Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth.
In view of its role in tumor promotion and signal transduction, protein kinase C (PKC) has proven to be an exciting target for cancer therapy. With the aid of molecular modeling, we rationally designed and stereoselectively synthesized a new class of rigidified pyrrolidone-based PKC activators. Pyrrolidone 15 was found to exhibit reasonable affinity for PKCdelta, with lower affinity for the other isozymes tested. Pyrrolidone 2 causes the dose-dependent induction of apoptosis in LNCaP prostate cancer cells. This apoptotic effect could be markedly potentiated by the use of LNCaP cells overexpressing the PKCalpha or delta isozymes.
Qiao
L
L
Department of Neurology, Georgetotwn University, Medical Center, Washington, DC 20007, USA.
Zhao
L Y
LY
Rong
S B
SB
Wu
X W
XW
Wang
S
S
Fujii
T
T
Kazanietz
M G
MG
Rauser
L
L
Savage
J
J
Roth
B L
BL
Flippen-Anderson
J
J
Kozikowski
A P
AP
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D020536:Enzyme Activators / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008297:Male; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D011493:Protein Kinase C / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D020536:Enzyme Activators; D007527:Isoenzymes; D011760:Pyrrolidinones; C434793:pyrollidone 15; C434794:pyrollidone 2; C496628:PRKCA protein, human; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta