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- Don-Doncow, Nicholas, et al.
(författare)
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Galiellalactone is a Direct Inhibitor of STAT3 in Prostate Cancer Cells.
- 2014
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 289:23, s. 15969-15978
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor STAT3 is constitutively active in several malignancies including castration-resistant prostate cancer and has been identified as a promising therapeutic target. The fungal metabolite galiellalactone, a STAT3 signaling inhibitor, inhibits the growth, both in vitro and in vivo, of prostate cancer cells expressing active STAT3 and induces apoptosis of prostate cancer stem cell-like cells expressing pSTAT3. However, the molecular mechanism of this STAT3 inhibiting effect by galiellalactone has not been clarified. A biotinylated analogue of galiellalactone (GL-biot) was synthesized to be used for identification of galiellalactone target proteins. By adding streptavidin-sepharose beads to GL-biot treated DU145 cell lysates, STAT3 was isolated and identified as a target protein. Confocal microscopy revealed GL-biot in both the cytoplasm and nucleus of DU145 cells treated with GL-biot, appearing to co-localize with STAT3 in the nucleus. Galiellalactone inhibited STAT3 binding to DNA in DU145 cell lysates without affecting phosphorylation status of STAT3. Mass spectrometry analysis of recombinant STAT3 protein pretreated with galiellalactone revealed three modified cysteines (cys-367, cys-468 and cys-542). We here demonstrate with chemical and molecular pharmacological methods that galiellalactone is a cysteine reactive inhibitor that covalently binds to one or more cysteines in STAT3 and that this leads to inhibition of STAT3 binding to DNA and thus blocks STAT3 signaling without affecting phosphorylation. This further validates galiellalactone as a promising direct STAT3 inhibitor for treatment of castration-resistant prostate cancer.
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| 2. |
- Escobar, Zilma, et al.
(författare)
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Synthesis of poinsettifolin A
- 2014
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020. ; 70:47, s. 9052-9056
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Tidskriftsartikel (refereegranskat)abstract
- A synthesis of poinsettifolin A (1), a prenylated flavonol isolated from Dorstenia poinsettifolia, is described. Two routes starting from quercetin were explored, and 1 could be prepared if a prenyl group first was incorporated at C-6 of the protected quercetin followed by a condensation with citral at C-8. The key synthetic steps are a Mitsunobu reaction, an europium (III)-catalysed Claisen rearrangement coupled with cross-metathesis, and a benzopyran-forming geranylation. The two geranylated 3,5,3',4'-tetrahydroxyflavonols prepared, 1 and 3, were assayed for antileishmanial activity against Leishmania amazonensis and Leishmania braziliensis, and found to be active. Compound 3 showed cytotoxic activity against leukaemia and lung cancer cells while 1 lacked cytotoxicity. (C) 2014 Elsevier Ltd. All rights reserved.
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