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Biologically Active Triterpenoid Derivatives I

Triterpenoids are naturally occurring substances showing a large range of biological activities, including strong cytotoxic activity. This would make them suitable for use as pharmaceuticals.

The present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, crystal form, complex, hydrate, or hydrolysable ester thereof, in the preparation of a medicament for treating a patient suffering from leukaemia, cancer or other proliferative disorder. A further embodiment relates to the use a compound of formula (I) in an assay for detecting the phosphorylation state of cellular substrates. The present invention also relates to novel compounds of formula (I), and the chemical synthesis thereof.

The invention provides a novel class of compounds possessing a cytotoxic activity to a wide range of tumor cell lines. Our recent data demonstrate that selected compounds covered by these patents are hedge-hog inhibitors, pro-apoptotic compounds inducing selective release of cytochrome c from tumor cells, tubulin polymerization inhibitors, hemoxygenase I inducers, HIV maturation inhibitors, etc. These compounds will be useful as medicaments for the treatment of cancer and other diseases connected with abnormal proliferation and/or HIV infection.

Laboratory scale, data on cell lines, limited ADME/Tox data, in vivo pharmacology and pharmacodynamics.

Kvasnica, M., Urban, M., Dickinson, N. J., Sarek, J. Pentacyclic triterpenoids with nitrogen- and sulfur-containing heterocycles: synthesis and medicinal signifi cance. Nat Prod Rep. 2015 Jun 1. PubMed PMID: 26030604 Borkova, L., Jasikova, L., Rehulka, J., Frisonsova, K., Urban, M., Frydrych, I., Popa, I.,Hajduch, M., Dickinson, N. J., Vlk, M., Dzubak, P., Sarek, J. Synthesis of cytotoxic 2,2-difl uoroderivatives of dihydrobetulinic acid and allobetulin and study of their impact on cancer cells. Eur J Med Chem. 2015 May 26, doi: 10.1016/j.ejmech.2015.03.068. Epub 2015 Apr 1. PubMed PMID: 25942059. Urban, M., Vlk, M., Dzubak, P., Hajduch, M., Sarek, J.Cytotoxic Heterocyclic Triterpenoids Derived from Betulin and Betulinic Acid. Bioorg. Med. Chem. 2012, 20, 3666. Urban, M., Sarek, J., Kvasnica, M., Tislerova, I., Hajduch, M. Triterpenoid pyrazines and benzopyrazines with cytotoxic activity. J. Nat. Prod. 2007, 70, 526. Urban, M., Klinot, J., Tislerova, I., Biedermann, D., Hajduch, M., Cisarova, I., Sarek, J. Reactions of activated lupane oxo-compounds with diazomethane: An approach to new derivatives of cytotoxic triterpenes. Synthesis-Stuttgart 2006, 3979. Sarek, J., Kvasnica, M., Urban, M., Klinot, J., Hajduch, M. Correlation of cytotoxic activity of betulinines and their hydroxy analogues. Bioorg. Med. Chem. Lett. 2005, 15, 4196. Urban, M., Sarek, J., Klinot, J., Korinkova, G., Hajduch, M. Synthesis of A-seco derivatives of betulinic acid with cytotoxic activity. J. Nat. Prod. 2004, 67, 1100. Urban, M., Sarek, J., Tislerova, I., Dzubak, P., Hajduch, M. Infl uence of esterifi cation and modifi cation of A-ring in a group of lupane acids on their cytotoxicity. Bioorg. Med. Chem. 2005, 13, 5527. Sarek, J., Klinot, J., Dzubak, P., Klinotova, E., Noskova, V., Krecek, V., Korinkova, G., Thomson, J.P., Janostakova, A., Wang, S. D., Parsons, S., Fischer, P. M., Zhelev, N. Z., Hajduch, M. New lupane derived compounds with pro-apoptotic activity in cancer cells: Synthesis and structure - Activity relationships. J. Med. Chem. 2003, 46, 5402.

Patent protection: GB 2362649 WO 01/90046 EP 1292562 US 7858606 US2004087561 AU 6248901

Palacky University Olomouc, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry Charles University Prague Cyclacel Ltd.