 | |
| Names | |
|---|---|
| Preferred IUPAC name 7H-Furo[3,2-g][1]benzopyran-7-one | |
| Identifiers | |
| |
3D model (JSmol) | |
| 152784 | |
| ChEBI | |
| ChEMBL | |
| ChemSpider |
|
| ECHA InfoCard | 100.000.581 |
| EC Number |
|
| KEGG | |
| UNII | |
| |
| |
| Properties | |
| C11H6O3 | |
| Molar mass | 186.16 g/mol |
| Melting point | 158 to 161 °C (316 to 322 °F; 431 to 434 K) |
| Hazards | |
| GHS labelling: | |
 | |
| Warning | |
| H302,H315,H319,H335 | |
| P261,P264,P270,P271,P280,P301+P312,P302+P352,P304+P340,P305+P351+P338,P312,P321,P330,P332+P313,P337+P313,P362,P403+P233,P405,P501 | |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Psoralen (also calledpsoralene) is the parent compound in a family of naturally occurring organic compounds known as the linearfuranocoumarins. It is structurally related tocoumarin by the addition of a fusedfuran ring, and may be considered as a derivative ofumbelliferone. Psoralen occurs naturally in the seeds ofPsoralea corylifolia, as well as in thecommon fig,celery,parsley,West Indian satinwood, and in allcitrus fruits. It is widely used inPUVA (psoralen +UVA) treatment forpsoriasis,eczema,vitiligo, andcutaneous T-cell lymphoma; these applications are typically through the use of medications such asMethoxsalen. Many furanocoumarins are extremely toxic to fish, and some are deposited in streams inIndonesia to catch fish.[1]
Psoralen is amutagen, and is used for this purpose in molecular biology research. Psoralenintercalates into DNA and on exposure to ultraviolet (UVA) radiation can formmonoadducts andcovalent interstrand cross-links (ICL) with thymines, preferentially at 5'-TpA sites in the genome, inducingapoptosis. Psoralen plus UVA (PUVA) therapy can be used to treat hyperproliferative skin disorders likepsoriasis and certain kinds ofskin cancer.[2] Unfortunately, PUVA treatment itself leads to a higher risk of skin cancer.[3]
An important use of psoralen is in PUVA treatment for skin problems such aspsoriasis and, to a lesser extent, eczema andvitiligo. This takes advantage of the highUV absorbance of psoralen. The psoralen is applied first to sensitise the skin, then UVA light is applied to address the condition. Psoralens are also used inphotopheresis, where they are mixed with the extracted leukocytes before UV radiation is applied.
Despite thephotocarcinogenic properties of psoralen,[4][5] it was used as atanning activator in sunscreens until 1996.[6] Psoralens are used in tanning accelerators, because psoralen increases the skin's sensitivity to light. Some patients have had severe skin loss after sunbathing with psoralen-containing tanning activators.[7] Patients with lighter skin colour suffer four times as much from the melanoma-generating properties of psoralens than those with darker skin.[6] Psoralens short term side effects include nausea, vomiting, erythrema, pruritus, xerosis, skin pain due to phototoxic damage of dermal nerve and may cause cutaneous and genital skin malignancies.[8]
An additional use for optimized psoralens is for the inactivation of pathogens in blood products. The synthetic amino-psoralen, amotosalen HCl, has been developed for the inactivation of infectious pathogens (bacteria, viruses, protozoa) in platelet and plasma blood components prepared for transfusion support of patients. Prior to clinical use, amotosalen-treated platelets have been tested and found to be non-carcinogenic when using the established p53knockout mouse model.[9] The technology is currently in routine use in certain European blood centers and has been recently approved in the US.[10][11][12][13]
Psoralenintercalates into the DNA double helix where it is ideally positioned to form one or moreadducts with adjacent pyrimidine bases, preferentially thymine, upon excitation by an ultraviolet photon.
Several physicochemical methods have been employed to derive binding constants for psoralen-DNA interactions. Classically, two chambers of psoralen and buffered DNA solution are partitioned by asemi-permeable membrane; the affinity of the psoralen for DNA is directly related to the concentration of the psoralen in the DNA chamber after equilibrium. Water solubility is important for two reasons:pharmacokinetics relating to drug solubility in blood and necessitating the use of organic solvents (e.g.DMSO). Psoralens can also be activated by irradiation with long wavelength UV light. WhileUVA range light is the clinical standard, research thatUVB is more efficient at forming photoadducts suggests that its use may lead to higher efficacy and lower treatment times.[14]
The photochemically reactive sites in psoralens are the alkene-like carbon-carbon double bonds in the furan ring (the five-member ring) and the pyrone ring (the six-member ring). When appropriately intercalated adjacent to a pyrimidine base, a four-center photocycloaddition reaction can lead to the formation of either of two cyclobutyl-type monoadducts. Ordinarily, furan-side monoadducts form in a higher proportion. The furan monoadduct can absorb a second UVA photon leading to a second four-center photocycloaddition at the pyrone end of the molecule and hence the formation of a diadduct or cross-link. Pyrone monoadducts do not absorb in the UVA range and hence cannot form cross-links with further UVA irradiation.[15]
Another important feature of this class of compounds is their ability to generatesinglet oxygen, although this process is in direct competition with adduct formation and may be an alternate pathway for the dissipation of excited state energy.
