PMID- 11741487
OWN - NLM
STAT- MEDLINE
DCOM- 20020114
LR  - 20220410
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 44
IP  - 26
DP  - 2001 Dec 20
TI  - Design, synthesis, and pharmacological evaluation of thapsigargin analogues for 
      targeting apoptosis to prostatic cancer cells.
PG  - 4696-703
AB  - 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 Ca(2+) concentration ([Ca(2+)](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 omega-amino acids [HOOC(CH(2))(n)()NH(2), 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.
FAU - Jakobsen, C M
AU  - Jakobsen CM
AD  - Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 
      Universitetsparken, DK-2100 Copenhagen, Denmark.
FAU - Denmeade, S R
AU  - Denmeade SR
FAU - Isaacs, J T
AU  - Isaacs JT
FAU - Gady, A
AU  - Gady A
FAU - Olsen, C E
AU  - Olsen CE
FAU - Christensen, S B
AU  - Christensen SB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (8-O-(12-(leucinoylamino)dodecanoyl)-8-O-debutanoylthapsigargin)
RN  - 0 (Antineoplastic Agents)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
RN  - EC 7.2.2.10 (Calcium-Transporting ATPases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*chemical synthesis/chemistry/pharmacology
MH  - *Apoptosis
MH  - Calcium/metabolism
MH  - Calcium-Transporting ATPases/metabolism
MH  - Drug Design
MH  - Drug Screening Assays, Antitumor
MH  - Humans
MH  - Male
MH  - Muscle, Skeletal/enzymology
MH  - Prostatic Neoplasms/*pathology
MH  - Rabbits
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases
MH  - Structure-Activity Relationship
MH  - Thapsigargin/*analogs & derivatives/*chemical synthesis/chemistry/pharmacology
MH  - Tumor Cells, Cultured
EDAT- 2001/12/14 10:00
MHDA- 2002/01/15 10:01
CRDT- 2001/12/14 10:00
PHST- 2001/12/14 10:00 [pubmed]
PHST- 2002/01/15 10:01 [medline]
PHST- 2001/12/14 10:00 [entrez]
AID - jm010985a [pii]
AID - 10.1021/jm010985a [doi]
PST - ppublish
SO  - J Med Chem. 2001 Dec 20;44(26):4696-703. doi: 10.1021/jm010985a.