Retinoic acid and analogs as potent inducers of differentiation and apoptosis. New promising chemopreventive and chemotherapeutic agents in oncology

In this report we will describe the preparation and the biological activity of a novel class of heterocyclic arotinoids endowed with potent cytotoxic and apoptotic acitivity. Structure-activity relationship studies revealed that the different stereochemistry at the C9 double bond of retinoids seems associated with a different biological activity: potent apop- totic activity for the cis-isomers, whereas differentiating activity for the trans structures. An interesting modified Wittig procedure that allows easily to arotinoids will also be described. The substitution of the alkenyl portion with a more flexible oxymethyl or aminomethyl moi- ety gave compounds with poor activity, whereas isoxazole-bridged arotinoids allowed com- pounds active also on multidrug-resistant (MDR) leukemia cell lines.