New complex polycyclic compounds: Synthesis, antiproliferative activity and mechanism of action.

• New polycycles derivatives 2a-c were synthesized. • These molecules bear on each of the two phenyl rings hydrophilic substituents. • These substituents are able to form hydrogen bonds and to decrease the logP. • The most active compound 2a activates within 24 h an autophagic response. • Substitution in 1 and 2 of phenyls with methyl groups leads to loss of activity. Polycyclic or O -glycoconiugate polycyclic compounds 1a-g were previously tested for their in vitro antiproliferative activity. In this series of compounds, activity increases as log P decreases. Specifically, compounds 1d and 1g showed lower log P values together with the best antiproliferative profiles. With the aim of extending our understanding of the structure–activity relationship (SAR) of this class of compounds, we prepared new polycyclic derivatives 2a-c , which bear on each of the two phenyl rings hydrophilic substituents (OH, SO 2 NH 2 or NHCOCH 3). These substituents are able to form hydrogen bonds and to decrease the partition coefficient value as compared with compound 1d. Compound 2a was slightly more active than 1d , while 2b and 2c had antiproliferative activity comparable to that of 1d. Finally, the role of the two phenyl groups of polycycle derivatives 1 was also investigated. The analog 3 , which bears two methyls instead of the two phenyls had a lower log P value (2.94 ± 1.22) than all the other compounds, but it had negligible antiproliferative activity at 10 µM. The analysis of the most active derivative 2a revealed a significant antiproliferative activity against the triple-negative breast cancer cell line MDA-MB231. After a 24 h treatment, an autophagic process was activated, as demonstrated by an increase in monodansylcadaverine-positive cells as well as by the appearance of the autophagic markers Beclin and LC3II. Prolonging the treatment to 48 h, 2a caused cytotoxicity through the activation of caspase-dependent apoptosis. [ABSTRACT FROM AUTHOR]