About us
Our company was established by separation of commercial activities of the Natural compounds research group from Charles University in Prague. Group was founded by Prof. Alois Vystrčil in the fifties of the last century. In the beginning the group was oriented to pentacyclic triterpenes, namely lupane and germanicane derivatives. The group acquired biggest esteem under the lead of husbands Klinot (1970 - 1999), when the stereochemistry, conformation, reactivity and spectral properties of semisynthetic compounds derived from betuline, allobetuline, apoallobetuline and betulinic acid were thoroughly studied. Betulin and betulinic acid are two important members of natural lupane triterpenoids, readily available from birch or plan bark.
During the basic research led by Prof. Jiří Klinot and doc. Eva Klinotová at the department of organic chemistry, Faculty of Science, Charles university in Prague more than 100 diploma and dissertation thesis were published, focused mainly on the synthesis a reactivity of the triterpenoid derivatives towards broad range of reagents. Reactivity of the lupane derivatives in the different positions of the skeleton was studied. Research focused mainly in the substitutions, selective oxidations, hydroxylation, reduction and also olefine synthesis via strategic elimination, cleavage of the rings and their degradation. More than 1000 new terpenoids and derivatives were prepared and their structure confirmed by professional spectral analysis (MS, IR and NMR) and results were published in more than 70 papers in international journals. Klinots thus formed the basic research base in the chemistry of triterpenoids.
In the year 1998 random screening of cytotoxic activity of some of the compounds prepared by Jan Šarek was completed in the cooperation with Dět. klin. FN Olomouc as part of his diploma work. One of tested compounds - JS 8 - showed ability to cause very fast apoptosis od CEM cell line, even faster than for paclitaxel, one of the most powerful pharmaceutically utilised natural cytostatics. JS 8 subsequently shown to posses high cytotoxic activity against broad range of cancer cell lines and that new unknown mechanism of action is taking place. This good fortune led to the close cooperation between us and LEM, led by MUDr. Marián Hajdúch and to synthesis of semisynthetic derivatives for cytotoxicity screening. During the year 1999 heterogeneous family of triterpenoids, including highly oxidised 18- and 20(29)-lupene a des-E-lupane derivatives which posses sgnificant cytotoxicity (IC50 < 5 µmol/L) and this compounds was namend BETULININES. Short time after that Betulinines were patented as three international patents: Betulinines I - III (WO0190136, WO0190146, WO 0190196). In the next years mechanism of action was intensely investigated in the group of natural compounds mechanism of action of JS 8. It was discovered that JS 8 is targeting mitochondrial respiratory chain, where it is blocking complex 3, primary molecular target is cytochrom c. Among other result is scaling of production technology into half-industrial scale (WO03045971) or invention of orally administrable soluble water based formulation of triterpenic derivatives (PCT/CZ2007/000088). Regarding technology of preparation of the lupane derivatives, isolation of betulin from birch bark was patented (PCT/CZ2008/000004).
Currently Betulinines are in preclinical phase, pharmacokinetical studies of most active derivatives are underway and most active derivatives will be selected for in vivo trials on mice.
