SLIM NUCLEOSIDES AND NUCLEOTIDES .1. SYNTHETIC, STRUCTURAL AND BIOPHYSICAL INVESTIGATIONS OF SHOWDOMYCINS

A new, convenient, and short synthesis of 2'-deoxyshowdomycin, along w ith an improved procedure for the preparation of showdomycin, have bee n presented. A single-crystal X-ray structure of 1-benzyl-2'-deoxyshow domycin (9) has been reported. Conformational studies using C.D. indic ated that showdomycin exists predominantly in an anti conformation in aqueous solution. Molecular mechanics calculations using AMBER point t o comparable binding energy of showdomycin-adenosine pair with the nat ural uridine-adenosine pair, but with a significant base-ribose confor mational deviation from the natural array in the former. Implications of such a conformational deviation on tumor and viral replications hav e been discussed. Base-pairing studies employing high resolution NMR s pectroscopy indicate that both showdomycin and epishowdomycin base-pai r with adenosine-5'-monophosphate (AMP); however, while showdomycin al so shows evidence of stacking, that was absent in epishowdomycin. Mole cular modeling studies using QUANTA/CHARMm show that showdomycin is ca pable of forming a homopolymer duplex by base-pairing with poly(A), bu t with a considerably broader and deeper major groove. A heteropolymer duplex with a single insert of showdomycin exhibits tighter coiling a t the point of insertion. A ten-picosecond dynamics simulation of the above heteroduplex revealed relaxation of the helix with disruption of H-bonding for two base pairs on either side of the insertion point, f orming a large central cavity.