Nortrilobolide, a New Potent Guaianolide Secretagogue from<i>Thapsi garganica</i>

Smitt, Ulla Wagner; Christensen, Siegfried B.

doi:10.1055/s-2006-960067

Cited by 24 publications

(12 citation statements)

References 4 publications

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“…The skin irritating component, named Tg, was isolated from T. garganica, along with other structurally-related guaianolides, by Christensen and co-workers in 1978 [3,4], whereas the full structure and the absolute configuration of this compound was established in 1985 [5].…”

Section: Introductionmentioning

confidence: 99%

Thapsigargin—From Traditional Medicine to Anticancer Drug

Jaskulska

Janecka

Gach-Janczak

2020

IJMS

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A sesquiterpene lactone, thapsigargin, is a phytochemical found in the roots and fruits of Mediterranean plants from Thapsia L. species that have been used for centuries in folk medicine to treat rheumatic pain, lung diseases, and female infertility. More recently thapsigargin was found to be a potent cytotoxin that induces apoptosis by inhibiting the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pump, which is necessary for cellular viability. This biological activity encouraged studies on the use of thapsigargin as a novel antineoplastic agent, which were, however, hampered due to high toxicity of this compound to normal cells. In this review, we summarized the recent knowledge on the biological activity and molecular mechanisms of thapsigargin action and advances in the synthesis of less-toxic thapsigargin derivatives that are being developed as novel anticancer drugs.

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Section: Introductionmentioning

confidence: 99%

Thapsigargin—From Traditional Medicine to Anticancer Drug

Jaskulska

Janecka

Gach-Janczak

2020

IJMS

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“…Besides Thapsigargin (1) several hexaoxygenated guaianolides only differing from Tg (1) by the acyl groups at O-2 and O-8 have been found in the genus Thapsia (2-13, Fig. 1) [14,15]. Two additional thapsigargins have been found in Laser trilobum Borkh.…”

Section: The Structures and Diversity Of Polyoxygenated Guaianolidesmentioning

confidence: 99%

“…Structures of the naturally occurring hexaoxygenated guaianolides found in L. trilobum [thapsigargins](14)(15).…”

mentioning

confidence: 99%

Thapsigargin, Origin, Chemistry, Structure-Activity Relationships and Prodrug Development

2015

CPD

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Thapsigargin was originally isolated from the roots of the Mediterranean umbelliferous plant Thapsia garganica in order to characterize the skin irritant principle. Characteristic chemical properties and semi-syntheses are reviewed. The biological activity was related to the subnanomolar affinity for the sarco/endoplasmic reticulum calcium ATPase. Prolonged inhibition of the pump afforded collapse of the calcium homeostasis and eventually apoptosis. Structure-activity relationships enabled design of an equipotent analogue containing a linker. Conjugation of the analogue containing the linker with peptides, which only are substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA) enabled design of prodrugs targeting a number of cancer diseases including prostate cancer (G115) and hepatocellular carcinoma (G202). Prodrug G202 has under the name of mipsagargin in phase II clinical trials shown promising properties against hepatocellular carcinoma.

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“…Since the discovery of thapsigargin in 1978 (Rasmussen, Brøgger Christensen & Sandberg, ) and its pharmaceutical properties in 1984 (Christensen et al ., ), Thapsia has been subject to chemical investigations searching for new specialized metabolites with drug lead potential. This has resulted in numerous publications on the chemistry and chemotaxonomy of Thapsia (Rasmussen, Christensen & Sandberg, ; Lemmich, Jensen & Rasmussen, ; Teresa et al ., 1985a, b, c, d, 1986a, b, c; Falsone, Haddad & Wendisch, ; Smitt et al ., , 1990a, b, ; Avato, ; Lemmich et al ., ; Smitt & Christensen, ; Avato, Jacobsen & Smitt, ; Smitt, ; Avato, Trabace & Smitt, ; Christensen, Andersen & Smitt, ; Avato & Smitt, ; Avato, Fanizzi & Rosito, ; Avato & Rosito, ; Liu, Olsen & Christensen, ; Rubal et al ., , , , ; Saouf et al ., 2005; 2006; Liu HZ et al ., ; Drew et al ., ; Goncalves et al ., ). However, our understanding of the chemical diversity of Thapsia has been complicated by the taxonomic complexity of the genus.…”

Section: Introductionmentioning

confidence: 99%

Resurrecting deadly carrots: towards a revision ofThapsia(Apiaceae) based on phylogenetic analysis of nrITS sequences and chemical profiles

et al. 2014

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Thapsia is a small genus of herbaceous perennials in Apiaceae. Thapsia occurs around the Mediterranean, extending from the Atlantic coasts of Portugal and Morocco to Crete and other Greek Islands. Thapsia is commonly known as deadly carrot because of its poisonous effects. The resin from Thapsia spp. has been used in traditional medicine and included in European pharmacopoeias, and several species contain biologically important sesquiterpene lactones, such as thapsigargin. Accordingly, Thapsia has for decades been subject to chemical investigations searching for new specialized metabolites with potential as drug leads. However, no generally accepted taxonomic concept of > 40 species and synonyms exists. To address the phylogenetics and circumscription of Thapsia, we present the first molecular phylogenetic hypothesis of Thapsia based on sequences of the nuclear ribosomal internal transcribed spacer (nrITS) region from 50 accessions of Thapsia and representatives of all currently recognized genera in subtribe Daucinae. Phylogenetic analysis using maximum parsimony and Bayesian inference resulted in a well-resolved topology with strong support for inclusion of all the species studied here from Ammodaucus, Distichoselinum, Elaeoselinum, Guillonea and Margotia in Thapsia, in correspondence with previous phylogenetic studies of Apiaceae. Elaeoselinum is not monophyletic. Clades in Thapsia correlate well with previous observations of groupings based on the occurrence of biologically important sesquiterpene lactones, such as thapsigargin and thapsane and derivatives thereof. The result of the phylogenetic analysis necessitates nomenclatural adjustments. Thus, we propose a broader generic concept for Thapsia. Here T. asclepium, T. gummifera and T. tenuifolia are reinstated, new name combinations are made for T. leucotricha, T. scabra and T. thapsioides, and one new species, T. smittii, is established from T. maxima type II.

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Nortrilobolide, a New Potent Guaianolide Secretagogue fromThapsi garganica

Cited by 24 publications

References 4 publications

Thapsigargin—From Traditional Medicine to Anticancer Drug

Thapsigargin—From Traditional Medicine to Anticancer Drug

Thapsigargin, Origin, Chemistry, Structure-Activity Relationships and Prodrug Development

Resurrecting deadly carrots: towards a revision ofThapsia(Apiaceae) based on phylogenetic analysis of nrITS sequences and chemical profiles

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