Design and modular parallel synthesis of a MCR derived α-helix mimetic protein-protein interaction inhibitor scaffold

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 6, 2006, Pages 1740-1743

  Antuch, Walfrido ^b   Menon, Sanjay ^c   Chen, Quin Zene ^c   Lu, Yingchun ^c   Sakamuri, Sukumar ^c   Beck, Barbara ^b   Schauer Vukašinović, Vesna ^b   Agarwal, Seema ^c   Hess, Sibylle ^b   Dömling, Alexander ^a  

^a ABC Pharma   (Germany)

^b Biovertis AG   (Germany)

^c Morphochem Inc   (United States)

Author keywords

Apoptosis; Bcl family; Cancer; Isocyanide; Multicomponent reaction; Protein interaction antagonist

Indexed keywords

IMIDAZOLE; TERPHENYL DERIVATIVE;

ALPHA HELIX; APOPTOSIS; ARTICLE; CELL PROLIFERATION; ENZYME INHIBITION; PROTEIN PROTEIN INTERACTION; PROTEIN STRUCTURE; PROTEIN SYNTHESIS;

APOPTOSIS; APOPTOSIS REGULATORY PROTEINS; BCL-2 HOMOLOGOUS ANTAGONIST-KILLER PROTEIN; BCL-X PROTEIN; BINDING SITES; BIOMIMETIC MATERIALS; CELL PROLIFERATION; DRUG DESIGN; HL-60 CELLS; HUMANS; IMIDAZOLES; MODELS, MOLECULAR; PEPTIDE FRAGMENTS; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN INTERACTION MAPPING; PROTEINS; PROTO-ONCOGENE PROTEINS C-BCL-2; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 32044464374     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.11.102     Document Type: Article

References (22)

1. C.-J. Tsai, S.L. Lin, H.J. Wolfson, and R. Nussinov J. Mol. Biol. 260 1996 604
2. P.L. Toogood J. Med. Chem. 45 2002 1543
3. L. Pagliaro, J. Felding, K. Audouze, S.J. Nielsen, R.B. Terry, C. Krog-Jensen, and S. Butcher Curr. Opin. Chem. Biol. 8 2004 442
4. M. Sattler, H. Liang, D. Nettesheim, R.P. Meadows, J.E. Harlan, M. Eberstadt, H.S. Yoon, S.B. Shuker, B.S. Chang, A.J. Minn, C.B. Thompson, and S.W. Fesik Science 275 1997 963
5. A. Böttger, V. Böttger, C. Garcia-Echeverria, P. Chène, H.-K. Hochkeppel, W. Sampson, K. Ang, S.F. Howard, S.M. Picksley, and D.P. Lane J. Mol. Biol. 259 1997 744
6. S.J. Haggarty, T.U. Mayer, D.T. Miyamoto, R. Fathi, R.W. King, T.J. Mitchison, and S.L. Schreiber Chem. Biol. 7 2000 275
7. W.P. Nolan, G.S. Ratcliffe, and D.C. Rees Tetrahedron Lett. 33 1992 6879
8. D.C. Horwell, W. Howson, G.S. Ratcliffe, and H.M.G. Willems Bioorg. Med. Chem. 4 1996 33
9. E. Jacoby Bioorg. Med. Chem. Let. 12 2002 891
10. O. Kutzki, H.S. Park, J.T. Ernst, B.P. Orner, H. Yin, and A.D. Hamilton J. Am. Chem. Soc. 124 2002 11838
11. B.P. Orner, J.T. Ernst, and A.D. Hamilton J. Am. Chem. Soc. 123 2001 5382
12. Moloc; Paul Gerber. Gerber Molecular Design, http://www.moloc.ch.
13. Recent reviews on van Leusen chemistry A.M. van Leusen, and D. van Leusen Org. React. 57 2003 419
14. http://www.organic-chemistry.org/Highlights/2005/05Mai.shtm.
15. A variety of substituted TosMICs are commercially available at: www.synthatex.com.
16. J. Sisko, A.J. Kassick, M. Mellinger, J. Filan, A. Allen, and M.A. Olsen J. Org. Chem. 65 2000 1516
17. 2 (20 mL) containing MeOH (1%) eluted the desired imidazole product (18 mg, 43%). MS (electrospray, + ions): m/z = 413 (M+H).
18. Cells were plated in 96-well plates in 50 μl of media at a density of 70,000 cells/well. Compounds were serially diluted into cell media as 2x stocks containing 1% DMSO and 50 μl of each dilution was added to the wells in triplicate. After 48 h of incubation with the compounds, cell survival was assessed by adding 10 μl WST-1 reagent (Roche Applied Science) in each well. After incubation for an additional 3 h, the plates were read in a plate reader (Spectramax 250 from Molecular Devices, Sunnyvale, CA) at 450 nm. The time 0-h for cells with only DMSO (final concentration 0.5%) was also assessed for each plate and was subtracted from the 48-h time points for both treated and untreated data points. The XLfit program (ID Business Solutions Inc., Parsippany, NJ) was used to obtain and calculate the GI50 values for each compound. Each experiment was done a minimum of three times.
19. 16 Camptothecin was used as a positive control in this assay.
20. J.L. Wang, J.G. Zhang, S. Choksi, S. Shan, Z. Lu, C.M. Croce, E.S. Alnemri, R. Korngold, and Z. Huang Cancer Res. 60 2000 1498
21. em = 535 nm using an UltraReader (Tecan) after 2 h incubation of the reaction mixture at room temperature. Validation of the assays was performed using non-labeled Bak-BH3 peptide as a control inhibitor.
22. H. Zhang, P. Nimmer, S.H. Rosenberg, S.C. Ng, and M. Joseph Anal. Biochem. 307 2002 70