Synthesis and cytotoxicity of 2-cyano-28-hydroxy-lup-1-en-3-ones

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 8, 2009, Pages 2168-2171

  Koohang, Ali ^a   Majewski, Nathan D ^a   Szotek, Erika L ^a   Mar, Aye Aye ^a   Eiznhamer, David A ^a   Flavin, Michael T ^a   Xu, Ze Qi ^a  

^a Advanced Life Sciences Inc   (United States)

Author keywords

2 Cyano 28 hydroxy lup 1 en 3 one; Betulin; Betulinic acid; Cytotoxicity; Triterpenoid

Indexed keywords

2 CYANO 28 HYDROXYLUP 1 EN 3 ONE DERIVATIVE; ANTINEOPLASTIC AGENT; BETULIN; CASPASE; DIHYDROBETULIN; UNCLASSIFIED DRUG;

APOPTOSIS; ARTICLE; CANCER CELL CULTURE; CONTROLLED STUDY; CYTOTOXICITY; DRUG ACTIVITY; DRUG SYNTHESIS; ENZYME ACTIVATION; HUMAN; HUMAN CELL; MELANOMA;

ANTINEOPLASTIC AGENTS, PHYTOGENIC; APOPTOSIS; CELL LINE, TUMOR; CELL PROLIFERATION; GROWTH INHIBITORS; HUMANS; TRITERPENES;

EID: 63149156363     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.02.107     Document Type: Article

References (25)

