Psoralen Derivatives with Enhanced Potency

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.

Tracing the Photoaddition of Pharmaceutical Psoralens to DNA

“…Once this state is populated, the investigated psoralens add to thymine with high efficiency. So, when optimizing psoralens for the PUVA therapy, a small dissociation constant K D [54], a low propensity for PET quenching by guanine [25] and a high triplet yield should be aimed at. Optimizations along these lines are presently undertaken by us.…”

A review on the important phytochemicals and their role in psoriasis

“…Treatment of psoriasis with synthetic medicines is restricted because of its practicability, comfort, and extreme unfavorable adverse effects like hepatotoxicity and renal damage. 5), Madecassoside (6), Astilbin (7), Biacalin (8), Berberine (9), Boswellic acid (10), Caffeine (11), Camptothecin (12) & Iso-Camptothecin (13), Cannabinoids (14,15,16,17), Chamazulene (18), Chlorogenic acid (19), Cholchicine (20), Curcumin (21), Delphinidine (22), Embelin (23), Fumeric acid (24), Genistein (25), Glycerhiznic acid (26), Gossypol (27), Hypericin (28), Hyperforin (29), Indirubin (30), Isoliquiritigenin (31), Koumine (32), Luteolin (33), P-anisaldehyde (34), Pcoumaric acid (35), P-resinol (36), Podophyllotoxin (37), Polyandric acid A (38), Polyandric acid B (39), Psoralen (40), Quercitin (41), Resveratrol (42), , Syllimarin (43), 4-methylthiobutylisothiocyanate (44).…”

“…Psoralens, when irradiated at 365 nm, covalently integrate with pyrimidine bases in nucleic acid. Cross connections between two DNA strands also occur when psoralens act as bivalent reagents, interact with opposite double helix strands through pyrimidine bases (Buhimschi et al, 2020). This inhibitory impact is one potential explanation of the psoralens effects and long-wave UV radiation in psoriasis, characterized by increased rate of epidermal cell turnover (Stern and Richard, 2020).…”

Anti-Inflammatory Effects of Psoralen Derivatives on RAW264.7 Cells via Regulation of the NF-κB and MAPK Signaling Pathways

“…Psoralen and its derivatives are known for clinical efficacy in several skin diseases, including cutaneous lichen planus, graft-versus-host disease, mycosis fungoides, vitiligo, and psoriasis [ 22 , 23 ]. Given the therapeutic relevance of psoralen and its derivatives, many studies aim to synthesize psoralens with even greater potency [ 24 , 25 ].…”