Molecular aspects of furocoumarin reactions: Photophysics, photochemistry, photobiology, and structural analysis

Journal of Photochemistry and Photobiology C: Photochemistry Reviews 6 (2005) 168–185

Review

Molecular aspects of furocoumarin reactions: Photophysics, photochemistry, photobiology, and structural analysis Noriko Kitamura a , Shigeru Kohtani a,b , Ryoichi Nakagaki a,b,∗ a

Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan b Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan Received 15 March 2005; received in revised form 11 August 2005; accepted 26 August 2005

Abstract The photophysics, photochemistry, photobiology, and structural analysis of furocoumarin derivatives have been reviewed from molecular and interdisciplinary points of view. The molecular aspects have been clear in the photoreaction of furocoumarins since the mid-1900s. Since furocoumarin derivatives absorb UVA light and act as photosensitizers, they have been used as helpful molecular probes and as skin disease drugs. The versatility of these compounds is entirely due to their optical properties. The photoexcited furocoumarins react with biomolecules, especially with pyrimidine bases in DNA, and form mono- and di-adducts. [2 + 2] Photocycloaddition reactions play an important role in the formation of mono- and di-adducts. The degree of photobinding in furocoumarins depends on the types of coumarin compounds, the DNA base sequences, the UVA light doses, excitation wavelengths, temperatures, solvents, and other factors. Consequently, choosing the appropriate conditions can easily control the photoreaction. Furocoumarins have been widely employed for many purposes, and the development of the understanding of their photobiology is still in progress. © 2005 Elsevier B.V. All rights reserved. Keywords: UVA radiation; Psoralens and their analogs; Mono- and di-adducts; [2 + 2] Photocycloaddition; Crystallographic analysis

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photophysics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Nature of excited states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Fluorescence and phosphorescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Triplet–triplet transitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Theoretical calculations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. [2 + 2] Photocycloaddition (cyclization reactions) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Reactions with nucleic acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Primary processes involving excited states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Sequence specificity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Probes for nucleic acid structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photobiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Photochemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Photopheresis (extracorporeal photochemotherapy) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Various psoralen derivatives for PUVA therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Alternative approach for reducing side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: +81 76 234 4425; fax: +81 76 234 4484. E-mail address: [email protected] (R. Nakagaki).

1389-5567/$20.00 © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jphotochemrev.2005.08.002

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Miscellaneous aspects of psoralen photochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Sterilization of blood products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Covalent binding of DNA with psoralen derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Photochemical bond formation with biomaterials other than nucleic acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Crystal and molecular structures of furocoumarin derivatives determined by X-ray crystallographic analysis . . . . . . . . . . . . . . . . . . . . . . . 6.1. Average geometry of aromatic rings in furocoumarins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Structures of photoadducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Noriko Kitamura was born in 1971 in Shiga Prefecture. She obtained her BS degree in 1993 at Kanazawa University. Since 1993 she has been working at Toray Research Center, Inc., located in Otsu. She became a research fellow in 2004. Since 2003 she has been studying with Prof. Ryoichi Nakagaki toward a PhD degree. Her interests focus on the chemical properties and applications of coumarin derivatives.

Shigeru Kohtani was born in 1967, in Toyama Prefecture. He graduated from Kanazawa University, Faculty of Pharmaceutical Sciences in 1990. He obtained his MSc degree from Tokyo Institute of Technology, Department of Electronic Chemistry in 1992. He was a Technical Assistant in the Faculty of Pharmaceutical Sciences, Kanazawa University (1992–1997). He received his PhD degree from Kanazawa University, Graduate School of Natural Science and Technology in 1997. He was a Research Associate in the Faculty of Pharmaceutical Sciences, Kanazawa University (1997–2000). He is currently a Research Associate in the Graduate School of Natural Science and Technology, Kanazawa University (2000-present). His scientific interests are in photochemistry and photocatalysis, especially, in development of new fluorescent and chemiluminescent probes to elucidate mechanisms of generation, elimination, and reactions of active oxygen species in solution and at solid/liquid interfaces. Ryoichi Nakagaki was born in 1950 in Tokyo. He received his BS degree from Nagoya University in 1973. He obtained his PhD in 1978 under the supervision of Professor Saburo Nagakura at the University of Tokyo. From 1982 to 1990 he was a Research Associate at the Institute of Molecular Science (IMS). Since 1990 he has been working at Kanazawa University. From 1993 to 1995 he was an Adjunct Associate Professor of IMS. He is now a Professor in the Graduate School of Natural Science and Technology, Kanazawa University. His research interests lie in photochemistry, photocatalysis, and photobiological processes. He has been continuing experimental research on magnetic field and magnetic isotope effects on photochemical reactions as well as photophysical processes of fluorescent organic compounds.

