Thapsigargin analogues for targeting programmed death of androgen-independent prostate cancer cells

A number of analogues of thapsigargin, a selective inhibitor of the sarco-endoplasmic reticulum Ca²⁺-ATPases have been synthesized. In all of the prepared analogues the butanoyl residue at O-8 has been replaced with a residue containing an aromatic amine. The amine can be used as an anchoring point for attaching a peptide group sensitive to the proteolytic enzyme, prostate specific antigen, secreted by prostate cancer cells. Like thapsigargin, the analogues are capable of elevating the cytoplasmic Ca²⁺ concentration approximately sevenfold when tested at effective cytotoxic doses. The analogues in which the 8-O-butanoyl group has been replaced with 3-(4-aminophenyl)propanoyl or 4-aminocinnamoyl were found potently to induce programmed cell death of the prostate cancer cells. Copyright (C) 1999 Elsevier Science Ltd.