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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androgens / metabolism
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Animals
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Apoptosis / drug effects
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Calcium / metabolism
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Calcium-Transporting ATPases / antagonists & inhibitors*
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Humans
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Inhibitory Concentration 50
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Male
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / enzymology
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Prodrugs / chemical synthesis
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Prodrugs / pharmacology
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Prostate-Specific Antigen / chemistry
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Prostate-Specific Antigen / metabolism
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Rabbits
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Sarcoplasmic Reticulum / drug effects
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Sarcoplasmic Reticulum / enzymology
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Structure-Activity Relationship
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Thapsigargin / analogs & derivatives*
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Thapsigargin / chemical synthesis
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Thapsigargin / pharmacology
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Tumor Cells, Cultured
Substances
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8-O-(3-(4-aminophenyl)propionyl)-8-O-debutanoylthapsigargin
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8-O-(4-(4-aminophenyl)butanoyl)-8-O-debutanoylthapsigargin
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Androgens
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Enzyme Inhibitors
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Prodrugs
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Thapsigargin
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Prostate-Specific Antigen
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Calcium-Transporting ATPases
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Calcium