Betulinic acid and its derivatives: a patent review (2008-2013)

Betulinic acid (BA) is a triterpenoid that can be obtained from renewable resources. BA is cytotoxic to many human tumor cell lines mainly by apoptosis but cell death might also be triggered by nonapoptotic pathways. Many derivatives have been synthesized to improve the very weak solubility of parent BA and to increase its cytotoxicity as well as its selectivity toward tumor cells.

A brief introduction into cancer is given reflecting the different pathways this disease might be treated using chemotherapy using natural product analogs especially triterpenes. The different ways of action of BA in cancer cells are discussed. Finally, this review describes the main synthetic modifications that have been performed and discusses, in short, the structure-activity relationships of these analogs, investigated between 2008 and 2013 including some important publications from early 2014.

A number of patents on BA analogs for the chemotherapy of cancer have been reported between 2008 and 2013. Most of these patents deal with modifications at positions C-3, C-20 and C-28. There are only a few compounds meeting the needs of a sufficient hydrosolubility, while retaining high cytotoxicity and selectivity toward tumor cells. Thus, one might expect that there will be some efforts in developing molecules of improved solubility and to find new and more efficient forms of administration (liposomes, transdermal application and nanoemulsions). An important sideline might be the treatment of the age-dependent degeneration of the macula, a possible caveat of which might be a certain degree of CNS toxicity associated with several derivatives of BA.