title: Rational design, synthesis, and biological evaluation of rigid pyrrolidone analogues as potential inhibitors of prostate cancer cell growth.
abstract: 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.
authors.affiliation: Department of Neurology, Georgetotwn University, Medical Center, Washington, DC 20007, USA.
authors.forename: L
authors.initials: L
authors.lastname: Qiao
authors.forename: L Y
authors.initials: LY
authors.lastname: Zhao
authors.forename: S B
authors.initials: SB
authors.lastname: Rong
authors.forename: X W
authors.initials: XW
authors.lastname: Wu
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: T
authors.initials: T
authors.lastname: Fujii
authors.forename: M G
authors.initials: MG
authors.lastname: Kazanietz
authors.forename: L
authors.initials: L
authors.lastname: Rauser
authors.forename: J
authors.initials: J
authors.lastname: Savage
authors.forename: B L
authors.initials: BL
authors.lastname: Roth
authors.forename: J
authors.initials: J
authors.lastname: Flippen-Anderson
authors.forename: A P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: 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
chemical_list: 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