Synthesis and hybridization properties of RNA containing 8-chloroadenosine.
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 approximately 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.
Chen
Lisa S
LS
Department of Chemistry, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA.
Sheppard
Terry L
TL
D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry* / Q000528:radiation effects; D002942:Circular Dichroism; D006358:Hot Temperature; D015394:Molecular Structure; D009691:Nucleic Acid Denaturation / Q000528:radiation effects; D009693:Nucleic Acid Hybridization; D012313:RNA / Q000138:chemical synthesis* / Q000737:chemistry* / Q000528:radiation effects; D020871:RNA Stability / Q000528:radiation effects; D018075:RNA, Complementary / Q000737:chemistry; D014466:Ultraviolet Rays
D018075:RNA, Complementary; D015762:2-Chloroadenosine; D012313:RNA; C075440:8-chloroadenosine