The Potencies of Thapsigargin and Analogues as Activators of Rat Peritoneal Mast Cells

Norup, Elsebeth; Smitt, Ulla Wagner; Christensen, Steffan Wittrup

doi:10.1055/s-2007-969144

Cited by 28 publications

(10 citation statements)

References 14 publications

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“…Previously, a positive correlation between lipophilicity and histamine-releasing activity was found in a series of O-2 and O-8 substituted TG analogues. 21 The previously prepared aromatic analogues 3c,e,f were 328, 81, and 4.4 times less potent SERCA inhibitors than TG, respectively, and >800, 533, and 103 times less cytotoxic, respectively. 10 Apparently, the potency also in this case increases with increasing lipophilicity.…”

Section: Resultsmentioning

confidence: 91%

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

Jakobsen¹,

Denmeade²,

Isaacs³

et al. 2001

J. Med. Chem.

128

102

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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.

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Section: Resultsmentioning

confidence: 91%

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

Jakobsen¹,

Denmeade²,

Isaacs³

et al. 2001

J. Med. Chem.

128

102

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“…Thapsigargins 1-11, 14, 15, 17 and 18 have all been shown to have histamine releasing abilities to varying degrees (Christensen et al 1984a;Liu et al 2006;Norup et al 1986;Rasmussen et al 1981). Thus, the structure-activity relationship of thapsigargins seems rather flexible regarding the residues positioned at C(2) and C(8); as long as the correct stereochemistry is maintained, all are expected to bind to SERCA to some extent.…”

Section: T Nitidamentioning

confidence: 99%

Guaianolides in apiaceae: perspectives on pharmacology and biosynthesis

et al. 2009

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The guaianolide group of sesquiterpene lactones contains a large number of compounds with biological activity. One of these guaianolides, thapsigargin from the genus Thapsia (Apiaceae), has been a subject of particular interest in recent years because of its ability to induce apoptosis, as the active part of a pro-drug, has produced promising results for the targeted treatment of prostate cancer. In this review, recent advances in understanding the biosynthetic pathway of sesquiterpenes in plants is described with a special emphasis on guaianolides, and a hypothetical pathway for the biosynthesis of thapsigargin is presented. Eighty-seven guaianolides from Apiaceae are presented. These compounds provide clues to possible enzymatic mechanisms generating the guaianolides in Apiaceae. Some of these 87 compounds have proven or might prove interesting with regards to their biological activity.

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“…To test for the role of intracellular calcium stores, thapsigargin (1 M), which inhibits the endoplasmic reticulum Ca 2ϩ ATPase and prevents a refill of the Ca 2ϩ stores (Norup et al, 1986), was washed for 60 min. This decreased the size of the black wave evoked by afferent stimulation (Fig.…”

Section: Thapsigargin and Protein Kinase Cmentioning

confidence: 99%

A Novel Role of Vasopressin in the Brain: Modulation of Activity-Dependent Water Flux in the Neocortex

et al. 2001

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The brain contains an intrinsic vasopressin fiber system the function of which is unknown. It has been demonstrated recently that astrocytes express high levels of a water channel, aquaporin-4 (AQP4). Because vasopressin is known to regulate aquaporin expression and translocation in kidney collecting ducts and thereby control water reabsorption, we hypothesized that vasopressin might serve a similar function in the brain. By recording intrinsic optical signals in an acute cortical slice preparation we showed that evoked neuronal activity generates a radial water flux in the neocortex. The rapid onset and high capacity of this flux suggest that it is mediated through the AQP4-containing astrocytic syncytium that spans the entire thickness of the neocortical mantle. Vasopressin and vasopressin receptor V1a agonists were found to facilitate this flux. V1a antagonists blocked the facilitatory effect of vasopressin and reduced the water flux even in the absence of any exogenous agonist. V2 agonists or antagonists had no effect. These data suggest that vasopressin and V1a receptors play a crucial role in the regulation of brain water and ion homeostasis, most probably by modulating aquaporin-mediated water flux through astrocyte plasma membranes.

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The Potencies of Thapsigargin and Analogues as Activators of Rat Peritoneal Mast Cells

Cited by 28 publications

References 14 publications

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

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

Guaianolides in apiaceae: perspectives on pharmacology and biosynthesis

A Novel Role of Vasopressin in the Brain: Modulation of Activity-Dependent Water Flux in the Neocortex

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