Work

Isoquinoline alkaloids are promising candidates for development of novel semi-synthetic drugs. Berberine is one of the best known representatives of this group, which is widely used as a dietary supplement for prevention of diabetes, hypertension and hypercholesterolemia due to its low toxicity to normal tissues and lack of thiol-targeting activity. However, low bioavailability and hence insufficient antitumor potential severely limit use of berberine in medical practice. The idea of ​​the project is to eliminate the above-mentioned disadvantages of berberine by synthesis of novel semi-synthetic 9-O-modified berberine derivatives and thoroughful study of their mechanisms of action. We believe that these compounds should possess higher bioavailability and stronger antitumor effect while preserving low side effects in patients. During project implementation cytotoxic activity of sanguinarine, berberine and its 9-O-modified derivatives will be compared towards pseudonormal and malignant mammalian cell lines. In order to reveal cell death mechanisms, induced by these alkaloids, role of oxidative stress, mitochondrial dysfunction, and glutathione system in these processes will be elucidated. At the final stage of the work, therapeutic potential of the most active berberine derivatives will be compared with traditional anti-cancer drugs (doxorubicin). Namely, effect of these compounds on tumor size, key indicators of hematological and biochemical profiles of experimental animals and their lifespan will be revealed. The obtained results will allow to draw conlcusions about the effectiveness of chemical modification in 9-O position of berberine for enhancement of its antitumor activity against malignant cells.