Biaryl purine derivatives as potent antiproliferative agents: inhibitors of cyclin dependent kinases. Part I.
The introduction of an aryl ring onto the 4-position of the C-6 benzyl amino group of the Cdk inhibitor roscovitine (2), maintained the potent Cdk inhibition demonstrated by roscovitine (2) as well as greatly improving the antiproliferative activity. A series of C-6 biarylmethylamino derivatives was prepared addressing modifications on the C-6 biaryl rings, N-9 and C-2 positions to provide compounds that displayed potent cytotoxic activity against tumor cell lines. In particular, derivative 21h demonstrated a >750-fold improvement in the growth inhibition of HeLa cells compared to roscovitine (2).
AMRI, Medicinal Chemistry Department, 26 Corporate Circle, Albany, NY 12212-5098, USA.
Michael P
MP
Trova
Keith D
KD
Barnes
Curt
C
Barford
Travis
T
Benanti
Mark
M
Bielaska
Lori
L
Burry
John M
JM
Lehman
Christine
C
Murphy
Harold
H
O'Grady
Denise
D
Peace
Susan
S
Salamone
Jennifer
J
Smith
Patricia
P
Snider
Joseph
J
Toporowski
Steven
S
Tregay
Alison
A
Wilson
Michael
M
Wyle
Xiaozhang
X
Zheng
Thomas D
TD
Friedrich
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000077546:Roscovitine; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases