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

A series of conjugates of diterpenoid isosteviol (16-oxo-<i>ent</i>-beyran-19-oic acid) and uracil (nucleoterpenoids) was synthesized and examined for their <i>in vitro</i> cytotoxicity against 9 human cancer cell lines. Nucleoterpenoids <b>13c</b>,<b>f</b>,<b>15</b> exhibited the best <i>in vitro</i> 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 <i>in vitro</i> cytotoxic effect of nucleoterpenoids <b>13f</b> and <b>15</b> against M-HeLa cancer cell line (cervical carcinoma) were studied using flow cytofluorometry and enzyme-linked immunosorbent assay (ELISA). The results obtained indicated that <b>13f</b> and <b>15</b> 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 <b>13c</b>,<b>f</b>, and <b>15</b> 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.