Trilobolide-porphyrin conjugates: On synthesis and biological effects evaluation

0444157 - ÚOCHB 2016 RIV US eng J - Journal Article
Tomanová, P. - Rimpelová, S. - Jurášek, M. - Buděšínský, Miloš - Vejvodová, L. - Ruml, T. - Kmoníčková, E. - Drašar, P. B.
Trilobolide-porphyrin conjugates: On synthesis and biological effects evaluation.
Steroids. Roč. 97, SI (2015), s. 8-12. ISSN 0039-128X. E-ISSN 1878-5867
Grant - others:GA ČR(CZ) GA14-04329S; GA MŠk(CZ) ED2.1.00/03.0076
Institutional support: RVO:61388963
Keywords : trilobolide * porphyrin * nitric oxide * fluorescence microscopy
Subject RIV: CE - Biochemistry
Impact factor: 2.513, year: 2015

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.
Permanent Link: http://hdl.handle.net/11104/0246762