Betulinic Acid - Anticancer Derivatives

Anticancer Derivatives

A major inconvenience for the future clinical development of betulinic acid and analogues resides in their poor solubility in aqueous media such as blood serum and polar solvents used for bioassays. To circumvent this problem of hydrosolubility and to enhance pharmacological properties, many derivatives were synthesized and evaluated for cytotoxic activity. One study showed C-20 modifications involve the loss of cytotoxicity. Another study demonstrated the importance of the presence of the -COOH group, since compounds substituted at this position, such as lupeol and methyl betulinate, were less active on human melanoma than betulinic acid. Moreover, some C-28 amino acids and C-3 phthalates derivatives exhibited higher cytotoxic activity against cancer cell lines with improved selective toxicity and water solubility. Chatterjee et al. obtained the 28-O-β-D-glucopyranoside of betulinic acid by microbial transformation with Cunninghamella species, while Baglin et al. obtained it by organic synthesis. This glucoside did not exhibit any significant in vitro activity on human melanoma (MEL-2) and human colorectal adenocarcinoma (HT-29) cell lines, which confirms the importance of the carboxylic acid function to preserve the cytotoxicity. Recently, Gauthier et al. synthesized a series of 3-O-glycosides of betulinic acid which exhibited a strongly potent in vitro anticancer activity against human cancer cell lines. A source of soluble and ingestible betulinic acid (and its precursor, betulin) is the chaga (Inonotus obliquus), a slow-growing medicinal fungus found as a parasite on birch trees in the coldest regions of the Northern Hemisphere. This mushroom converts the betulin present in the bark of the birch into a soluble and ingestible form of betulinic acid. Using a proper extraction protocol (alcohol/ethanol extraction) will make the compounds available for oral consumption. The slow-growing nature of the fungus (7-10 years minimum) and because it cannot be cultivated without losing most of its properties make this an unreliable source, though.