Psoralen and Bergapten: In Silico Metabolism and Toxicophoric Analysis of Drugs Used to Treat Vitiligo

Abstract

PURPOSE: to discuss the contribution of psoralen and bergapten metabolites on psoralens toxicity. METHODS: Computational chemistry prediction of metabolic reactions and toxicophoric groups based on the expert systems Derek and Meteor. RESULTS: a total of 15 metabolites were suggested for both psoralen and bergapten based on phase 1 and 2 biotransformations until the 3rd generation. Five toxicophoric substructures were shared among psoralen, bergapten and their corresponding metabolites; one toxicophoric marker (resorcinol) was only identified in bergapten and its biotransformation products. CONCLUSION: Although the toxic effects of psoralens are well known and documented, there is little information concerning the role of their metabolites in this process. We believe this work add to the knowledge of which molecular substructures are relevant to the process of metabolism and toxicity induction, thus guiding the search and development of more effective and less toxic drugs to treat vitiligo.

4-[(E)-(4-Hydroxy-2-oxo-2H-chromen-3-yl)methylideneamino]-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one monohydrate

“…For general background and biological activity of pyranocoumarin and substituted coumarin derivatives, see: Aries (1974); da Silva et al (2009); Huang et al (2010); Skulnick et al (1997); Spino et al (1998); Kokil et al (2010); Abdelhafez et al (2010); Honmantgad et al (1985); Delporte et al (1998); Ibrahim et al (2006); Bissonnette et al (2009). For a related structure, see: Arshad et al (2010).…”

“…Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL and PLATON (Spek, 2009). A number of pyranocoumarin and substituted coumarin derivatives reported to possess multiple biological activities (Aries, 1974) are used in the treatment of vitiligo (da Silva et al, 2009) and other dermal diseases. Coumarins show various activities such as anticancer (Huang et al, 2010), anti-HIV agents (Skulnick et al, 1997;Spino et al, 1998), antifungal (Kokil et al, 2010), anticoagulant (Abdelhafez et al, 2010), antibacterial (Honmantgad et al, 1985), antipyretic (Delporte et al, 1998), analgesic (Ibrahim et al, 2006) and anti-inflammatory (Bissonnette et al, 2009) properties.…”

Combinations of Blue and Red LEDs Increase the Morphophysiological Performance and Furanocoumarin Production of Brosimum gaudichaudii Trécul in vitro

“…Of all compounds involved in the treatment of depigmentation disorders, linear furanocoumarins (psoralen and bergapten) are the most used in clinical trials, as they have been combined with ultraviolet radiation in the treatment of diseases such as psoriasis, vitiligo, eczema, alopecia, primary T-cell lymphomas (fungal mycosis), and central nervous system and circulatory system disorders (Sumorek-Wiadro et al, 2020;Zhao et al, 2020). Psoralen and bergapten, as well as other furanocoumarin compounds, exert their photosensitizing effects by covalently bonding DNA, which is triggered by light of specific wavelengths (320-410 nm) (da Silva et al, 2009). Psoralen and bergapten can be obtained from plant extraction or chemical synthesis, but the former is preferred because the synthesis of furanocoumarins is expensive and generates toxic waste (Martins et al, 2015a).…”

An Improved LC-MS/MS Method for Simultaneous Determination of the Eleven Bioactive Constituents for Quality Control of Radix Angelicae Pubescentis and Its Related Preparations

“…Osthole, isolated from RAP, has antiproliferative effect in rat vascular smooth muscle cells. It was also noticed that some coumarins have been linked to phototoxic, mutagenic, carcinogenic, and hepatotoxic effects [ 16 , 17 ]. With these various functions in mind, it is not surprising that coumarins impact significantly on the clinical efficacy and safety of herbal medicine.…”