1. Introduction During the latter half of the 20th century, there have been remarkable advances in optical engineering for light sources and optical fibers, computer technology, chemical and structural analyses, and molecular genetics. High-intensity monochromatic light sources such as lasers [1,2] have revolutionized spectroscopy [3,4], photochemistry [5,6], photobiology [7], and

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photomedicine [8]. Increasingly powerful computers have also facilitated quantum mechanical calculations, scientific measurements, and technical control of medical machines. Sophistication of chemical and structural analyses has been achieved through progress in spectroscopy and quantum chemistry [9,10]. Recent advances in life sciences are closely related to molecular biology and the biotechnology of nucleic acids [11,12]. Ancient Egyptians utilized extracts of Ammi majus L. (umbelliferae), a weed found in the Nile delta, as a cure for leukoderma (vitiligo). However, this ancient people probably did not know why the ingestion of an Ammi plant preparation in conjunction with exposure to sunlight is an effective treatment for skin diseases. The pharmacognostic isolation and the purification of crystalline psoralen derivatives led to modern clinical studies concerning the treatment of vitiligo in the late 1940s and early 1950s [13–18]. Photochemotherapy utilizes both light and chemical agents in order to remedy certain types of cutaneous maladies. The term “photochemotherapy” has been coined to describe the necessary interaction of UVA light and drugs that results in a beneficial effect against diseases [19]. One of the most important furocoumarins, 8-methoxypsoralen (8-MOP), has been used for the clinical treatment of psoriasis as well as vitiligo [8]. The molecular basis of photochemotherapy or photodynamic therapy for skin diseases was firmly founded during the 1970s [20–24]. For instance, the Woodward–Hoffmann rules [25] revealed the conservation of molecular orbital symmetry and gave a comprehensive view on [2 + 2] cycloaddition reactions, such as the commonly observed cyclobutane formation reaction for pyrimidine bases. In the year 1911, Thomas isolated xanthotoxin (8-MOP) from Fagara xanthoxyloides L. [26], and then in 1933, Sp¨ath and Holzen [27] clarified its chemical structure and reported on its synthesis. It was not until 1972 that the crystalline and molecular structures of xanthotoxin were established by the X-ray diffraction method [28]. The chemical name psoralen has been generally used instead of its systematic nomenclature designation, 7H-furo[3,2g][1]benzopyran-7-one. Fig. 1 shows molecular structure of furan, coumarin, and psoralen (furocoumarin) together with the numbering of skeletal atoms. Furocoumarin is a tricyclic aromatic compound in which the C2 C3 -bond in furan is fused to the C6 C7 -bond of the bicyclic coumarin moiety. Even before the term “psoralen” became widely accepted, the substance had several different names. For example, two crys-

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Fig. 1. Molecular structure of (A) furan, (B) coumarin (2H-1-benzopyran-2one), (C) psoralen (furocoumarin) and (D) 7H-furo[3,2-g][1]benzopyran-7-one. Two different numbering systems for skeletal atoms correspond to different nomenclature.

