Synthesis and application of functionally diverse 2,6,9-trisubstituted purine libraries as CDK inhibitors.
BACKGROUND
Purines constitute a structural class of protein ligands involved in mediating an astonishing array of metabolic processes and signal pathways in all living organisms. Synthesis of purine derivatives targeting specific purine-binding proteins in vivo could lead to versatile lead compounds for use as biological probes or drug candidates.


RESULTS
We synthesized several libraries of 2,6, 9-trisubstituted purines using both solution- and solid-phase chemistry, and screened the compounds for inhibition of cyclin-dependent kinase (CDK) activity and human leukemic cell growth. Lead compounds were optimized by iterative synthesis based on structure-activity relationships (SARs), as well as analysis of several CDK-inhibitor cocrystal structures, to afford several interesting compounds including one of the most potent CDK inhibitors known to date. Unexpectedly, some compounds with similar CDK inhibitory activity arrested cellular proliferation at distinctly different phases of the cell cycle and another inhibitor directly induced apoptosis, bypassing cell-cycle arrest. Some of these compounds selectively inhibited growth of cells derived from specific tumors.


CONCLUSIONS
2,6,9-Trisubstituted purines have various and potent biological activities, despite high concentrations of competing endogenous purine ligands in living cells. Purine libraries constitute a versatile source of small molecules that affect distinct biochemical pathways mediating different cellular functions.
Chang
Y T
YT
Lawrence Berkeley National Laboratory, Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, California 94720, USA.
Gray
N S
NS
Rosania
G R
GR
Sutherlin
D P
DP
Kwon
S
S
Norman
T C
TC
Sarohia
R
R
Leost
M
M
Meijer
L
L
Schultz
P G
PG
D000225:Adenine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D019925:Cyclin A / Q000037:antagonists & inhibitors / Q000737:chemistry; D019926:Cyclin B / Q000037:antagonists & inhibitors / Q000737:chemistry; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D019925:Cyclin A; D019926:Cyclin B; D004791:Enzyme Inhibitors; D008024:Ligands; D011687:Purines; C113584:purvalanol B; D016203:CDC2 Protein Kinase; D018844:Cyclin-Dependent Kinases; D000225:Adenine