Synthesis and antiproliferative properties of new hydrophilic esters of triterpenic acids

0482509 - ÚOCHB 2018 RIV FR eng J - Článek v odborném periodiku
Eignerová, Barbara - Tichý, Michal - Krasulová, Jana - Kvasnica, Miroslav - Rárová, L. - Christová, R. - Urban, M. - Bednarczyk-Cwynar, B. - Hajdúch, M. - Šarek, J.
Synthesis and antiproliferative properties of new hydrophilic esters of triterpenic acids.
European Journal of Medicinal Chemistry. Roč. 140, Nov 10 (2017), s. 403-420. ISSN 0223-5234. E-ISSN 1768-3254
Grant CEP: GA MŠMT(CZ) LO1304
Institucionální podpora: RVO:61388963 ; RVO:61389030
Klíčová slova: cytotoxicity * triterpenic acids * betulinic acid * hydrophilic ester * prodrug
Obor OECD: Organic chemistry
Impakt faktor: 4.816, rok: 2017

To improve the properties of cytotoxic triterpenoid acids 1-5, a large set of hydrophilic esters was synthesized. We choose betulinic acid (1), dihydrobetulinic acid (2), 21-oxoacid 3 along with highly active des-E lupane acids 4 and 5 as a model set of compounds for esterification of which the properties needed to be improved. As ester moieties were used- methoxyethanol and 2-(2-methoxyethoxy)ethanol and glycolic unit (type a-d), pyrrolidinoethanol, piperidinoethanol and morpholinoethanol (type f-h), and monosaccharide groups (type i-I). As a result, 56 triterpenic esters (49 new compounds) were obtained and their cytotoxicity on four cancer cell lines and normal human fibroblasts was tested. All new compounds were fully soluble at all tested concentrations, which used to be a problem of the parent compounds 1 and 2. 16 compounds had IC50 < 10 mu M on at least one cancer cell line, 12 compounds had cytotoxicity of <10 mu M against at least three of four tested cancer cell lines. The highest activity was found for compound 3c (1.8 mu M on MCF7, 2.8 mu M on HeLa, and 1.6 mu M on G-361 cells) which also had no toxicity on non-cancerous BJ fibroblasts at the highest tested concentration (50 mu M). High, selective cytotoxicity was also found in compounds 1k, 2k, 3c, and 3i that are ideal candidates for drug development. Therefore, more studies to identify the mechanism of action were performed in case of 1k, 3c, and 3g such as effects on cell cycle and apoptosis. It was found that compounds 3c and 3g can induce apoptosis via caspase-3 activation and modulation of protein Bc1-2 in G-361 cells. In conclusion, compounds 1k, 3c, and 3g show high and selective cytotoxicity, therefore they are significantly better candidates for anti-cancer drug development than the parent acids 1-5.
Trvalý link: http://hdl.handle.net/11104/0277938