Fig. 3. Schematic representation of the energy levels of psoralen in the excited state.

tion (e.g., energy and electron transfer) [34]. The following kinetic parameters on the electronically excited states have been determined: fluorescence quantum yields and lifetimes, phosphorescence lifetimes and quantum yields, quantum yields of intersystem crossing, and singlet oxygen generation [35–45]. 2.1. Nature of excited states

Fig. 2. Molecular structure of angelicin (isopsoralen) and substituted psoralens.

talline principles extracted from the fruits of Ammi Majus, ammoidin and ammidin, were identified as xanthotoxin (8methoxypsoralen) and imperatorin (8-isoamylenoxypsoralen), respectively [16,18]. Fig. 2 illustrates the structure of angelicin (ispsoralen) and psoralen derivatives. Since the photoscience of psoralens has been extensively reviewed [6,7,20–24], the current article deals mainly with the photoreactions of furocoumarins from the molecular point of view. This review aspires to show that the photoreactions of furocoumarins are of interdisciplinary interest. Special attention will be paid to the photophysics, photochemistry, photobiology, and structural analysis of 8-MOP and related compounds. The review will not include details concerning synthetic chemistry, phytochemistry, pharmacognosy, pharmacology, toxicology, or clinical dermatology, because these topics have been dealt with elsewhere [8,29–33]. 2. Photophysics The important photophysical processes of psoralens are as follows: photoabsorption (excitation), radiative transitions (fluorescence and phosphorescence), and non-radiative deactiva-

The nature of excited states has been studied by use of several spectroscopic methods [35–38]. Bicyclic coumarin can serve as a model compound for elucidating the spectroscopic characteristics of tricyclic psoralens and their analogs, because its structure is similar to that of psoralen. There may be two different types of electronic transitions for coumarins and psoralens, in the ultraviolet and near-ultraviolet (200–400 nm) regions of the spectrum. Two electronic transitions are possible, namely, the transition from the non-bonding electron in the carbonyl group to the antibonding ␲* orbital and that from the electron in the bonding ␲ orbital to the antibonding ␲* orbital. These transitions produce n–␲* and ␲–␲* excited states. The fluorescent and phosphorescent states (S1 and T1 ) have been assigned to the ␲–␲* excited state on account of their polarization spectra, lifetimes, theoretical transition energies, and transition moments. Both the spectroscopic and quantum chemical calculations of the electronic structures of coumarin’s excited states indicate that excitation is substantially localized in the pyrone moiety [35,36]. The energy levels of psoralen’s singlet and triplet states are assigned by use of substituted coumarin derivatives. Fig. 3 shows the Jablonski diagram for the relative orientations of energy levels in the excited states [36]. 2.2. Fluorescence and phosphorescence Psoralens and coumarins fluoresce weakly, while they phosphoresce relatively strongly [36]. Fluorescence emission can be observed from ca. 380 to 600 nm, depending upon the nature of the substituents and that of the solvent. The fluorescence lifetime is usually short and varies with the type of psoralen derivative and the solvent conditions. Typical values vary from 1 to 5 ns. The

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quantum yield for fluorescence is also very small, ranging from 0.01 to 0.02 [36,40,42]. The emission intensity from the triplet state of the psoralens is significantly greater than that of the singlet state because of efficient intersystem crossing. Phosphorescence can usually be observed from ca. 450 to 600 nm [40,42]. Phosphorescence intensity of psoralens is significantly sstronger than that of the fluorescence because of the efficient intersystem crossing. The lifetime of the triplet state also varies with the psoralen derivative type, ranging from 1 ␮s to 1 s [40,42]. The fluorescence lifetime measurements of furocoumarins are very complicated for two reasons. The first is that the fluorescence efficiency is rather small and highly dependent on the polarity and hydrogen-bonding capabilities of solvents. Secondly, non-single exponential fluorescence decays were often observed even in dilute and homogeneous solutions under conditions where the solute molecules did not aggregate. In addition, the fastest lifetime component is in the picosecond region, going on the assumption that the decay function is represented by a sum of exponentials [38–41]. In most cases, more than one fluorescence lifetime was observed, and this was discussed in terms of the ground-state and excited-state complex formations between the solvent and the furan moiety of the psoralens [40]. The strong temperature and solvent dependence of the fluorescence and triplet formation for psoralens are due to the efficient S1 –S0 internal conversion that arises from the proximity of the lowest energy ␲–␲* and n–␲* singlet states [38]. The S1 –S0 internal conversion rate increases when the temperature increases and the solvent polarity decreases. This is in accordance with the prediction of model calculations concerning the proximity effects and the photophysical behavior of aromatic carbonyls with close-lying ␲–␲* and n–␲* singlet states. Time-resolved and energy-resolved fluorescence decays clearly indicate the important role of solvent relaxation in determining the relative importance of the proximity effect through its influence on the energy separation between the ␲–␲* and n–␲* singlet states. 2.3. Triplet–triplet transitions The triplet–triplet (T–T) absorption spectra of psoralen, isopsoralen (angelicin), 5-methoxypsoralen, and 8-methoxypsoralen have been determined by use of a technique consisting of pulse radiolysis and laser flash photolysis in benzene and water [46]. The extinction coefficients of the T–T transitions were measured to determine the singlet–triplet intersystem-crossing (ISC) yields for excitation at 353 nm. ISC quantum yields were dependent on the solvent used. The highest yields were determined to be 0.45 and 0.33 for psoralen and isopsoralen in water, respectively. With the use of the laser photolysis technique, similar transient spectra have been detected for various psoralen derivatives [47–49]. 2.4. Theoretical calculations Earlier molecular orbital calculations predicted that the excitation of coumarin is mainly localized on the pyrone ring [35,36]. In a recent study, the excitation energies for S1 and T1 were com-

