Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 22, 2007, Pages 6280-6285

  Garbaccio, Robert M ^a   Huang, Shaei ^a   Tasber, Edward S ^a   Fraley, Mark E ^a   Yan, Youwei ^a   Munshi, Sanjeev ^a   Ikuta, Mari ^a   Kuo, Lawrence ^a   Kreatsoulas, Constanine ^a   Stirdivant, Steve ^a   Drakas, Bob ^a   Rickert, Keith ^a   Walsh, Eileen S ^a   Hamilton, Kelly A ^a   Buser, Carolyn A ^a   Hardwick, James ^a   Mao, Xianzhi ^a   Beck, Stephen C ^a   Abrams, Marc T ^a   Tao, Weikang ^a   Lobell, Rob ^a   Sepp Lorenzino, Laura ^a   Hartman, George D ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Apoptosis; Benzoisoquinolinones; Cancer; Checkpoint escape; Chek1 kinase; Chk1 kinase; DNA damaging agents; Kinases; Mitotic arrest; p53 Deficient cancer; Photochemistry; PSA

Indexed keywords

ADENOSINE TRIPHOSPHATE; AMINE; BENZOQUINONE DERIVATIVE; CAMPTOTHECIN; CASPASE; CHECKPOINT KINASE 1; GLUTAMIC ACID; QUINOLINE DERIVED ANTIINFECTIVE AGENT; SOLVENT;

ACIDITY; ARTICLE; CELL STRAIN HT29; CONTROLLED STUDY; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; HUMAN; HUMAN CELL; HYDROGEN BOND; IC 50; PHOTOCHEMISTRY; REACTION ANALYSIS; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

APOPTOSIS; BINDING SITES; CELL LINE, TUMOR; CRYSTALLOGRAPHY, X-RAY; DRUG EVALUATION, PRECLINICAL; ENZYME INHIBITORS; HUMANS; INHIBITORY CONCENTRATION 50; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PHOTOCHEMISTRY; PROTEIN KINASES; QUINOLONES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 35148834201     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.09.007     Document Type: Article

References (18)

1. Zhou B.B., and Bartek J. Nat. Rev. Cancer 4 (2004) 1
2. Bartek J., and Lukas J. Cancer Cell 3 (2003) 421
3. Kong N., Fotouhi N., Wovkulioch P.M., and Roberts J. Drug Future 28 (2003) 881
4. Kawabe T. Mol. Cancer Ther. 3 (2004) 513
5. Prudhomme M. Recent Patent Anti-Cancer Drug Dis. 1 (2006) 55
6. Tao Z.-F., and Lin N.-H. Anti-Cancer Agents in Med. Chem. 6 (2006) 377
7. Thompson J.E., Cubbon R.M., Cummings R.T., Wicker L.S., Frankshun R., Cunningham B.R., Cameron P.M., Meinke P.T., Liverton N., Weng Y., and DeMartino J.A. Biorg. Med. Chem. Lett. 12 (2002) 1219
8. Goulet, J. L.; Hong, X.; Sinclair, P. J.; Thompson, J. E.; Cubbon, R. M.; Cummings, R. T. PCT Int. Appl. WO 2003011285, 2003.
9. Huang S., Garbaccio R.M., Fraley M.E., Steen J., Kreatsoulas C., Hartman G., Stirdivant S., Drakas B., Rickert K., Walsh E., Hamilton K., Buser C.A., Hardwick J., Mao X., Abrams M., Beck S., Tao W., Lobell R., Sepp-Lorenzino L., Yan Y., Ikuta M., Zugay-Murphy J., Sardana V., Munshi S., Kuo L., Reilly M., and Mahan E. Biorg. Med. Chem. Lett. 22 (2006) 5907
10. 1H NMR and high resolution mass spectrometry. For detailed experimental procedures, see patent WO 2007008502.
11. Kumler P.L., and Dybas R.A. J. Org. Chem. 35 (1970) 125
12. Traxler P., and Furet P. Pharmacol. Ther. 82 (1999) 195
13. 50 values.
14. 50of checkpoint escape mediated by Chk1 inhibition was determined with 10-point series diluted Chk1 inhibitor treated tetraplicate cell samples.
15. m for ATP (0.1 mM). In the cell assay, the ATP concentration is 2.0 mM resulting in an inherent 10-fold potency shift between these assays.
16. PSA calculations are done using the method published by Clark in 1999:. Clark D.E. J. Pharm. Sci. 88 (1999) 807
17. 4 cells per well in DMEM media +10% fetal calf serum. When cells reached 50% confluency, 100 nM camptothecin was added in fresh media and incubation continued for 24 h after which the media was again replaced with fresh media containing 30, 100 or 300 nM of compound 22. After 24 h of exposure to the Chek1 inhibitor, caspase 3 activity in cells was measured using the Caspase 3 Assay Kit (Becton-Dickinson) according to the manufacturer's instructions. Fluorescence was measured on a Spectramax Gemini plate reader (Molecular Devices).
18. sym = 0.051, and completeness = 99%. The complex structure was refined to an R-factor of 0.195. The detailed X-ray diffraction data and refinement statistics are listed under PDB code 2R0U at the protein data bank.