ABSTRACT
Herein, we report the synthesis of 4'-C-trifluoromethyl (4'-CF3) thymidine (T4'-CF3) and its incorporation into oligodeoxynucleotides (ODNs) through solid-supported DNA synthesis. The 4'-CF3 modification leads to a marginal effect on the deoxyribose conformation and a local helical structure perturbation for ODN/RNA duplexes. This type of modification slightly decreases the thermal stability of ODN/RNA duplexes (-1 °C/modification) and leads to improved nuclease resistance. Like the well-known phosphorothioate (PS) modification, heavy 4'-CF3 modifications enable direct cellular uptake of the modified ODNs without any delivery reagents. This work highlights that 4'-CF3 modified ODNs are promising candidates for antisense-based therapeutics, which will, in turn, inspire us to develop more potent modifications for antisense ODNs and siRNAs.
Subject(s)
Hydrocarbons, Fluorinated/chemistry , Oligodeoxyribonucleotides/pharmacokinetics , HeLa Cells , Humans , Hydrocarbons, Fluorinated/blood , Microscopy, Confocal , Molecular Conformation , Oligodeoxyribonucleotides/blood , Oligodeoxyribonucleotides/chemistry , Tissue DistributionABSTRACT
RNA cleavage via internal transesterification is a fundamental reaction involved in RNA processing and metabolism, and the regulation thereof. Herein, the influence of ribose conformation on this reaction was investigated with conformationally constrained ribonucleotides. RNA cleavage rates were found to decrease in the order South-constrained ribonucleotide > native ribonucleotide â« North-constrained counterpart, indicating that the ribose conformation plays an important role in modulating RNA cleavage via internal transesterification.
Subject(s)
Oligoribonucleotides/chemistry , RNA Cleavage , RNA/chemistry , Ribose/chemistry , Density Functional Theory , Esterification , Kinetics , Models, Chemical , Nucleic Acid Conformation , Oligoribonucleotides/chemical synthesisABSTRACT
Owing to the unique physical properties of a fluorine atom, incorporating fluoro-modifications into nucleic acids offers striking biophysical and biochemical features, and thus significantly extends the breadth and depth of biological applications of nucleic acids. In this review, fluoro-modified nucleic acids that have been synthesized through either solid phase synthesis or the enzymatic approach are briefly summarised, followed by a section describing their biomedical applications in nucleic acid-based therapeutics, 18F PET imaging and mechanistic studies of DNA modifying enzymes. In the last part, the utility of 19F NMR and MRI for probing the structure, dynamics and molecular interactions of fluorinated nucleic acids is reviewed.
Subject(s)
DNA/chemical synthesis , DNA/metabolism , Enzymes/metabolism , Fluorine/chemistry , Biomedical Research , DNA/chemistry , Positron-Emission Tomography , Solid-Phase Synthesis TechniquesABSTRACT
Described herein is a facile and efficient methodology toward the synthesis of Morusin scaffolds and Morusignin L scaffolds 4-9 and 12via a novel three-step approach (Michael addition or prenylation, cyclization and cyclization) and use a rapid, microwave-accelerated cyclization as the key step. Furthermore, their biological activities have been preliminarily demonstrated by in vitro evaluation for anti-osteoporosis activity. These Morusin, Morusignin L and newly synthesized compounds 5b, 6a, 8e, 8f greatly exhibited the highest potency, especially at the 10-5mol/L (P<0.01), and had good in vitro anti-osteoporosis activities using the commercially available standard drug Ipriflavone as a positive control. The mechanisms associated with anti-osteoporosis effects of these compounds may be through the inhibition of TRAP enzyme activity and bone resorption in osteoclasts, and promotion effect of osteoblast proliferation in vitro. The results indicated that Morusin scaffolds and Morusignin L scaffolds may be useful leads for further anti-osteoporosis activity screenings.