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puted by means of density functional theory, resulting in the agreement with experimental data within 0.2 eV [50]. Quantum chemical calculations for a large set of furocoumarin compounds have already elucidated excitation energy, oscillator strength, and transition probability for intersystem crossing in relation with their photoreactions [50–52]. Molecular dynamics and molecular mechanics were used to study the formation of psoralen–DNA intercalation complexes in the dark [53,54]. The theoretical calculations can be useful in designing new photochemotherapy drugs with improved therapeutic profiles. 3. Photochemistry Fig. 4 summarizes several different reactions that are induced by the photoexcitation of psoralens with UVA light. Photochemical reactions can be classified into two major categories, oxygen-dependent (Type I) and oxygen-independent (anoxic, Type II) processes [50,55]. Psoralens are recycled as sensitizers in the former photosensitization process, while they undergo permanent chemical changes in the latter. In oxygen-dependent type I sensitization, the psoralens are first pumped from the ground state (S0 ) to the lowest excited singlet state (S1 ). The short-lived S1 state then undergoes intersystem crossing to create a relatively long-lived lowest excited triplet state (T1 ). An electron donor, such as one of the DNA bases, may readily reduce the psoralens in the excited triplet state. A subsequent electron transfer from the reduced photosensitizer to molecular oxygen results in the formation of reactive superoxide anions and fragmention of the substrate cations. In oxygen-dependent type II sensitization, the excitation energy of the first excited triplet state of the psoralens is transferred to molecular oxygen [56,57]. The excited singlet molecular oxygen (1
g state, ca. 0.98 eV above the ground state) can then react rapidly and rather indiscriminately with a wide variety of biomaterials (e.g., nucleic acids, proteins, and unsaturated lipids), causing severe damage. Type II reactions were disturbed by several constraints. For the effective photoreaction, the sensitizer must possess a high quantum yield for intersystem crossing, and the triplet state must be relatively long-lived. The photosensitizer must have a higher triplet energy than that of the singlet oxygen state (1
g state) and must also not be susceptible to attack by the generated singlet oxygen. Fig. 5 illustrates the schematic energy level diagram for the energy transfer processes among the photosensitizer (8-MOP), oxygen, solvent, and quencher [45]. In the oxygen-independent photoreaction, the excited psoralen reacts with the target compound. This type of photobinding reaction occurs if the target compounds are DNA bases that can be in close proximity or are intercalated. The reactions proceed very rapidly through the first excited singlet state of the psoralen, in which the C3 C4 and C4 C5 bonds of the pyrone and furan moieties, respectively, can undergo four-membered ring formations with the unsaturated lipid bonds or the C5 C6 double bonds of the DNA base, thymine (see the atomic numbering in Fig. 9). Other possible furocoumarin compound reactions are direct electron transfer and auto-ionization reactions. In the former

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Fig. 4. Possible reactions of psoralen compounds (Ps) upon absorption of UVA radiation.

