title: Thapsigargin analogues for targeting programmed death of androgen-independent prostate cancer cells.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen. sbc@mail.dfh.dk
authors.forename: S B
authors.initials: SB
authors.lastname: Christensen
authors.forename: A
authors.initials: A
authors.lastname: Andersen
authors.forename: H
authors.initials: H
authors.lastname: Kromann
authors.forename: M
authors.initials: M
authors.lastname: Treiman
authors.forename: B
authors.initials: B
authors.lastname: Tombal
authors.forename: S
authors.initials: S
authors.lastname: Denmeade
authors.forename: J T
authors.initials: JT
authors.lastname: Isaacs
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000737:chemistry / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D019284:Thapsigargin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C121613:8-O-(3-(4-aminophenyl)propionyl)-8-O-debutanoylthapsigargin; C121614:8-O-(4-(4-aminophenyl)butanoyl)-8-O-debutanoylthapsigargin; D000728:Androgens; D004791:Enzyme Inhibitors; D011355:Prodrugs; D019284:Thapsigargin; D017430:Prostate-Specific Antigen; D000252:Calcium-Transporting ATPases; D002118:Calcium