, 1217, 963, 702 cm^-1; ¹H NMR (DMSO-d ₆ ): δ = 7.35 (d, J = 7 Hz, 4 H), 7.22 (t, J = 7 Hz, 4 H), 7.16 (t, J = 7 Hz, 4 H), 7.07 (br t, 2 H, NH), 3.43 (t, J = 6 Hz, 2 H); ¹³C NMR (DMSO-d ₆ ): δ = 42.9, 126.1, 127.1, 131.0, 147.8, 172.5; ¹¹B NMR (DMSO-d ₆ ): δ = +5.03; MS (EI): m/z = 239, 238, 162 (base peak), 161, 132, 104, 77.