Abstract
8-Chloroadenosine (8-Cl-Ado) has shown potential as a chemotherapeutic agent for the treatment of multiple myeloma and certain leukemias. 8-Cl-Ado treatment leads to a decrease in global RNA levels and incorporation of the analog into cellular RNA in malignant cells. To investigate the effects of 8-Cl-Ado modifications on RNA structure and function, an 8-Cl-Ado phosphoramidite and controlled-pore glass support were synthesized and used to introduce 8-Cl-Ado at internal and 3′- terminal positions, respectively. RNA oligonucleotides containing 8-chloroadenine (8-Cl-A) residues were synthesized and hybridized with complementary RNA strands. Circular dichroism spectroscopy of the resulting RNA duplexes revealed that the modified nucleobase does not perturb the overall A-form helix geometry. The thermal stabilities of 8-Cl-Ado modified duplexes were determined by UV thermal denaturation analysis and were compared with analogous natural duplexes containing standard and mismatched base pairs. The 8-Cl-Ado modification destabilizes RNA duplexes by ∼ 5 kcal/mole, approximately as much as a U:U mismatched base pair. The duplex destabilization of 8-Cl-A may result from perturbation of Watson-Crick base pairing induced by conformational preferences of 8-halogenated nucleosides.
Original language | English (US) |
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Pages (from-to) | 599-617 |
Number of pages | 19 |
Journal | Nucleosides, Nucleotides and Nucleic Acids |
Volume | 21 |
Issue number | 8-9 |
DOIs | |
State | Published - 2002 |
Externally published | Yes |
Keywords
- 8-Chloroadenosine
- Nucleoside
- Phosphoramidite
- RNA duplex stability
- RNA synthesis
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Genetics