Elucidation of the topography of the thapsigargin binding site in the sarco-endoplasmic calcium ATPase

Skytte, Dorthe Mondrup; Møller, Jesper; Liu, Huizhen; Nielsen, Helle Østergren; Svenningsen, L; Jensen, C. E.; Olsen, Carl Erik; Christensen, Søren Brøgger

doi:10.1016/j.bmc.2010.06.032

Cited by 25 publications

(36 citation statements)

References 27 publications

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“…Masking of the OH-8 and OH-11 by reaction with 2,2-dimethoxypropane yields an isopropylidende derivative (22, Scheme 3) in which the polycyclic nature prevents relactonization. Treatment of 22 with strong base affords 23 and traces of 24 (Scheme 3) [20,21]. As expected the , -unsaturated angeloyl group at C-3 is more stable towards basic hydrolysis than the other acyl groups in the molecule.…”

Section: Selective Substitutions Of the Ester Group At O-2 O-10 And O-8mentioning

confidence: 60%

“…Removal of the isopropylidene group with acid in an aqueous medium affords 27 in which O-8 selectively can be acylated affording 28 (Scheme 4). In total, the procedure enables selective replacement of all the acyl groups in the starting material except for the angeloyl group [20,21].…”

Section: Selective Substitutions Of the Ester Group At O-2 O-10 And O-8mentioning

confidence: 99%

“…Below are presented Tables 1-10 illustrating the effects of changes of the structure of Tg (1). The data given in the table are mainly taken from the references: [21,[30][31][32][33][34][35].…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

“…Whereas a large diversity of substituents at O-2 and O-8 are accepted only a limited number of nonflexible groups are allowed at O-3. Very pronounced is the significant loss of activity by moving the methyl group from the meta to the para position of benzoic acid [21]. A little more diversity is allowed in the cavity near the O-10 [21].…”

Section: The Pharmacophore Of Thapsigarginmentioning

confidence: 99%

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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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Section: Selective Substitutions Of the Ester Group At O-2 O-10 And O-8mentioning

confidence: 60%

Section: Selective Substitutions Of the Ester Group At O-2 O-10 And O-8mentioning

confidence: 99%

Section: Structure-activity Relationshipsmentioning

confidence: 99%

Section: The Pharmacophore Of Thapsigarginmentioning

confidence: 99%

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

2015

CPD

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“…Based on the activities as pump inhibitors of derivatives prepared by these methods the above mentioned pharmacophore has been verified. Reversing the absolute configuration at C3 or C8 strongly decrease the affinity demonstrating the importance of correct stereochemistry at these positions [25], similar removal of the hydrophobic acyl groups at O3, O8 or O10 also reduces the affinity [25,26]. To confirm a similar binding of different analogues X-ray structures of the complex of the analogue with high affinity and SERCA have been solved [27].…”

Section: Medicinal Chemistry Of Thapsigarginmentioning

confidence: 99%

Targeting thapsigargin towards tumors

et al. 2015

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The skin irritating principle from Thapsia garganica was isolated, named thapsigargin and the structure elucidated. By inhibiting the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) thapsigargin provokes apoptosis in almost all cells. By conjugating thapsigargin to peptides, which are only substrates for either prostate specific antigen (PSA) or prostate specific membrane antigen (PSMA) prodrugs were created, which selectively affect prostate cancer cells or neovascular tissue in tumors. One of the prodrug is currently tested in clinical phase II. The prodrug under clinical trial has been named mipsagargin.

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Synthesis of Tetra‐Substituted 3‐Hydroxyphthalide Esters by Isothiourea‐Catalysed Acylative Dynamic Kinetic Resolution

Agrawal,

Majhi,

Goodfellow

et al. 2024

Angewandte Chemie

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A general and highly enantioselective method for the preparation of tetra‐substituted 3‐hydroxyphthalide esters via isothiourea‐catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2S,3R)‐HyperBTM (5 mol%) as the catalyst, the scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields observed (>40 examples, up to 99%, 99:1 er). Substitution of the aromatic core within the 3‐hydroxyphthalide skeleton, as well as aliphatic and aromatic substitution at C(3)‐, is readily tolerated. A diverse range of anhydrides, including those from bioactive and pharmaceutically relevant acids, can also be used. The high enantioselectivity observed in this DKR process has been probed computation, with a key substrate heteroatom donor O•••acyl‐isothiouronium interaction identified through DFT analysis as necessary for enantiodiscrimination.

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Elucidation of the topography of the thapsigargin binding site in the sarco-endoplasmic calcium ATPase

Cited by 25 publications

References 27 publications

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

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

Targeting thapsigargin towards tumors

Synthesis of Tetra‐Substituted 3‐Hydroxyphthalide Esters by Isothiourea‐Catalysed Acylative Dynamic Kinetic Resolution

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