ABSTRACT
We recently reported that 4-epi-jaspine B exhibits potent inhibitory activity towards sphingosine kinases (SphKs). In this study, we investigated the effects of modifying the 2-alkyl group, as well as the functional groups on the THF ring of 4-epi-jaspine B using a diversity-oriented synthesis approach based on a late-stage cross metathesis reaction. The introduction of a p-phenylene tether to the alkyl group was favored in most cases, whereas the replacement of a carbon atom with an oxygen atom led to a decrease in the inhibitory activity. Furthermore, the introduction of a bulky alkyl group at the terminus led to a slight increase in the inhibitory activity of this series towards SphKs compared with 4-epi-jaspine B (the Q values of compound 13 for SphK1 and SphK2 were 0.2 and 0.4, respectively). Based on this study, we identified two isoform selective inhibitors, including the m-phenylene derivative 4 [IC50 (SphK1) ≥30µM; IC50 (SphK2)=2.2µM] and the methyl ether derivative 22 [IC50 (SphK1)=4.0µM; IC50 (SphK2) ≥30µM].
Subject(s)
Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Sphingosine/analogs & derivatives , Humans , Molecular Docking Simulation , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Sphingosine/chemistry , Sphingosine/pharmacology , Structure-Activity RelationshipABSTRACT
PURPOSE: Previously, we reported that the cationic liposomes composed of a cationic cholesterol derivative, cholesteryl (2-((2-hydroxyethyl)amino)ethyl)carbamate (OH-C-Chol) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) (termed LP-C), could deliver small interfering RNAs (siRNAs) with high transfection efficiency into tumor cells. In this study, to develop a liposomal vector for siRNA delivery in vivo, we prepared the poly(ethyleneglycol) (PEG)-modified cationic liposomes (LP-C-PEG) and evaluated their transfection efficiency in vitro and in vivo. MATERIALS AND METHODS: We prepared LP-C-PEG/siRNA complexes (LP-C-PEG lipoplexes) formed in water or 50 mM NaCl solution, and evaluated their siRNA biodistribution and gene silencing effect in mice after intravenous injection. RESULTS: LP-C-PEG lipoplexes strongly exhibited in vitro gene silencing effects in human breast tumor MCF-7 cells as well as LP-C lipoplexes. In particular, formation of LP-C and LP-C-PEG lipoplexes in the NaCl solution increased the cellular association. When LP-C-PEG lipoplexes with Cy5.5-labeled siRNA formed in water or NaCl solution were injected into mice, accumulation of the siRNA was observed in the liver. Furthermore, injection of LP-C-PEG lipoplexes with ApoB siRNA could suppress ApoB mRNA levels in the liver and reduce very-low-density lipoprotein/low-density lipoprotein levels in serum compared with that after Cont siRNA transfection, although the presence of NaCl solution in forming the lipoplexes did not affect gene silencing effects in vivo. CONCLUSIONS: LP-C-PEG may have potential as a gene vector for siRNA delivery to the liver.
Subject(s)
Cholesterol/chemistry , Gene Transfer Techniques , Liposomes/chemistry , Liver/drug effects , RNA, Small Interfering/chemistry , Animals , Cations , Female , Gene Silencing , Humans , Lipoproteins, LDL/chemistry , Lipoproteins, LDL/metabolism , Liposomes/administration & dosage , Liposomes/pharmacology , MCF-7 Cells , Mice, Inbred BALB C , Particle Size , Polyethylene Glycols/chemistry , RNA, Small Interfering/administration & dosage , Surface Properties , Transfection/methodsABSTRACT
Two classes of modified analogs of 4-(thiazol-5-yl)benzoic acid-type CK2 inhibitors were designed. The azabenzene analogs, pyridine- and pyridazine-carboxylic acid derivatives, showed potent protein kinase CK2 inhibitory activities [IC50 (CK2α)=0.014-0.017µM; IC50 (CK2α')=0.0046-0.010µM]. Introduction of a 2-halo- or 2-methoxy-benzyloxy group at the 3-position of the benzoic acid moiety maintained the potent CK2 inhibitory activities [IC50 (CK2α)=0.014-0.016µM; IC50 (CK2α')=0.0088-0.014µM] and led to antiproliferative activities [CC50 (A549)=1.5-3.3µM] three to six times higher than those of the parent compound.
