Psoralen
intercalates into the DNA double helix where it is ideally positioned to form one or more
adducts 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 a
semi-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. While
UVA range light is the clinical standard, research that
UVB is more efficient at forming photoadducts suggests that its use may lead to higher efficacy and lower treatment times. 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. Another important feature of this class of compounds is their ability to generate
singlet 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 the
ErbB2 receptor which is overexpressed in certain aggressive types of breast cancer. A synthetic derivative of
bergapten, 5-(4-phenoxybutoxy)psoralen, shows promise as an immunosuppressant by inhibiting a specific
potassium channel. Its structure prevents intercalation into DNA, and it only very weakly produces singlet oxygen, majorly reducing unwanted toxicity and mutagenicity
in vivo. This has implications for the treatment of various autoimmune diseases (e.g.
multiple sclerosis,
type-1 diabetes, and
rheumatoid arthritis). While cell-surface modification and ion channel blocking are two newly discovered mechanisms of action, much research remains to be done.
Structure Most furanocoumarins can be regarded as derivatives of either psoralen or
angelicin. Psoralen and its derivatives are often referred to as the
linear furanocoumarins, so called since they exhibit a linear chemical structure. Important linear furanocoumarins include xanthotoxin (also called
methoxsalen),
bergapten,
imperatorin, and
nodakenetin. The structure of psoralen was originally deduced by identifying the products of its degradation reactions. It exhibits the normal reactions of the
lactone of coumarin, such as ring opening by
alkali to give a
coumarinic acid or
coumaric acid derivative.
Potassium permanganate causes oxidation of the furan ring, while other methods of oxidation produce furan-2,3-carboxylic acid.
Synthesis Psoralen is difficult to synthesize because
umbelliferone undergoes
substitution at the 8-position rather than at the desired 6 position.
Benzofuran reacts preferentially in the
furan ring rather than in the
benzene 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 a
Gattermann–Koch reaction followed by a
Perkin condensation using
acetic anhydride. The synthesis is then completed by
dehydrogenation of the five-membered ring to produce the furan ring. ==Biosynthesis==