Abstract: Studies on structure-activity relationship of phenothiazines (PTZs) for inhibition of protein kinase C (PKC)and reversal of multidrug resistance (MDR) has been made in vitro. The results showedthat the order of potency of reversaleffect of PTZs on MDR is as follows: 2-COC3H7>2-CF3>2-COCH3>H. The type of piperazinyl substitution also signifi-cantly affected potency against MDR. The results show the order: CH3>COOC2H5>C3H4OH. In addition, PKC plays amarked role in diverse cellular process including MDR. Some derivatives of PTZ was tested for inhibition of PKC, of whichPTZ11 showed the highest inhibitory effect of MDR and PKC, implying a potential reversal agent of MDR for tumor therapy inthe future. We also tried to explore the possible binding model of PTZs to PKC. Our molecular-modeling study preliminarilysuggests how these PTZs bind to PKC and provides a structural basis for the design of high affinity PKC-modulator. The infor-mation may be used in the rational design of more effective drugs.

Key words: Phenothiazines, Phenothiazines, Multidrug resistance, Multidrug resistance, Molecular modeling, Molecular modeling, Protein kinase C, Protein kinase C