Christophe D Guillon, Yi-Hua Jan, Natalie Foster, Mridula Choudhuri, Jaya Saxena, Thomas M Mariano, Diane E Heck, Jeffrey D Laskin, Ned D Heindel
The natural product 8-methoxypsoralen (methoxsalen or 8-MOP) in combination with long wavelength ultraviolet light (UVA, 320-400 nm), also referred to as PUVA therapy, is used for the treatment of cutaneous proliferative disorders including psoriasis, vitiligo and mycosis fungoides. The use of 8-MOP (3) is limited by its poor water solubility and there remains a need to develop more water-soluble psoralens to enhance bioavailability following oral administration of the drug. In the present studies a water-soluble dimethylaminoethyl ether analog of 8-MOP was synthesized and analyzed for biological activity. This analog, (8-[2-(N,N-dimethylamino)ethoxy]-psoralen hydrochloride (1) [or CAS name: 9-[2-(dimethylamino)ethoxy]-7H-furo[3,2-g][1]benzopyran-7-one, hydrochloride], was found to be significantly more active than 3 in keratinocyte growth inhibition assays (IC50 = 12 nM and 130 nM for 1 and 3, respectively). The partially reduced dihydro derivative of 1, 8-[2-(N,N-dimethylamino)ethoxy]-4',5'-dihydropsoralen hydrochloride (2) [or CAS name: 9-[2-(dimethylamino)ethoxy]-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one, hydrochloride] and the partially reduced 4',5'-dihydro-8-methoxypsoralen (4) lacking the water-solubilizing side-chain were significantly less active. As inhibitors of keratinocyte growth they ranked as IC50 = 13,000 nM and 70,000 nM for 2 and 4, respectively, indicating that an unsaturated furan ring in the psoralen was required for maximal activity. Compound (1) was found to readily intercalate and damage DNA following UVA light treatment as determined by plasmid DNA nicking and unwinding experiments in neutral and alkaline agarose gels. Taken together, these data demonstrate that a water-soluble dimethylaminoethyl ether psoralen targets DNA, is highly active as a photosensitizer, and may be useful in the treatment of skin diseases involving abnormal keratinocyte proliferation.
{"title":"SYNTHESIS AND EVALUATION OF WATER-SOLUBLE DIMETHYLAMINOETHYL ETHERS OF METHOXSALEN FOR PROLIFERATIVE SKIN DISORDERS.","authors":"Christophe D Guillon, Yi-Hua Jan, Natalie Foster, Mridula Choudhuri, Jaya Saxena, Thomas M Mariano, Diane E Heck, Jeffrey D Laskin, Ned D Heindel","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The natural product 8-methoxypsoralen (methoxsalen or 8-MOP) in combination with long wavelength ultraviolet light (UVA, 320-400 nm), also referred to as PUVA therapy, is used for the treatment of cutaneous proliferative disorders including psoriasis, vitiligo and mycosis fungoides. The use of 8-MOP (<b>3</b>) is limited by its poor water solubility and there remains a need to develop more water-soluble psoralens to enhance bioavailability following oral administration of the drug. In the present studies a water-soluble dimethylaminoethyl ether analog of 8-MOP was synthesized and analyzed for biological activity. This analog, (8-[2-(N,N-dimethylamino)ethoxy]-psoralen hydrochloride (<b>1</b>) [or CAS name: 9-[2-(dimethylamino)ethoxy]-7<i>H</i>-furo[3,2-<i>g</i>][1]benzopyran-7-one, hydrochloride], was found to be significantly more active than <b>3</b> in keratinocyte growth inhibition assays (IC<sub>50</sub> = 12 nM and 130 nM for <b>1</b> and <b>3</b>, respectively). The partially reduced dihydro derivative of <b>1</b>, 8-[2-(N,N-dimethylamino)ethoxy]-4',5'-dihydropsoralen hydrochloride (<b>2</b>) [or CAS name: 9-[2-(dimethylamino)ethoxy]-2,3-dihydro-7<i>H</i>-furo[3,2-<i>g</i>][1]benzopyran-7-one, hydrochloride] and the partially reduced 4',5'-dihydro-8-methoxypsoralen (<b>4</b>) lacking the water-solubilizing side-chain were significantly less active. As inhibitors of keratinocyte growth they ranked as IC<sub>50</sub> = 13,000 nM and 70,000 nM for <b>2</b> and <b>4</b>, respectively, indicating that an unsaturated furan ring in the psoralen was required for maximal activity. Compound (<b>1</b>) was found to readily intercalate and damage DNA following UVA light treatment as determined by plasmid DNA nicking and unwinding experiments in neutral and alkaline agarose gels. Taken together, these data demonstrate that a water-soluble dimethylaminoethyl ether psoralen targets DNA, is highly active as a photosensitizer, and may be useful in the treatment of skin diseases involving abnormal keratinocyte proliferation.</p>","PeriodicalId":44091,"journal":{"name":"Heterocyclic Letters","volume":"8 4","pages":"729-736"},"PeriodicalIF":0.1,"publicationDate":"2018-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875182/pdf/nihms-1029725.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25360465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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