Total Synthesis of Thapsigargin, a Potent SERCA Pump Inhibitor

Ball, Matthew; Andrews, Stephen P.; Wierschem, Frank; Cleator, Ed; Smith, and Martin D.; Ley, Steven V.

doi:10.1021/ol062947x

Cited by 65 publications

(27 citation statements)

References 21 publications

(17 reference statements)

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“…This compound was originally isolated from the roots of Thapsia garganica L. (Apiaceae) by the group of Prof. Søren Brøgger Christensen (Danish University of Pharmaceutical Sciences, Copenhagen, Denmark) [112], with the structure and relative configuration determined by chemica1 and spectroscopic investigations, together with X-ray analysis of its 7,11-epoxide analogue [113]. The absolute configuration of TPG was established using CD spectroscopy with the application of Horeau’s method [114], and the enantioselective total synthesis of TPG has been completed through a total of 42 steps of reactions involving regioselective introduction of the internal olefin at C-4–C-5, judicious protecting group choice to allow chelation-controlled reduction at C-3, and selective esterification (Scheme 11) [115, 116]. …”

Section: 8-o-(12-{l-leucinoylamino}dodecanoyl)-8-o-debutanoylthapsmentioning

confidence: 99%

Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones

Ren¹,

Yu²,

Kinghorn

2016

CMC

134

121

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Sesquiterpene lactones are of considerable interest due to their potent bioactivities, including cancer cell cytotoxicity and antineoplastic efficacy in in vivo studies. Among these compounds, artesunate, dimethylaminoparthenolide, and L12ADT peptide prodrug, a derivative of thapsigargin, are being evaluated in current cancer clinical or preclinical trials. Based on the structures of several antitumor sesquiterpene lactones, a number of analogues showing greater potency have been either isolated as natural products or partially synthesized, and some potential anticancer agents that have emerged from this group of lead compounds have been investigated extensively. The present review focuses on artemisinin, parthenolide, thapsigargin, and their naturally occurring or synthetic analogues showing potential anticancer activity. This provides an overview of the advances in the development of these types of sesquiterpene lactones as potential anticancer agents, including their structural characterization, synthesis and synthetic modification, and antitumor potential, with the mechanism of action and structure-activity relationships also discussed. It is hoped that this will be helpful in stimulating the further interest in developing sesquiterpene lactones and their derivatives as new anticancer agents.

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Section: 8-o-(12-{l-leucinoylamino}dodecanoyl)-8-o-debutanoylthapsmentioning

confidence: 99%

Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones

Ren¹,

Yu²,

Kinghorn

2016

CMC

134

121

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“…Because of their small size, these compounds can be prepared from inexpensive starting materials in only a few synthetic steps. This constitutes a considerable advantage over TG-based inhibitors, whose complex total synthesis entails 42 steps, has an overall yield of 0.6%, and requires the use of multiple protecting groups 7.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of hydroquinone derivatives as novel inhibitors of the sarco/endoplasmic reticulum calcium ATPase

Paula

Abell

Deye

et al. 2009

Bioorganic & Medicinal Chemistry

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Analogues of the compound 2,5-di-tert-butylhydroquinone (BHQ) are capable of inhibiting the enzyme sarco/endoplasmic reticulum ATPase (SERCA) in the low micromolar and submicromolar concentration ranges. Not only are SERCA inhibitors valuable research tools, but they also have potential medicinal value as agents against prostate cancer. This study describes the synthesis of thirteen compounds representing several classes of BHQ analogues, such as hydroquinones with a single aromatic substituent, symmetrically and unsymmetrically disubstituted hydroquinones, and hydroquinones with ω-amino acid tethers attached to their hydroxyl groups. Structure-activity relationships were established by measuring the inhibitory potencies of all synthesized compounds in bioassays. The assays were complemented by computational ligand docking for an analysis of the relevant ligand/receptor interactions.

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“…The addition of Thapsigargin (TG), a highly specific SERCA pump inhibitor, irreversibly blocks the calcium pumping from the cytosol into the ER lumen. TG binds to the functional cavity of SERCA on the ER membrane and locks the pump into a conformation with poor calcium and ATP affinity [67,68]. Although SERCA and the plasma membrane calcium ATPase pump (PMCA) share many structural similarities, TG is ineffective against PMCA.…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies have shown that the PMCA pump lacks Glu residue involved in calcium translocation in the SERCA [69]. The structural difference between SERCA and PMCA and specific structural requirement for TG binding may explain the different actions of TG [67–71]. …”

Section: Methodsmentioning

confidence: 99%

Paclitaxel Induces Apoptosis in Breast Cancer Cells through Different Calcium—Regulating Mechanisms Depending on External Calcium Conditions

Pan

Avila

Gollahon

2014

IJMS

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Previously, we reported that endoplasmic reticulum calcium stores were a direct target for paclitaxel initiation of apoptosis. Furthermore, the actions of paclitaxel attenuated Bcl-2 resistance to apoptosis through endoplasmic reticulum-mediated calcium release. To better understand the calcium-regulated mechanisms of paclitaxel-induced apoptosis in breast cancer cells, we investigated the role of extracellular calcium, specifically; whether influx of extracellular calcium contributed to and/or was necessary for paclitaxel-induced apoptosis. Our results demonstrated that paclitaxel induced extracellular calcium influx. This mobilization of extracellular calcium contributed to subsequent cytosolic calcium elevation differently, depending on dosage. Under normal extracellular calcium conditions, high dose paclitaxel induced apoptosis-promoting calcium influx, which did not occur in calcium-free conditions. In the absence of extracellular calcium an “Enhanced Calcium Efflux” mechanism in which high dose paclitaxel stimulated calcium efflux immediately, leading to dramatic cytosolic calcium decrease, was observed. In the absence of extracellular calcium, high dose paclitaxel’s stimulatory effects on capacitative calcium entry and apoptosis could not be completely restored. Thus, normal extracellular calcium concentrations are critical for high dose paclitaxel-induced apoptosis. In contrast, low dose paclitaxel mirrored controls, indicating that it occurs independent of extracellular calcium. Thus, extracellular calcium conditions only affect efficacy of high dose paclitaxel-induced apoptosis.

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Total Synthesis of Thapsigargin, a Potent SERCA Pump Inhibitor

Cited by 65 publications

References 21 publications

Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones

Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones

Design, synthesis, and biological evaluation of hydroquinone derivatives as novel inhibitors of the sarco/endoplasmic reticulum calcium ATPase

Paclitaxel Induces Apoptosis in Breast Cancer Cells through Different Calcium—Regulating Mechanisms Depending on External Calcium Conditions

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