Improved Total Synthesis andBiological Evaluationof Potent Apratoxin S4 Based Anticancer Agents with Differential Stabilityand Further Enhanced Activity

摘要

Apratoxins are cytotoxic natural products originally isolated from marine cyanobacteria that act by preventing cotranslational translocation early in the secretory pathway to downregulate receptor levels and inhibit growth factor secretion, leading to potent antiproliferative activity. Through rational design and total synthesis of an apratoxin A/E hybrid, apratoxin S4 (>1a), we have previously improved the antitumor activity and tolerability in vivo. Compound >1a and newly designed analogues apratoxins S7–S9 (>1b–>d), with various degrees of methylation at C34 (>1b,>c) or epimeric configuration at C30 (>1d), were efficiently synthesized utilizing improved procedures. Optimizations have been applied to the synthesis of key intermediate aldehyde >7 and further include the application of Leighton’s silanes and modifications of Kelly’s methods to induce thiazoline ring formation in other crucial steps of the apratoxin synthesis. Apratoxin S9 (>1d) exhibited increased activity with subnanomolar potency. Apratoxin S8 (>1c) lacks the propensity to be deactivated by dehydration and showed efficacyin a human HCT116 xenograft mouse model.