Design, synthesis and investigation of mechanisms of action of novel protein kinase C inhibitors: perylenequinonoid pigments.

A series of perylenequinonoid pigments (PQPs) and related compounds were synthesized and screened for the inhibition of protein kinase C (PKC), a key enzyme involved in cellular differentiation and proliferation, and a potential target for anticancer and antiviral chemotherapeutic drugs. This study has established PQPs as efficient PKC inhibitors, and elucidated aspects of the light-enhanced action mode of the PKC inhibitors. Comparative studies between natural and synthetic PQPs led to the recognition of the effect of certain structural features of PQPs on PKC inhibition, including the skeleton of the 3,10-dihydroxy-4,9-perylenequinonoid chromophore and the configuration of the two side chains at positions 1 and 12. Calphostin C was identified as a superior PKC inhibitor of the POP class, and with the latter as a representative structure, we investigated the mechanism of PKC inhibition by PQPs via electron paramagnetic resonance spectroscopy in conjunction with the spin-trapping technique, absorption and fluorescence spectroscopy, photochemical and photobiological studies, and enzyme methodology. Multiple modes of action are suggested for PKC inhibition, comprising the following steps: (1) the binding of PQPs to the PKC regulatory domain via complexation; (2) the photobonding between mercapto groups of PKC cysteine residues and the PQP quinonoid moiety; and (3) the PQP-sensitized photodamage of PKC via Type I and/or Type II photosensitization.