Fig. 5. Schematic energy level diagram valid for the energy transfer processes among photosensitizer (8-MOP), oxygen, solvent and quencher.

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Fig. 6. Photodimerization products of coumarin: cHH (cis-head-to-head), tHH (trans-head-to-head), cHT (cis-head-to-tail), and tHT (trans-head-to-tail).

process, a direct photo-induced charge separation takes place between psoralen and molecular oxygen (“direct electron transfer” in Fig. 4). In the latter process, one sensitizer in the T1 or S0 state can reduce another sensitizer that is in the excited triplet state, thus forming a pair that consists of a radical anion and a radical cation. The term of auto-ionization refers to the process of charge-separation between the two identical molecules. The psoralen may finally become ionized, either directly or through an excited state, and may possibly react with the target compound in the form of a radical cation [50]. 3.1. [2 + 2] Photocycloaddition (cyclization reactions) Photo-induced dimerization of coumarin takes place at the C3 C4 double bond, which may lead to formation of four isomers, trans-head-to-head, trans-head-to-tail, cis-head-to-head, and cis-head-to-tail, all of which are shown in Fig. 6 [58]. A triplet-sensitized reaction predominantly yields the transhead-to-head structure, with a small amount of the trans-headto-tail one [58]. Psoralen undergoes similar photodimerization that involves the C3 C4 double bond, with a dominant yield of the trans-head-to-head structure [58]. The photochemistry of psoralens with olefinic compounds becomes much more complex than a simple homo-dimerization, and there has been a compilation of experimental data for [2 + 2] heterodimerization between psoralens and unsaturated molecules [6].

Fig. 7. Photocycloaddition products of psoralen with a substituted ethylene.

A substituted ethylene H2 C CHX can form two regioisomers at each site during photocyclization with psoralens. When mono-adducts form at both sites of the olefin with the C3 C4 double bond, the resulting cyclobutanes are either syn and anti or cis and trans, depending upon the relative orientation of X with respect to the psoralen ring system. Fig. 7 shows the monoadduct structure of psoralen with the olefin H2 C CHX. Since one cyclobutane ring formation can generate four isomers, psoralen mono-adducts can have eight isomers if the presence of enantiomers is neglected. In addition to the C3 C4 double bond of the pyrone ring, the C4 C5 bond of the furan moiety can also undergo photoinduced cyclization. The total number of diadducts is then doubled, therefore becoming 16 isomers [6]. Although a surprisingly large number of isomers are possible when an optically active substance such as DNA is involved in cyclobutane formation, it is very rare that all of the possible isomers have been identified in the psoralen photoreactions with DNA or its components, such as the pyrimidine bases. 3.2. Reactions with nucleic acids The photochemical reactions of psoralens with nucleic acids have been very well characterized [34,59]. It has been suggested that a major action site of photosensitization with psoralen derivatives is in the cellular nucleus [60,61]. The results that

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Fig. 8. Schematic diagram illustrating chemical bond formation between 8-MOP and pyrimidine bases on different strands of a DNA molecule.

indicate the uptake of psoralen derivatives by cellular nuclei were obtained based on fluorescence microscopic observations of human oral mucosa cells that were treated in vitro with 8-MOP and 5-MOP. Fluorescence spectroscopic analysis was performed for the derivatives interacting with DNA in an aqueous solution [60]. In the dark, psoralen molecules form complexes with DNA hydrogen-bonded base pairs. Following irradiation with UVA or visible light, photoadditions occur at the C4 C5 -bond of the furan moiety and probably at the C3 C4 -bond of the pyrone moiety. Each of these adducts has a cyclobutane ring that at the C5 C6 -bond of a pyrimidine. The extent of photoadduct formation depends on the suitability (base sequence) and accessibility (protein contacts, DNA bending) of the intercalation sites between the DNA base pairs. The C4 C5 -adducts on the furan-side can absorb a second photon, forming an interstrand cross-link with another thymine in the adjacent base pairs in a T–A site [59]. Fig. 8 shows that the 8-MOP binds to DNA after being activated by ultraviolet radiation. On reaching the cell nucleus, 8-MOP slides between the paired bases of the DNA chain (step 1). After absorbing a UVA photon, the molecule then forms a pair of bonds with a nucleotide base on one DNA strand (step 2). After absorbing a second photon, the 8-MOP can bind to a base on the other DNA strand (step 3) [62].

