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It is well known that this property contributes to psoralen\u2019s clinical efficacy in several disease contexts, which include vitiligo, psoriasis, graft\u2010versus\u2010host disease and cutaneous T\u2010cell 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\u2032\u2010aminomethyl\u20104,5\u2032,8\u2010trimethylpsoralen (AMT), one of the most potent psoralens identified to date. Using MALDI\u2010TOF 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\u2019 therapeutic potential. Finally, the structure\u2013activity insights we have gained shed light on several opportunities to study currently underappreciated aspects of psoralen\u2019s mechanism.<\/jats:p>","DOI":"10.1111\/php.13263","type":"journal-article","created":{"date-parts":[[2020,3,28]],"date-time":"2020-03-28T08:20:18Z","timestamp":1585383618000},"page":"1014-1031","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Psoralen Derivatives with Enhanced Potency"],"prefix":"10.1111","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8951-7967","authenticated-orcid":false,"given":"Alexandru D.","family":"Buhimschi","sequence":"first","affiliation":[{"name":"Medical Scientist Training Program Northwestern University Feinberg School of Medicine Chicago IL"},{"name":"Photobiology Laboratory Hamden Hall Country Day School Hamden CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Gooden","sequence":"additional","affiliation":[{"name":"Department of Chemistry Duke University Durham NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9690-587X","authenticated-orcid":false,"given":"Hongwu","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology University of Illinois College of Medicine Chicago IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane R.","family":"Fels","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Duke University Medical Center Durham NC"},{"name":"Duke Cancer Institute Duke University Medical Center Durham NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine S.","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Duke University Medical Center Durham NC"},{"name":"Duke Cancer Institute Duke University Medical Center Durham NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Wayne F.","family":"Beyer","sequence":"additional","affiliation":[{"name":"Immunolight LLC Detroit MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark W.","family":"Dewhirst","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Duke University Medical Center Durham NC"},{"name":"Duke Cancer Institute Duke University Medical Center Durham NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harold","family":"Walder","sequence":"additional","affiliation":[{"name":"Immunolight LLC Detroit MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7941-5799","authenticated-orcid":false,"given":"Francis P.","family":"Gasparro","sequence":"additional","affiliation":[{"name":"Photobiology Laboratory Hamden Hall Country Day School Hamden CT"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,24]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0738-081X(89)90062-X"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphotochemrev.2005.08.002"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.1952.tb15880.x"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.1964.tb14475.x"},{"key":"e_1_2_8_6_1","first-page":"1","article-title":"Further study on treatment of leucodermia with Ammi mafus linn","volume":"35","author":"El\u2010Mofty A. 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