Synthesis and cytotoxic activity of new α-pinene-based cineol-like compounds

Monoterpenes and their derivatives are often considered as widespread and cheap raw materials for the transformation into the valuable chemicals using for the development of new drugs. In this study, a series of compounds with methanofuro[3,2-c]pyran and methanopyrano[4,3-b]pyran scaffolds were synthesized starting from (+)- and (−)-α-pinene-derived monoterpenoids and p-halogen substituted aromatic aldehydes. These compounds contain a fragment of 1,4- and 1,8-cineoles ‒ monoterpenes exhibited a wide range of biological effects. Methanofuro[3,2-c]pyrans 18 with a fragment of 1,4-cineole were synthesized from 8-acetoxy-6-hydroxymethyllimonene in the presence of K10 dried at 105 °C in solvent-free conditions. Optimized conditions for the synthesis of the methanopyrano[4,3-b]pyrans 19 bearing the 1,8-cineol moiety were developed. It was shown that the 8-hydroxy-6-hydroxymethyllimonene reactions with aldehydes proceed with high selectivity towards product 19 when catalyzed by K10 (dried at 200 °C) in methylene chloride. Cytotoxic activity of cineol-like compounds was studied against HeLa, MCF7 and A-172 cells. It was shown that cytotoxic activity of compounds 18b-d and 19b-d is depended on both their (+)/(−) configuration and halogen atom presence in a particular structure. The most active compounds - methanopyrano[4,3-b]pyrans (+)-19c and (+)-19d with Cl and Br substituents exhibited high toxicity to cancerous cells, but were little toxic to Vero cells. Compounds (+)-19c and (+)-19d can exert cytostatic effects in HeLa cells or induce apoptotic cell death in MCF7 and A-172 cells.