Capuramycin analogues with a variety of substituents in place of the azepan-2-one moiety were synthesized from A-500359E and were tested for their translocase I inhibitory activity and in vitro antimycobacterial activity. Phenyl-type moieties were found to be effective substituents for capuramycin analogues.
Aminoglycosides/chemical synthesis , Aminoglycosides/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Azepines/chemistry , Azepines/pharmacology , Aminoglycosides/chemistry , Anti-Bacterial Agents/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Microbial Sensitivity Tests , Mycobacterium/drug effects , Structure-Activity Relationship , Transferases/antagonists & inhibitors
Acylated derivatives of capuramycin and A-500359A were synthesized and tested for antimycobacterial activity. Compound 20 having a decanoyl group showed very potent activity.
Aminoglycosides/chemical synthesis , Aminoglycosides/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Acylation , Aminoglycosides/chemistry , Anti-Bacterial Agents/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Isomerism , Microbial Sensitivity Tests , Mycobacterium/drug effects , Prodrugs/chemistry , Prodrugs/pharmacology , Structure-Activity Relationship , Transferases/antagonists & inhibitors
Novel bicyclo nucleosides, 2'-O,4'-C-ethylene nucleosides and 2'-O,4'-C-propylene nucleosides, were synthesized as building blocks for antisense oligonucleotides to further optimize the 2'-O,4'-C-methylene-linkage of bridged nucleic acids (2',4'-BNA) or locked nucleic acids (LNA). Both the 2'-O,4'-C-ethylene- and propylene-linkage within these nucleosides restrict the sugar puckering to the N-conformation of RNA as do 2',4'-BNA/LNA. Furthermore, ethylene-bridged nucleic acids (ENA) having 2'-O,4'-C-ethylene nucleosides had considerably increased the affinity to complementary RNA, and were as high as that of 2',4'-BNA/LNA (DeltaT(m)=+3 approximately 5 degrees C per modification). On the other hand, addition of 2'-O,4'-C-propylene modifications in oligonucleotides led to a decrease in the affinity to complementary RNA. As for the stability against nucleases, incorporation of one 2'-O,4'-C-ethylene or one 2'-O,4'-C-propylene nucleoside into oligonucleotides considerably increased their resistance against exonucleases to an extent greater than 2',4'-BNA/LNA. These results indicate that ENA is more suitable as an antisense oligonucleotide and is expected to have better antisense activity than 2',4'-BNA/LNA.
Bridged-Ring Compounds/chemical synthesis , Nucleosides/chemical synthesis , Oligonucleotides, Antisense/chemical synthesis , Alkenes/chemistry , Circular Dichroism , Crystallography , Drug Design , Drug Stability , Ethylenes/chemistry , Molecular Structure , Nuclease Protection Assays , RNA/chemistry , Ribonucleases/chemistry , Ribonucleases/metabolism , Stereoisomerism , Structure-Activity Relationship , Transition Temperature
To develop antisense oligonucleotides, novel nucleosides, 2'-O,4'-C-ethylene nucleosides and their corresponding phosphoramidites, were synthesized as building blocks. The 1H NMR analysis showed that the 2'-O,4'-C-ethylene linkage of these nucleosides restricts the sugar puckering to the N-conformation as well as the linkage of 2'-O,4'-C-methylene nucleosides which are known as bridged nucleic acids (BNA) or locked nucleic acids (LNA). The ethylene-bridged nucleic acids (ENA) showed a high binding affinity for the complementary RNA strand (DeltaT(m)=+5.2 degrees C/modification) and were more nuclease-resistant than natural DNA and BNA/LNA. These results indicate that ENA have better properties as antisense oligonucleotides than BNA/LNA.
Oligonucleotides, Antisense/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/metabolism , DNA, Complementary/chemistry , Drug Design , Drug Stability , Kinetics , Oligonucleotides, Antisense/chemistry , Oligonucleotides, Antisense/metabolism , RNA, Complementary/chemistry , Single-Strand Specific DNA and RNA Endonucleases/metabolism , Structure-Activity Relationship , Temperature , Thymidine/chemistry