Research on psoralen has historically focused on interactions with DNA and RNA (in particular, ICL formation). Psoralen, however, has also been shown to block signaling of theErbB2 receptor which is overexpressed in certain aggressive types of breast cancer.[16] A synthetic derivative ofbergapten, 5-(4-phenoxybutoxy)psoralen, shows promise as an immunosuppressant by inhibiting a specificpotassium channel. Its structure prevents intercalation into DNA, and it only very weakly produces singlet oxygen, majorly reducing unwanted toxicity and mutagenicityin vivo. This has implications for the treatment of various autoimmune diseases (e.g.multiple sclerosis,type-1 diabetes, andrheumatoid arthritis).[17] While cell-surface modification and ion channel blocking are two newly discovered mechanisms of action, much research remains to be done.
Most furanocoumarins can be regarded as derivatives of either psoralen orangelicin. Psoralen and its derivatives are often referred to as thelinear furanocoumarins, so called since they exhibit a linear chemical structure. Important linear furanocoumarins include xanthotoxin (also calledmethoxsalen),bergapten,imperatorin, andnodakenetin.
The structure of psoralen was originally deduced by identifying the products of its degradation reactions. It exhibits the normal reactions of thelactone of coumarin, such as ring opening byalkali to give acoumarinic acid orcoumaric acid derivative.Potassium permanganate causes oxidation of the furan ring, while other methods of oxidation produce furan-2,3-carboxylic acid.
Psoralen is difficult to synthesize becauseumbelliferone undergoessubstitution at the 8-position rather than at the desired 6 position.Benzofuran reacts preferentially in thefuran ring rather than in thebenzene ring. However, the 7-hydroxy derivative of 2,3-dihydrobenzofuran (also called coumaran) does undergo substitution at the desired 6-position allowing the following synthesis of the coumarin system via aGattermann–Koch reaction followed by aPerkin condensation usingacetic anhydride. The synthesis is then completed bydehydrogenation of the five-membered ring to produce the furan ring.
Psoralen originates fromcoumarins in theshikimate pathway; its biosynthesis is shown in the figure below. The aromatic ring in 6 is activated at positions ortho to the hydroxyl group, and is alkylated by 5, analkylating agent. The dimethylallyl group in 7 then undergoes cyclization with the phenol group to give 8. This transformation is catalysed by a cytochrome P-450-dependent monooxygenase17 (psoralen 5-monooxygenase), and cofactors (NADPH) and molecular oxygen.[18]
A biosynthetic pathway in which psoralen is formed is shown in the figure below. A secondP-450-dependentmonooxygenase enzyme (psoralen synthase) then cleaves off 10 (in the form of 11) from 8 to give 1. This pathway does not involve any hydroxylated intermediate, and cleavage is postulated to be initiated by aradical reaction.[18]
Ficus carica (fig) is probably the most abundant source of psoralens. They are also found in small quantities inAmmi visnaga (bisnaga),Pastinaca sativa (parsnip),Petroselinum crispum (parsley),Levisticum officinale (lovage),Foeniculum vulgare (fruit, i.e., fennel seeds),Daucus carota (carrot),Psoralea corylifolia (babchi),Apium graveolens (celery),bergamot oil (bergapten,bergamottin).[19]
PUVA treatment produces bothDNA interstrand crosslinks (ICLs) and monoadducts. The ICLs introduced by psoralen are highlygenotoxic to actively replicating cells. The covalent linkage impedesreplication fork progression. Thus unlinking the ICL is required before replication can resume. The initial steps in repair ordinarily involve incisions in one parental strand on both sides of the crosslink.[20] Subsequently, repair of the lesion can occur by an accurate or an inaccurate process.
The accurate process for repairing crosslinks ishomologous recombinational repair (HRR). This involves replacing the damaged information using the intact information from anotherhomologous chromosome in the same cell.Escherichia coli cells deficient in HRR are highly sensitive to PUVA compared to wild-type cells.[21] HRR appears to be efficient. InE. coli, even though one or two unrepaired crosslinks are sufficient to inactivate a cell, a wild-type cell can repair and therefore recover from 53 to 71 psoralen crosslinks.[21] In the yeastSaccharomyces cerevisiae HRR is a major pathway for accurately removing psoralen-crosslinks.[22] In wild-type yeast, the recombination events associated with crosslink removal by HRR are predominantly non-crossovergene conversion events. Psoralen crosslinks in virus DNA also appear to be removed by a recombinational repair process as occurs in SV40 virus infected cells,[23] and in herpes simplex virus infected cells.[24]
One inaccurate process for repairing psoralen crosslinks appears to employ aDNA polymerase to fill in the gap formed in the strand with the two incisions. This process is inaccurate because the complementary un-incised strand still retains a portion of the crosslink and thus cannot serve as an adequate template for accurate repair synthesis. Inaccurate repair synthesis can causemutation. Psoralen monoadducts in the template DNA strand may also cause inaccurate replication bypass (translesion synthesis) that can lead to mutation. Inphage T4, the increase in mutation observed after PUVA treatment was found to reflect translesion synthesis by wild-type DNA polymerase, likely due to imperfect proof reading capability.
Psoralens can reversibly crosslink nucleic acids double helices, and therefore have been used extensively for the analysis of interactions and structures for both DNA and RNA.[25][26]
