Design, synthesis, and characterization of piperazinedione-based dual protein inhibitors for both farnesyltransferase and geranylgeranyltransferase-I

• Published in: European journal of medicinal chemistry Vol. 46; no. 6; pp. 2264 - 2273
• Main Authors: Qiao, Yuqin, Gao, Jinbo, Qiu, Yongge, Wu, Long, Guo, Fei, Kam-Wing Lo, Kenneth, Li, Ding
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.06.2011; Elsevier
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Alkyl and Aryl Transferases - metabolism; Antineoplastic agents; Biological and medical sciences; Cancer; Chemistry, Medicinal; Dose-Response Relationship, Drug; Drug Design; Dual protein inhibitor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Farnesyltransferase; Farnesyltranstransferase - antagonists & inhibitors; Farnesyltranstransferase - metabolism; General aspects; Geranylgeranyltransferase; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Piperazinedione; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Piperazinedione; Dual protein inhibitor; Geranylgeranyltransferase; Farnesyltransferase; Cancer; CRYSTAL-STRUCTURE; ACUTE MYELOID-LEUKEMIA; TIPIFARNIB; PRENYLATION; MOUSE MODEL; DISEASE; FLUORESCENCE ASSAY; PHASE-I; REVEALS; Nitrogen heterocycle; Cyclic peptides; Protein farnesyltransferase; Modeling; Structure activity relation; Chlorine Organic compounds; Six membered ring; Molecular model; Bicyclic compound; Binding mode; Chemical synthesis; Ether; Enzyme; Transferases; Benzene derivatives; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Protein geranylgeranyltransferase type I; Dipeptides; Kinetics; Indole derivatives
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.03.007

Farnesyltransferase (FTase) and geranylgeranyltransferase type-I (GGTase-I) both catalyze the prenylation of protein substrate containing a typical –CAAX motif at the carboxyl terminus. The inhibitors for these two enzymes have been widely studied as potential cancer chemotherapeutic agents. In the present study, various piperazinedione derivatives were designed and synthesized as a new type of peptide mimetic compounds, which were characterized and found to be dual protein inhibitors for both FTase and GGTase-I. These compounds have similar chemical and physical properties to –CAAX motif of the protein substrate, which may facilitate their transfer to appropriate drug target in vivo. The best inhibitor compound 26b was found to occupy both isoprenoid and peptide substrate binding sites through kinetics and computer molecular docking studies. Various piperazinedione derivatives were designed and synthesized as a new type of peptide mimetic compounds, which were characterized and found to be dual protein inhibitors for both Farnesyltransferase and Geranylgeranyltransferase-I. [Display omitted] ► Various piperazinedione derivatives were designed and synthesized as a new type of peptide mimetic compounds, which were characterized and found to be dual protein inhibitors for both FTase and GGTase-I. ► These compounds have similar chemical and physical properties to –CAAX motif of the protein substrate, which may facilitate their transfer to appropriate drug target in vivo. ► The best inhibitor compound 26b was found to occupy both isoprenoid and peptide substrate binding sites through kinetics and computer molecular docking studies.