Multidrug resistance reverting activity and antitumor profile of new phenothiazine derivatives

A series of easily affordable phenothiazine derivatives bearing a rigid but-2-ynyl amino side chain were synthesized and tested to evaluate the MDR reverting activity and full antitumor profile. Some compounds endowed with remarkable MDR reverting effect were identified, and the most active one (6c) was shown to increase doxorubicin retention in multidrug resistant cells, suggesting a direct interaction with P-glycoprotein. Furthermore, a broad range of cellular activities were observed for different compounds. In particular, the ability of some derivatives to induce antiproliferative effects on resistant cell lines and to interfere with the G(1) phase of the cell cycle, a phase usually not affected by classical antitumor agents, was noted. Moreover, the most cytotoxic compounds of the series were able to induce apoptosis in resistant cell lines, via an atypical pathway of caspase cascade activation, and a synergistic effect in combination with doxorubicin was also found.