Psoralen Derivatives with Enhanced Potency

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

Research output: Contribution to journalArticle

Abstract

Psoralen is a furocoumarin natural product that intercalates within DNA and forms covalent adducts when activated by ultraviolet radiation. It is well known that this property contributes to psoralen’s clinical efficacy in several disease contexts, which include vitiligo, psoriasis, graft-versus-host disease and cutaneous T-cell lymphoma. Given the therapeutic relevance of psoralen and its derivatives, we attempted to synthesize psoralens with even greater potency. In this study, we report a library of 73 novel psoralens, the largest collection of its kind. When screened for the ability to reduce cell proliferation, 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 MALDI-TOF MS, we studied the DNA adduct formation for a subset of novel psoralens and found that in most cases enhanced DNA binding correlated well with cytotoxicity. Generally, our most potent derivatives contain positively charged substituents, which we believe increase DNA affinity and enhance psoralen 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 underappreciated aspects of psoralen’s mechanism.

Original languageEnglish (US)
JournalPhotochemistry and Photobiology
DOIs
StateAccepted/In press - 2020
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry

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  • Cite this

    Buhimschi, A. D., Gooden, D. M., Jing, H., Fels, D. R., Hansen, K. S., Beyer, W. F., Dewhirst, M. W., Walder, H., & Gasparro, F. P. (Accepted/In press). Psoralen Derivatives with Enhanced Potency. Photochemistry and Photobiology. https://doi.org/10.1111/php.13263