Synthesis And Antiprolifeative Activities Of OSW-1 Analogues

1.Synthesis of OS W-1 analogues bearing 2-acylamino-xylose residuesOSW-1(1),a naturally occurring steroidal saponin isolated from the bulbs of Ornithogalum saundersiae,is known for its exceptionally strong potent antiproliferative activity against tumor cells.SBF-1(2),a synthetic analogue bearing an ester chain at C22 that can be readily prepared via a stereoselective aldol reaction,displays similar or even better antitumor activities as the natural product.Despite the tremendous efforts in synthetic realm,derivatization and structure-activity relationships studies,the mechanism of the antitumor activity of OSW-1 remains elusive.Based on SBF-1(2),we established an effective route for the synthesis of OSW-1 analogues bearing 2-acylamino-xylose residues.A library of 25(1→3)-linked and 13(1→4)-linked disaccharide analogues were prepared accordingly,including a photoaffinity and clickable probe 4.The evaluation of their antiproliferative activities indicated that the replacement with 2-acylamino-xylose residues could significantly increase the activities with the lowest IC50 value being down to 0.11 nM.In addition,the(1→3)-linkage of the disaccharide was confirmed to be crucial to retain the potent activities.2.Synthesis of OSW-1 analogues bearing 2-O-p-acylaminobenzoyl-xylose residuesBased on our structure-activity relationship studies,as reported in the first part,we designed and prepared a small library of 23 OSW-1 analogues with a variety of p-acylamino-benzoyl groups installed at C2 of the xylose residue,wherein a regioselective(1→3)-glycosylation of arabinoside 3,4-diol has been achieved by manipulation of the protecting groups on the imidate donors.Bioassays lead to new structure-activity relationships as well as two applicable fluorescent probes(161 and 167),which were found to localize to lysosomes in HeLa cells and could be used in further antitumor mechanism studies of OSW-1 in living cells.