Synthesis of Perylenequinone Analogs

3 See reference [45] for a study of atropisomerization thresholds for model biaryls and perylenequinones. 

In addition to the possible C2,C2 -substituent interactions with a hydrophobic pocket in the regulatory domain site, the much higher affinity of calphostin A (Chart 7.1 4a, R1 = R2 = COPh, IC50 = 0.25 pM) compared to calphostin D (4d, R1 = R2 = H, IC50 = 6.4 pM) also points to interaction of the C7,C7 -portion with the binding site [51]. The C2,C2 - and C7,C7 -analogs would be invaluable in understanding the relative importance of each of these interactions. To determine 

Chart 7.3 Potency (IC50) of selected perylenequinones against PKC 

As predicted, the C2,C2 -isopropoxy and propoxy groups are more potent than the corresponding methoxy (0.8 and 1.5 pM vs. 6.4 pM). In addition, C3,C3 -substitution has an effect on both the potency and photopotentiation factor. Although the absorption at 670 nm was improved with C3 substitution, the potency against PKC decreased for analogs 90, 92, and 97. 

The development of new synthetic methodology has successfully enabled the investigation of structure-activity relationships (SAR) of perylenequinone agents for use in photodynamic therapy. Simplified analogs, such as (M)-96, that have potency equal to the natural product hypocrellin and superior chromophores to improve photoactivation in the therapeutic window were prepared. 

---