Development of a Gene Expression Control Medicine and Analysis of the Interaction with a DNA Duplex.

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Organic compounds capable of controlling gene expression by recognizing DNA sequence-specificity are expected to be viable gene therapy medicine. The nucleosides bearing pyrrolepolyamide which is minor groove binder were designed and synthesized as a lead compounds for gene therapy medicine and the analysis of DNA interaction with these compounds by Tm values and Circular Dichroism (CD) spectra was performed. In addition, the synthesis of {(5R)-D-[5-^2H_1;5-^<13>C]ribofuranosyl}nucleoside that is useful for structural analysis of conformation in DNA was carried out. 1.Deoxyguanosine bearing pyrrolepolyamide using 3-aminopropyl linker (GAP), using aminopropyonyl linker (GBP) and adenosine bearing pyrrolepolyamide (Apy) were synthesized. 2.The investigation of affinity for DNA duplexes by Tm values and CD spectra showed that DNA included the sequence of 5'-AAATT-3' with GAP complex has potential of highly selectivity as compare with complexes of other DNA. In this result, GAP might have usable sequence selectively in gene therapy, and provide possibility to be new series of antisense or antigene drugs. 3.Highly diastereoselective synthesis of {(5R)-D-[5-^2H_1;5-^<13>C]ribofuranosyl}thymine was established. A preparation of {(5R)-D-[5-^2H_1;5-^<13>C]ribose derivative of 1,2:5,6-di-O-isopropyliden-α-D-allofranose was successfully achieved by a ^<13>C Wittig reaction using Ph_3P^<13>CH_3I-BuLi to 5-oxoribose derivative and subsequent transformation into D-[5-^<13>C]ribose derivative with an AD reaction, selective acylation, oxidation with NaIO_4, and a stereoselective deuteride transfer reaction from Alpine-Borane-d to 5-oxo-D-[5-^<13>C]ribose derivative as the main reaction. {(5R)-D-[5-^2H_1;5-^<13>C]ribofuranosyl}thymine was synthesized in the established manner from this 5-^<13>C/^2H_1-double-labeled ribose.