3,5-Bis(benzylidene)-1-[3-(2-hydroxyethylthio)propanoyl]piperidin-4-ones: A Novel Cluster of Potent Tumor-Selective Cytotoxins

Novel 3,5-bis(benzylidene)-1-[3-(2-hydroxyethylthio)propanoyl]piperidin-4-ones (<b>3a-e)</b> display potent cytotoxicity and a preferential lethality toward various neoplasms compared to some normal cells. The corresponding sulfonic acid analogues <b>5a</b>−<b>e</b> and an isostere <b>4</b> demonstrated substantially lower activity. The leads <b>3d</b> and <b>3e</b> possess very high activity against colon cancer and leukemia cell lines, caused DNA fragmentation, and activated caspase-3 in HL-60 cells. The enones <b>3b</b>−<b>e</b> were well tolerated in a short-term toxicity screen in mice.