Fig. 9 shows that the stereochemistry of all of the 8-MOPDNA adducts is cis-syn. Syn for the furan-side describes the structure as having the furan O1 and the pyrimidine N1 on the adjacent corners of the cyclobutane ring. Syn for the pyrone-side is defined as having the carbonyl-carbon (C2 ) of the psoralen and the N1 of the pyrimidine on adjacent corners of the cyclobutane ring [23]. Fig. 10 illustrates schematic representation of the cis-syn configurational isomers. In this figure, the large slabs represent the 8-MOP with the furan ring at the left end, as indicated by the black markers. The handles projecting from these slabs represent the methoxy group at C8 in the psoralen. The smaller slabs are the pyrimidine bases, and the handles represent the deoxyribose sugar [23]. As shown in Fig. 11, the only species present that was capable of absorbing an appreciable amount of 341.5-nm light was the furan-side mono-adduct. The furan-side mono-adducts in these sites can be converted, to a lesser extent, to the 3,4-(pyrone-side) mono-adduct. A plausible mechanism for conversion of furanside mono-adduct to pyrone-side mono-adduct is as follows. Absorption of 341.5-nm light by furan-side mono-adducts in non-cross-linkable sites gives rise to photoreversal to release 8MOP. The non-bound 8-MOP formed in this process diffuses out of the helix, intercalates in a new binding site, and forms a new mono-adduct. A certain portion of mono-adducts may be newly formed at the pyrone-side. Fig. 12 shows the proposed

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Fig. 11. Absorption spectra of 8-MOP-thymidine adducts. Pyron: pyrone-side monoadduct, Furan 1 and 2: diastereomeric furan-side monoadducts. Cross-link: diadduct. (Reproduced, with permission, from the Annual Review of Biochemistry, Volume 54 [23] 1985 Annual Reviews www.annualreviews.org.).

mechanism for the conversion of the furan-side mono-adduct to the pyrone-side mono-adduct and to the di-adduct [63]. 3.3. Primary processes involving excited states Fig. 9. Molecular structures of adducts formed between 8-MOP and dT(thymidine). Deoxyribose is designated by dRib. (Reproduced with permission from [63] (1985 American Chemical Society.).

The hypothesis that the furocoumarin triplet state should be the reactive precursor to mono-adduct formation was supported by steady state photolysis and laser flash photolysis experiments [46,49,64,65]. However, there has been no definite evidence for triplet formation of the DNA-complexed furocoumarins [42,47–49]. The fluorescence spectra are similar in nature for psoralen and 8-MOP, and they are attributed to the drug’s binding to DNA. Their singlet-excited states are quenched by intercalation into DNA, and an excited singlet-state mechanism has been suggested for furocoumarin-DNA mono-adduct formation [42,47–49]. When furocoumarins are intercalated into DNA base pairs, both the fluorescence yield and the triplet formation yield decrease remarkably [42,47–49]. The 8-MOP triplet state’s yield when bound to DNA was found to be similar, if not identical, to the one measured in the absence of DNA [47,49]. Crosslink formation in DNA by absorption of a second photon can occur via the excited singlet state of the 4 ,5 -mono-adduct, as suggested by the occurrence of a [2 + 2] photocycloaddition reaction between the 8-MOP-thymidine 4 ,5 -mono-adduct and the tetramethylethylene in solution [49,66]. 3.4. Sequence specificity

Fig. 10. Schematic representation for the 8-MOP-thymidine adducts of cis-syn configuration. (Reproduced, with permission, from the Annual Review of Biochemistry, Volume 54 [23] 1985 Annual Reviews www.annualreviews.org.).

The adenine base can quench the excited singlet state of the coumarins more efficiently than did the thymine base. However, furocoumarin photocycloadducts were formed predominantly with thymine, not with adenine. It was reported that the poly[dA–dT]·poly[dA–dT] sequence region was the most favorable site for the photocycloaddition reaction of furocoumarins.

