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      Large Scale Conversion of Trilobolide into the Payload of Mipsagargin: 8- O-(12-Aminododecanoyl)-8- O-Debutanoylthapsigargin

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          Abstract

          In spite of the impressing cytotoxicity of thapsigargin ( Tg), this compound cannot be used as a chemotherapeutic drug because of general toxicity, causing unacceptable side effects. Instead, a prodrug targeted towards tumors, mipsagargin, was brought into clinical trials. What substantially reduces the clinical potential is the limited access to Tg and its derivatives and cost-inefficient syntheses with unacceptably low yields. Laser trilobum, which contains a structurally related sesquiterpene lactone, trilobolide ( Tb), is successfully cultivated. Here, we report scalable isolation of Tb from L. trilobum and a transformation of Tb to 8- O-(12-aminododecanoyl)-8- O-debutanoylthapsigargin in seven steps. The use of cultivated L. trilobum offers an unlimited source of the active principle in mipsagargin.

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          Most cited references36

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          Mitosis-targeted anti-cancer therapies: where they stand

          The strategy of clinically targeting cancerous cells at their most vulnerable state during mitosis has instigated numerous studies into the mitotic cell death (MCD) pathway. As the hallmark of cancer revolves around cell-cycle deregulation, it is not surprising that antimitotic therapies are effective against the abnormal proliferation of transformed cells. Moreover, these antimitotic drugs are also highly selective and sensitive. Despite the robust rate of discovery and the development of mitosis-selective inhibitors, the unpredictable complexities of the human body's response to these drugs still herald the biggest challenge towards clinical success. Undoubtedly, the need to bridge the gap between promising preclinical trials and effective translational bedside treatment prompts further investigations towards mapping out the mechanistic pathways of MCD, understanding how these drugs work as medicine in the body and more comprehensive target validations. In this review, current antimitotic agents are summarized with particular emphasis on the evaluation of their clinical efficacy as well as their limitations. In addition, we discuss the basis behind the lack of activity of these inhibitors in human trials and the potential and future directions of mitotic anticancer strategies.
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            Supercritical fluid extraction of vegetable matrices: Applications, trends and future perspectives of a convincing green technology

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              Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+depletion and the unfolded protein response

              Calcium (Ca 2+ ) is a fundamental regulator of cell signaling and function. Thapsigargin (Tg) blocks the sarco/endoplasmic reticulum (ER) Ca 2+ -ATPase (SERCA), disrupts Ca 2+ homeostasis, and causes cell death. However, the exact mechanisms whereby SERCA inhibition induces cell death are incompletely understood. Here, we report that low (0.1 μ m ) concentrations of Tg and Tg analogs with various long-chain substitutions at the O-8 position extensively inhibit SERCA1a-mediated Ca 2+ transport. We also found that, in both prostate and breast cancer cells, exposure to Tg or Tg analogs for 1 day caused extensive drainage of the ER Ca 2+ stores. This Ca 2+ depletion was followed by markedly reduced cell proliferation rates and morphological changes that developed over 2–4 days and culminated in cell death. Interestingly, these changes were not accompanied by bulk increases in cytosolic Ca 2+ levels. Moreover, knockdown of two key store-operated Ca 2+ entry (SOCE) components, Orai1 and STIM1, did not reduce Tg cytotoxicity, indicating that SOCE and Ca 2+ entry are not critical for Tg-induced cell death. However, we observed a correlation between the abilities of Tg and Tg analogs to deplete ER Ca 2+ stores and their detrimental effects on cell viability. Furthermore, caspase activation and cell death were associated with a sustained unfolded protein response. We conclude that ER Ca 2+ drainage and sustained unfolded protein response activation are key for initiation of apoptosis at low concentrations of Tg and Tg analogs, whereas high cytosolic Ca 2+ levels and SOCE are not required.
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                Author and article information

                Journal
                Biomolecules
                Biomolecules
                biomolecules
                Biomolecules
                MDPI
                2218-273X
                05 December 2020
                December 2020
                : 10
                : 12
                : 1640
                Affiliations
                [1 ]Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague, Technická 5, 166 28 Prague, Czech Republic; tomas.zimmermann@ 123456vscht.cz (T.Z.); pavel.drasar@ 123456vscht.cz (P.D.)
                [2 ]Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, 166 28 Prague, Czech Republic; silvie.rimpelova@ 123456vscht.cz
                [3 ]Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, DK-2100 Copenhagen, Denmark; soren.christensen@ 123456sund.ku.dk
                [4 ]Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich St. 5, 220141 Minsk, Belarus; khripach@ 123456iboch.by
                Author notes
                Author information
                https://orcid.org/0000-0003-0093-7007
                https://orcid.org/0000-0002-3008-1396
                https://orcid.org/0000-0002-5773-6874
                Article
                biomolecules-10-01640
                10.3390/biom10121640
                7762042
                33291419
                74d9950e-3643-4a7a-9265-aeb8c329622d
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 November 2020
                : 03 December 2020
                Categories
                Article

                chemical synthesis,extraction,mipsagargin,trilobolide isolation from fruits,optimization and scale-up,laser trilobum cultivation,sarco/endoplasmic reticulum calcium atpase (serca),sesquiterpene lactones,thapsigargin,trilobolide,8-o-(12-aminododecanoyl)-8-o-debutanoylthapsigargin

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