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Trilobolide-porphyrin conjugates: On synthesis and biological effects evaluation
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SYSNO ASEP 0444157 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Trilobolide-porphyrin conjugates: On synthesis and biological effects evaluation Author(s) Tomanová, P. (CZ)
Rimpelová, S. (CZ)
Jurášek, M. (CZ)
Buděšínský, Miloš (UOCHB-X) RID, ORCID
Vejvodová, L. (CZ)
Ruml, T. (CZ)
Kmoníčková, E. (CZ)
Drašar, P. B. (CZ)Number of authors 8 Source Title Steroids. - : Elsevier - ISSN 0039-128X
Roč. 97, SI (2015), s. 8-12Number of pages 5 s. Language eng - English Country US - United States Keywords trilobolide ; porphyrin ; nitric oxide ; fluorescence microscopy Subject RIV CE - Biochemistry Institutional support UOCHB-X - RVO:61388963 UT WOS 000353178800003 EID SCOPUS 84925460002 DOI 10.1016/j.steroids.2014.08.024 Annotation Trilobolide (Tb), a potent natural counterpart of thapsigargin, is a sesquiterpene lactone of guaianolide type isolated from horse caraway (Laser trilobum, L. Borkh). Tb exerts remarkable pharmacological properties based on irreversible inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA), thus being of increasing interest for cancer cure. Additionally, another pharmacological activity of Tb, as well as of thapsigargin, was reported in several studies, Tb as being an effective inductor of nitric oxide and cytokine production. These extraordinary biological properties move these molecules in further pre-clinical evaluation. Because of ubiquitous character of SERCA expression, development of specifically targeted bioactive molecules is inevitable. Since it is well known that porphyrins are preferentially taken up by cancer cells, we have designed and synthesized novel Tb-porphyrin conjugates. Copper-catalyzed azide-alkyne cycloaddition was used to link Tb with porphyrin at once. Two model conjugates of Tb and porphyrin were synthesized and properly characterized. Employing naturally occurring fluorescence properties of porphyrins, we investigated the intracellular localization of the conjugates employing fluorescence microscopy in living cells. Intriguingly, the prepared conjugates localized both in mitochondria and lysosomes of HeLa and LNCaP cells. Furthermore, the cytotoxicity of Tb-porphyrin conjugates was assessed in a number of human cancer cell lines and rat peritoneal cells. Likewise in cancer cell lines, viability of rat peritoneal cells was not affected by the tested conjugates. Interestingly, we observed dose-dependent nitric oxide (iNOS) production induced by the tested conjugates. The effect was related to the type of a linker used and the overall size of the molecule. Another potent immunobiological effects are under evaluation. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2016
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