Nucleoterpenoids on the basis of diterpenoid isosteviol, nucleobases and nucleoside analogues. Synthesis and cytotoxicity of a series of conjugates of isosteviol and uracil. Part 2.

Abstract

A series of conjugates of diterpenoid isosteviol (16-oxo-ent-beyran-19-oic acid) and uracil (nucleoterpenoids) was synthesized and examined for their in vitro cytotoxicity against 9 human cancer cell lines. Nucleoterpenoids 13c,f,15 exhibited the best in vitro cytotoxic activity against cancer cell lines M-HeLa, MCF-7, and PC3 (IC₅₀ = 12.7-21.3 µM) among the synthesized compounds. The mechanisms of the in vitro cytotoxic effect of nucleoterpenoids 13f and 15 against M-HeLa cancer cell line (cervical carcinoma) were studied using flow cytofluorometry and enzyme-linked immunosorbent assay (ELISA). The results obtained indicated that 13f and 15 by acting on M-HeLa cancer cells reduced the mitochondrial membrane potential, caused oxidative stress, blocked anti-apoptotic protein Bcl-2, activated apoptosis-initiating caspase-9, thus inducing apoptosis occurring along the mitochondrial pathway. It should be emphasized that although isosteviol and uracil do not have cytotoxicity against human cancer cells, nucleoterpenoids 13c,f, and 15 containing isosteviol and uracil as fragments exhibited good cytotoxicity against M-HeLa, MCF-7, and PC3 cancer cells. Thus, it can be considered that conjugation of diterpenoid isosteviol and nucleic bases is a promising way to search for new cytotoxic agents of unusual structure.