Back to Search
Start Over
Structure-based design, synthesis, and biological evaluation of potent and selective macrocyclic checkpoint kinase 1 inhibitors.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2007 Apr 05; Vol. 50 (7), pp. 1514-27. Date of Electronic Publication: 2007 Mar 13. - Publication Year :
- 2007
-
Abstract
- Based on the crystallographic analysis of a urea-checkpoint kinase 1 (Chk1) complex and molecular modeling, a class of macrocyclic Chk1 inhibitors were designed and their biological activities were evaluated. An efficient synthetic methodology for macrocyclic ureas was developed with Grubbs metathesis macrocyclization as the key step. The structure-activity relationship studies demonstrated that the macrocyclization retains full Chk1 inhibition activity and that the 4-position of the phenyl ring can tolerate a wide variety of substituents. These novel Chk1 inhibitors exhibit excellent selectivity over a panel of more than 70 kinases. Compounds 5b, 5c, 5f, 15, 16d, 17g, 17h, 17k, 18d, and 22 were identified as ideal Chk1 inhibitors, which showed little or no single-agent activity but significantly potentiate the cytotoxicities of the DNA-damaging antitumor agents doxorubicin and camptothecin. These novel Chk1 inhibitors abrogate the doxorubicin-induced G2 and camptothecin-induced S checkpoint arrests, confirming that their potent biological activities are mechanism-based through Chk1 inhibition.
- Subjects :
- Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Camptothecin pharmacology
Cell Line, Tumor
Checkpoint Kinase 1
Crystallography, X-Ray
DNA Damage
Doxorubicin pharmacology
Drug Design
Drug Screening Assays, Antitumor
Drug Synergism
Humans
Macrocyclic Compounds chemistry
Macrocyclic Compounds pharmacology
Models, Molecular
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology
Protein Kinases metabolism
Structure-Activity Relationship
Urea chemistry
Urea pharmacology
Antineoplastic Agents chemical synthesis
Macrocyclic Compounds chemical synthesis
Protein Kinase Inhibitors chemical synthesis
Protein Kinases chemistry
Urea analogs & derivatives
Urea chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 50
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 17352464
- Full Text :
- https://doi.org/10.1021/jm061247v