Synthesis and biological evaluation of quinoxaline-5,8-diones that inhibit vascular smooth muscle cell proliferation

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 14, 2005, Pages 3380-3384

  Chung, Hwa Jin ^a   Jung, Ok Jai ^a   Mi, Jin Chae ^a   Hong, Sung Yu ^b,c   Chung, Kwang Hoe ^b,c   Sang, Kook Lee ^a   Ryu, Chung Kyu ^a  

^a Ewha Womans University   (South Korea)

^b BioBud Inc   (South Korea)

^c Yonsei University College of Medicine   (South Korea)

Author keywords

Antiproliferative activity; ERK1 2; Quinoxaline 5,8 dione; Smooth muscle cell

Indexed keywords

MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; QUINOXALINE DERIVATIVE;

ANIMAL CELL; ARTICLE; CELL PROLIFERATION; CONTROLLED STUDY; DRUG ACTIVITY; DRUG EFFECT; DRUG MECHANISM; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; MITOSIS INHIBITION; NONHUMAN; RAT; SIGNAL TRANSDUCTION; SMOOTH MUSCLE FIBER; VASCULAR SMOOTH MUSCLE;

ANIMALS; CELL CYCLE; CELL PROLIFERATION; DRUG DESIGN; GROWTH INHIBITORS; MOLECULAR STRUCTURE; MUSCLE, SMOOTH, VASCULAR; QUINOXALINES; RATS; SIGNAL TRANSDUCTION; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 20644468406     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.05.022     Document Type: Article

References (21)

1. R. Ross Nature 362 1993 801
2. A.C. Newby, and S.J. George Cardiovasc. Res. 27 1993 1173
3. G.A. Ferns, E.W. Raines, K.H. Sprugel, A.S. Motani, M.A. Reidy, and R. Ross Science 253 1991 1129
4. R.W. Middleton, and J. Parrick S. Patai Z. Rappoport The Chemistry of The Quinonoid Compounds Part 2 1988 John Wiley London 1019 1066
5. G. Malesani, F. Marcolin, and G. Rodighiero J. Med. Chem 13 1970 161
6. T.H. Porter, A. Von Klaudy, and K. Folkers J. Med. Chem. 16 1973 1310
7. H. Lee, S. Cho, K. Namgoong, J.-K. Jung, J. Cho, and S.-I. Yang Bioorg. Med. Chem. Lett. 14 2004 1235
8. Lin, H.-S.; Enrico, R. M. WO Patent 99,522,365, 1999; Chem. Abstr. 1999, 131, 295, 573
9. Medwid, J. B.; Torley, L. W. U.S. Patent 4,692,449, 1987; Chem. Abstr. 1988, 108, 6049
10. K.E. Bornfeldt, J.S. Campbell, H. Koyama, G.M. Argast, C.C. Leslie, E.W. Raines, E.G. Krebs, and R. Ross J. Clin. Invest. 100 1997 875
11. I. Petrache, M.E. Choi, L.E. Otterbein, B.Y. Chin, L.L. Mantell, S. Horowitz, and A.M. Choi Am. J. Physiol. 277 1999 589
12. A. Roulston, C. Reinhard, P. Amiri, and L.T. Williams J. Biol. Chem. 273 1998 10232
13. M. Mayr, and Q. Xu Exp. Gerontol. 36 2001 969
14. L. Weinberger, and A.R. Day J. Org. Chem. 24 1959 1451
15. X.-H. Bu, H. Liu, M. Du, K.M.-C. Wong, V.W.-W. Yam, and M. Shionoya Inorg. Chem. 40 2001 4143
16. 3 cells/well in 200 μL of DMEM containing 10% (v/v) fetal bovine serum in 96-well flat-bottomed plates (Costar, Corning, NY, USA). After 24 h incubation, the complete medium was replaced with DMEM containing 0.2% FBS, and incubated for an additional 72 h. And then the cells were treated with test compounds in 100 μL of DMEM containing PDGF (5 ng/mL) and 5% (v/v) fetal bovine serum for 48 h. Proliferation of the cells was determined using a colorimetric assay kit based on the uptake of WST by viable cells (Premix WST-1 cell proliferation assay system, Takara Bio, Otsu, Japan). The assay kit is dependent on the reduction of tetrazolium salt WST-1, which results in formation of a dark red formazan product, by various mitochondrial dehydrogenase of viable cells
17. Y.D. Sohn, H.J. Lim, K.C. Hwang, J.H. Kwon, H.Y. Park, K.-H. Chung, S.Y. Cho, and Y. Jang Biochem. Biophys. Res. Commun. 284 2001 931
18. P.J. Mohacsi, D. Tüller, B. Hulliger, and P.L. Wijngaard J. Heart Lung Transplant. 16 1997 484
19. 6 cells) were seeded in 100-mm culture dish and incubated with 10% FBS DMEM. After 24 h, medium was changed in DMEM free, and SMC was further incubated for 24 h. Subsequently, SMC was again incubated in 10% FBS DMEM containing test sample 2c (1 μg/mL). After 48 h of treatment, both floating and adherent cells were collected. The cell suspensions were then fixed with 70% ice-cold ethanol and transferred to the freezer until use followed by washing with PBS, cells were stained with 50 μg/mL propidium iodide (PI) in the presence of 0.25 mg/mL ribonuclease (RNase) at 37°C for 30 min. Stained cells were analyzed by flow cytometry (Becton-Dickinson, USA)
20. 6 cells/mL in DMEM containing 10% FBS. After 24 h incubation, the cells were washed twice with 5 mL PBS. The stimulation mixture contained vehicle only or the indicated concentration of test compound 2c in supplemented DMEM and then incubated for 48 h. After washing with PBS twice, 1 mL boiling 2x concentrated electrophoresis sample buffer (1x = 125 mM Tris-HCl buffer, pH 6.8, 2% SDS, 5% glycerol, 0.003% bromophenol blue, and 1% β-mercaptoethanol) was added to the cells, which were then scraped from the dish and boiled for 5 min. Each protein (30 μg) was then subjected to SDS-polyacrylamide gel electrophoresis using 10% acrylamide gels. Proteins were transferred onto polyvinylidene difluoride membranes (Millipore, MA). After blocking, the membranes were incubated with antibodies (goat anti-pRb, mouse anti-PCNA, rabbit-anti cdk2, rabbit anti-cyclin A, and rabbit anti-cyclin B1, diluted 1:1000) or anti-β-actin (1:5000 dilution) for 1 h, and then incubated with a corresponding secondary antibody (anti-rabbi IgG-HRP, anti-mouse IgG-HRP, 1:2000 dilution, Santa Cruz Biotechnology, Santa Cruz, CA) for 1 h. The blots were developed using an ECL detection kit (Amersham Life Science, Buckinghamshire, UK)
21. P. Calabro, I. Samudio, J.T. Willerson, and E.T.H. Yeh Circulation 110 2004 3335