Design, Synthesis, and Pharmacological Evaluation of Thapsigargin Analogues for Targeting Apoptosis to Prostatic Cancer Cells

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Abstract
A series of thapsigargin (TG) analogues, containing an amino acid applicable for conjugation to a peptide specifically cleaved by prostate-specific antigen (PSA), has been prepared to develop the drug-moiety of prodrugs for treatment of prostatic cancer. The analogues were synthesized by converting TG into O-8-debutanoylthapsigargin (DBTG) and esterifying O-8 of DBTG with various amino acid linkers. The compounds were evaluated for their ability to elevate the cytosolic Ca2+ concentration ([Ca2+]i) in TSU-Pr1 cells, their ability to inhibit the rabbit skeletal muscle SERCA pump, and their ability to induce apoptosis in TSU-Pr1 human prostatic cancer cells. The activity of analogues, in which DBTG were esterified with ω-amino acids [HOOC(CH2)nNH2, n = 5−7, 10, 11], increased with the linker length. Analogues with 3-[4-(l-leucinoylamino)phenyl]propanoyl, 6-(l-leucinoylamino)hexanoyl, and 12-(l-serinoylamino)dodecanoyl were considerably less active than TG, and analogues with 12-(l-alaninoylamino)dodecanoyl and 12-(l-phenylalaninoylamino)dodecanoyl were almost as active as TG. The 12-(l-leucinoylamino)dodecanoyl gave an analogue equipotent with TG, making this compound promising as the drug-moiety of a PSA sensitive prodrug of TG.