Identification of a Pyranocoumarin Photosensitizer that is a Potent Inhibitor of Keratinocyte Growth

• Published in: Photochemistry and photobiology Vol. 94; no. 3; pp. 577 - 582
• Main Authors: Laskin, Jeffrey D., Jan, Yi‐Hua, Jetter, Michele M., Guillon, Christophe D., Mariano, Thomas M., Heck, Diane E., Heindel, Ned D.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.05.2018
• Subjects: Biological activity; Deoxyribonucleic acid; Differentiation; DNA; DNA damage; Homology; Inhibitors; Medical treatment; Nicking endonuclease; Plasmids; Psoralen; Psoriasis; Rings (mathematics); Skin diseases; Ultraviolet radiation; Unwinding; Vitiligo
• ISSN: 0031-8655; 1751-1097
• DOI: 10.1111/php.12882

Photosensitizers are used in the treatment of epidermal proliferation and differentiation disorders such as psoriasis and vitiligo. In these studies, a ring‐expanded carbon homolog of the linear psoralen (furo[3,2‐g]benzopyran‐7‐one) class of photosensitizers, 4,10‐dimethyl‐2H,8H‐benzo[1,2‐b:5,4‐b′]dipyran‐2‐one (NDH2476), was synthesized and analyzed for biological activity. Following activation by ultraviolet light (UVA, 320‐400 nm), NDH2476 was found to be a potent inhibitor of keratinocyte growth (IC50 = 9 nm). Similar derivatives methylated in the pyran ring, or containing a saturated pyran ring structure, were markedly less active or inactive as photosensitizers. NDH2476 was found to intercalate and damage DNA following UVA light treatment as determined by plasmid DNA unwinding and nicking experiments. Taken together, these data demonstrate that an intact furan ring in psoralen photosensitizers is not required for keratinocyte growth inhibition or DNA damage. Our findings that low nanomolar concentrations of a benzopyranone derivative were active as a photosensitizer indicates that this or a structurally related compound may be useful in the treatment of skin diseases involving aberrant epidermal cell growth and differentiation. Psoralens are used in the treatment of epidermal proliferation and differentiation disorders such as psoriasis and vitiligo. A ring‐expanded carbon homolog of psoralen based on a pyranocoumarin structure (4,10‐dimethylpyranocoumarin) was synthesized and found to be a potent inhibitor of keratinocyte growth when activated by UVA light. The photoactivated pyranocoumarin readily modified DNA, an important target for this class of photosensitizers. As an effective inhibitor of keratinocyte growth, this compound may be useful in the treatment of skin diseases involving aberrant epidermal cell growth and differentiation.