Psoralen Derivatives with Enhanced Potency

In this study, we re port a library of 73 novel psoralens, the largest collection of its kind. When screened for the ability to induce cell death, we identified two derivatives even more cytotoxic than 4’‐aminomethyl‐4,5’,8‐trimethylpsoralen (AMT), one of the most potent psoralens identified to date. Using MAL DI‐TOF MS, we studied the DNA adduct formation of a subset of novel psoralens and found that in most cases enhanced DNA binding correlated well with cytotoxicity. Generally, our most active derivatives contain positively charged substituents, which we believe increase DNA affinity and enhance psor alen intercalation. Thus, we provide a rational approach to guide efforts toward further optimizing psoralens to fully capitalize on this drug class’ therapeutic potential. Finally, the structure‐activity insights we have gained shed light on several opportunities to study currently underappreci ated aspects of psoralen’s mechanism.

Source: Photochemistry and Photobiology - March 30, 2020 Category: Science Authors: Alexandru D. Buhimschi, David M. Gooden, Hongwu Jing, Diane R. Fels, Katherine S. Hansen, Wayne F. Beyer, Mark W. Dewhirst, Harold Walder, Francis P. Gasparro Tags: RESEARCH ARTICLE Source Type: research