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

1 Dembitsky VM. Srebnik M. Tetrahedon  2003,  59:  579 

2 Jabbour A. Steinberg D. Dembitsky VM. Moussaieff A. Zaks B. Srebnik M. J. Med. Chem.  2004,  47:  2409 

3 Bailey PJ. Cousin G. Snow GA. White A. Antimicrob. Agents Chemother.  1980,  17:  549 

4 Dobrydneva Y. Abelt CJ. Dovel B. Thadigiri CM. Williams RL. Blackmore PF. Mol. Pharmacol.  2006,  69:  247 

5 Velasco B. Trujillo-Ferrara JG. Fabila LH. Miranda R. Sánchez-Torres LE. Life Sci.  2007,  80:  1007 

6 Lang K, Nuetzel K, and Schubert F. inventors; German Patent  1130445.  ; Chem. Abstr. 1963, 58, 1488a

7 Skoog IH. J. Org. Chem.  1964,  29:  492 

8 Shih-Hua T. Kuo-Min C. Shih-Lu T. Chia-Chun L. Shih-Lin C. Chem. Abstr.  1967,  66:  37990m 

9 Nefkens GHL. Zwanenburg B. Tetrahedron  1983,  39:  2995 

10 Flückinger R. Henson E. Hess GM. Gallop PM. Biomed. Mass Spectrom.  1984,  11:  611 

11 Strang CJ. Henson E. Okamoto Y. Paz MA. Gallop PM. Anal. Biochem.  1989,  178:  276 

12 Farfán N. Silva D. Santillan R. Heteroat. Chem.  1993,  4:  533 

13 Trujillo J. Höpfl H. Castillo D. Santillan R. Farfán N. J. Organomet. Chem.  1998,  571:  21 

14 Chremos GN. Weidmann H. Zimmerman HK. J. Org. Chem.  1961,  26:  1683 

15 Rettig SJ. Trotter J. Can. J. Chem.  1977,  55:  958 

16

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%).

17

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.

18

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.