1. Dzubak P., Hajduch M., Vydra D., Hustova A., Kvasnica M., Biedermann D., Markova L., Urban M., and Sarek J. Nat. Prod. Rep. 23 (2006) 394
2. Liby K.T., Yore M.M., and Sporn M.B. Nat. Rev. Cancer 7 (2007) 357
3. Hyer M.L., Shi R., Krajewska M., Meyer C., Lebedeva I.V., Fisher P.B., and Reed J.C. Cancer Res. 68 (2008) 2927
4. Brookes P.S., Morse K., Ray D., Tompkins A., Young S.M., Hilchey S., Salim S., Konopleva M., Andreeff M., Phipps R., and Bernstein S.H. Cancer Res. 67 (2007) 1793
5. Ahmed R., Raina D., Meyer C., Kharbanda S., and Kufe D. J. Biol. Chem. 281 (2006) 35764
6. Liby K., Voong N., Williams C.R., Risingsong R., Royce D.B., Honda T., Gribble G.W., Sporn M.B., and Letterio J.J. Clin. Cancer Res. 12 (2006) 4288
7. Dinkova-Kostova A.T., Liby K.T., Stephenson K.K., Holtzclaw W.D., Gao X., Suh N., Williams C., Risingsong R., Honda T., Gribble G.W., Sporn M.B., and Talalay P. Proc. Natl. Acad. Sci. U.S.A. 102 (2005) 4584
8. Samudio I., Konopleva M., Hail Jr. N., Shi Y.-X., McQueen T., Hsu T., Evans R., Honda T., Gribble G.W., Sporn M., Gilbert H.F., Safe S., and Andreeff M. J. Biol. Chem. 280 (2000) 36273
9. Suh W.-S., Kim Y.S., Schimmer A.D., Kitada S., Minden M., Andreeff M., Suh N., Sporn M., and Reed J.C. Leukemia 17 (2003) 2122
10. Chadalapaka G., Jutooru I., McAlees A., Stefanac T., and Safe S. Bioorg. Med. Chem. Lett. 18 (2008) 2633
11. Chintharlapalli S., Papineni S., Jutooru I., McAlees A., and Safe S. Mol. Cancer Ther. 6 (2007) 1588
12. You Y.-J., Kim Y., Nam N.-H., and Ahn B.-Z. Bioorg. Med. Chem. Lett. 13 (2003) 3137
13. Honda T., Liby K.T., Su X., Sundararajan C., Honda Y., Suh N., Risingsong R., Williams C.R., Royce D.B., Sporn M.B., and Gribble G.W. Bioorg. Med. Chem. Lett. 16 (2006) 6306
14. Liby K., Honda T., Williams C.R., Risingsong R., Royce D.B., Suh N., Dinkova-Kostova A.T., Stephenson K.K., Talalay P., Sundararajan C., Gribble G.W., and Sporn M.B. Mol. Cancer Ther. 6 (2007) 2113
15. Chintharlapalli S., Papineni S., Liu S., Jutooru I., Chadalapaka G., Cho S.-D., Murthy R.S., You Y., and Safe S. Carcinogenesis 28 (2007) 2337
16. Fulda S. Int. J. Mol. Sci. 9 (2008) 1096
17. Mukherjee R., Kumar V., Srivastava S.K., Agrawal S.K., and Burman A.C. Anticancer Agents Med. Chem. 6 (2006) 271
18. Yogeeswari P., and Sriram D. Curr. Med. Chem. 12 (2005) 657
19. Eizenhamer D.A., and Xu Z.-Q. IDrugs 7 (2004) 359
20. Cichewicz R.H., and Kouzi S.A. Med. Res. Rev. 24 (2004) 90
21. Kim D.S.H.L., Pezzuto J.M., and Pisha E. Bioorg. Med. Chem. Lett. 8 (1998) 1707
22. 3) δ 0.87 (s, 3H), 0.94-1.18 (m, 4H), 0.98 (s, 3H), 1.05 (s, 6H), 1.15 (s, 3H), 1.20-1.48 (m, 10H), 1.52-1.74 (m, 7H), 1.69 (s, 3H), 1.85 (m, 1H), 1.96 (m, 2H), 2.40 (m, 1H), 3.35 (apparent d, J = 11.0 Hz, 1H), 3.79 (apparent t J = 9.2 Hz, 1H), 4.60 (s, 1H), 4.69 (s, 1H).
23. 4 per well) were plated onto a 96-well plate the evening before treatment in triplicate. Upon treatment with the test compound solutions in growth media, they were incubated for 72 h for all the cell lines with exception for OVCAR which was treated for 120 h. Next, the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphenyl)-2H-tetrazolium, inner salt) reagent was added and incubation was continued for 1.5-4 h at 37 °C. During the incubation, MTS is bioreduced to formazan by viable cells. The inhibitory effects were obtained by measuring the absorbance of the formazan at 490 nm on a Wallac Victor II plate reader and calculated by subtracting the absorbance measured at the same wavelength from DMSO-treated cells.
24. 5 per well) were plated in a 60 mm dish the evening before treatment. Upon treatment with the test compound solutions in growth media without FBS, the cells were incubated at 37 °C for 6 h. Next 10 % FCS was added to prevent cell damage and improve the efficiency of cell pelleting during subsequent centrifugation steps. After trypsinization and cell pelleting, the Nexin staining solution (including Annexin-V and 7-ADD) was added and incubation was continued on ice for 20 min. Apoptosis was measured on a Guava instrument by setting the gates as described in the manufactures protocol to establish quadrants and to measure the population of viable, mid apoptotic and late apoptotic/necrotic cells in each quadrant.
25. 4 per well) were plated on black-walled, clear-bottomed 96-well plates the evening before treatment, treated with test compound solutions in growth media without FBS, and incubated at 37 °C for 8 h prior to the addition of caspase reagent (DEVD-Rhodamine 110; Roche Homogenous Caspase Assay, fluorimetric, catalog # 03 005 372 001). Upon caspase activation, DEVD-Rhodamine 110 is cleaved. Fluorescent emission of the released rhodamine 110 was measured at 535 nm on Wallac plate reader using the homogeneous caspase program with excitation wavelength at 490 nm and the emission wave at 535 nm. The percentage changes in caspase activation reported are compared to the DMSO treatment. The assay detects caspases 2, 3 and 7 to a greater extent than caspases 6, 8, 9 and 10.