Stereo-enriched phosphorothioate oligodeoxynucleotides : Synthesis, biophysical and biological properties

Stereo-enriched [Rp] and [Sp]-phosphorothioate oligodeoxynucleotides are synthesized using oxazaphospholidine derivatized monomers. Three different designs of phosphorothioate oligodeoxynucleotides (PS-oligos), (i) stereo-enriched all-[Rp] or all-[Sp] PS-linkages, (ii) stereo-random mixture of PS-li...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2000, Vol.8 (1), p.275-284
Main Authors: DONG YU, KANDIMALLA, E. R, ROSKEY, A, QIUYAN ZHAO, LIHONG CHEN, JIANGDONG CHEN, AGRAWAL, S
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Base Sequence
Biological and medical sciences
Cell Division - drug effects
Circular Dichroism
General aspects
Male
Medical sciences
Mice
Nuclear Proteins
Organophosphorus Compounds - chemistry
Pharmacology. Drug treatments
Proto-Oncogene Proteins - antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2
Spectrophotometry, Ultraviolet
Thionucleotides - chemical synthesis
Thionucleotides - chemistry
Thionucleotides - pharmacology
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Summary:Stereo-enriched [Rp] and [Sp]-phosphorothioate oligodeoxynucleotides are synthesized using oxazaphospholidine derivatized monomers. Three different designs of phosphorothioate oligodeoxynucleotides (PS-oligos), (i) stereo-enriched all-[Rp] or all-[Sp] PS-linkages, (ii) stereo-random mixture of PS-linkages, and (iii) segments containing certain number of stereo-enriched [Rp] and [Sp] PS-linkages ([Sp-Rp-Sp] or [Rp-Sp-Rp]), have been studied. Thermal melting studies of these PS-oligos with RNA complementary strands showed that the binding affinities are in the order [Rp] > [Sp-Rp-Sp]-[Rp-Sp-Rp] > stereo-random > [Sp]. Circular dichroism (CD) studies suggest that the stereochemistry of the PS-oligo does not affect the global conformation of the duplex. The in vitro nuclease stability of these PS-oligos is in the order [Sp] > [Sp-Rp-Sp] > stereo-random > [Rp]. The RNase H activation is in the order [Rp] > stereo-random > [Rp-Sp-Rp] > [Sp] > [Sp-Rp-Sp]. Studies in a cancer cell line of PS-oligos targeted to MDM2 mRNA showed that all oligos had similar biological activity under the experimental conditions employed. Protein- and enzyme-binding studies showed insignificant stereo-dependent binding to proteins. The [Sp] and [Sp-Rp-Sp] chimeric and stereo-random PS-oligos that contained a CpG motif showed higher cell proliferation than [Rp] PS-oligo of the same sequence.
ISSN:0968-0896
DOI:10.1016/s0968-0896(99)00275-8