Synthesis of novel spiro-isoxazoline and spiro-isoxazolidine derivatives of tomentosin

Plants have a long history as therapeutics in the treatment of human diseases and have been a continuous source of inspiration for the development of new medicines. Among them, the genus Inula (Asteraceae) comprisesmore than 100 species, many of which are widely used in traditional medicine for a variety of biological purposes including anti-inammatory, anti-cancer and antibacterial activities. Numerous compounds of interest have been isolated and identied from these plants such as avonoids, monoterpenes, triterpenoids, and polyphenols. This genus is also a rich source of sesquiterpene acids and lactones. Many studies have focused on sesquiterpene lactones since they exhibit a wide range of biological properties and have candidates in different phases of clinical trials such as parthenolide, costunolide, helenalin, and artemisinin (Fig. 1). The cytotoxicity of sesquiterpene lactones was partly attributed to the presence of potential alkylating agents such as the a-methylene-g-lactone moiety, which are prone to covalently react with biological nucleophiles, e.g., L-cysteine, in a Michaeltype addition. This highly electrophilic structure may also be the origin of a major contact allergen effect and plants that contain sesquiterpene lactones are held responsible for an increasing number of cases of contact dermatitis. Using this reactive site, various structural modications have been carried out to obtain less toxic and more reactive candidates and lately the introduction of spiro-heterocyclic molecular