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Fig. 12. Formation mechanism for mono- and di-adducts. (Reproduced with permission from [63] 1985 American Chemical Society.).

The results imply that adenine contributes to the singlet-state photocycloaddition reactions of furocoumarins with thymine [49]. Some photophysical properties have been investigated for bichromophoric psoralen derivatives that contain an adenine as an electron donor linked by various lengths of polymethylene chains. The role of adenine in the complexation process has also been clarified [67,68]. In order to understand the relationship between the photoadduct modes and the genetic changes induced, and to be able to interpret the mutational modes of psoralens, it is important to know the sequence specificity of psoralen DNA photobinding [24,69,70]. The sequence specificity in the photoreaction of various psoralens with DNA was investigated by use of DNA sequencing methodology. Psoralen photoaddition maps reveal evidence that thymine residues in a GC environment are not as favorable and that the adjacent thymines are better targets. 5 -TpA sites are more strongly preferred versus 5 -ApT, and the alternating (AT)n sequences are the most favorable for photoaddition [71–73]. Photoactive furocoumarins bind not only to DNA, but also to RNA. For the 8-MOP, photoreactivity with DNA is found to be 6–8 times higher than that with RNA [74]. The reactions of different psoralens with various RNAs have demonstrated that uridine is the preferred site for photoreaction. The most reactive positions occur in the locations that are relatively unstable and facilitate intercalation. Particularly susceptible sites occur near the ends of helices, adjacent to the GU pairs, or at the ends of uridine runs. Cross-links involving cytidine have also been found, but at low yields. Of course, there are also non-Watson–Crick pairing schemes that could also be cross-linked. Such structures may be inherently less reactive, because the melting of the tertiary structure in tRNA greatly enhances the psoralen reaction [75–77]. The mono-adducts and cross-links are chemically stable, allowing for analysis under various chemical conditions [23], and therefore, the positions of the covalent cross-links can be enzymatically mapped [23,78]. 3.5. Probes for nucleic acid structure The versatility of psoralen photochemistry allows for control of the reaction degree by light doses, and also control of the relative importance of mono-addition to cross-linkage by either selection of suitable wavelengths to induce the chemistry or by controlled timing of actinic light delivery. Furthermore, the mono-adducts and di-adducts (cross-links) formed between psoralen and the pyrimidine bases can be split into original

monomers under irradiation with short wavelength UV light. This property is used frequently to determine the nucleic acid secondary structure with the use of psoralens [23,63,79–81]. The selective reaction of psoralens with nucleic acids, which is most efficient in the helical regions, allows one to probe both static and dynamic nucleic acid structures under in vitro and in vivo conditions [23]. Psoralens are used as versatile molecular tools to elucidate the nucleic acid structure and function [23]. They are able to penetrate most biological structures and are not highly toxic to cells in the absence of ultraviolet light. They are ideal probes for the nucleic acid structure wherever the exciting light at long wavelength can be transmitted. The use of psoralens for the determination of the nucleic acid secondary structure has been reviewed in detail [23]. Cross-link formation requires the displacement of the psoralen toward the initially unmodified strand and is accompanied by a change in the hybridization of the thymines C5 and C6 and a change in the local helix twist [82]. 4. Photobiology When psoralens are in the excited state, they can react with various molecules. Among other things, the most important psoralen photochemical reactions are those with nucleic acids. Because of their photoreactivities, psoralens have been used as molecular probes and treatment drugs for skin diseases. Although psoralen photobiology and photochemotherapy have a 50-year-old history in the fields of science and modern medicine, many problems still remain unsolved. The biological impact of psoralen photoadducts in DNA was assumed to be manifested purely as a strict anti-proliferative effect. At present, it appears that these adducts may lead to more complicated effects that include apoptosis and antigenicity [59,83]. Elaborate work by Krueger et al. has shown that cytokinereleasing lymphocytes that reside in the epidermis of psoriasis patients are much more sensitive to the effects of PUVA therapy than keratinocytes [84–87]. The relative importance of PUVA therapy for psoriasis may be decreasing, because immunodepressant drugs have been found to provide better relief. Photobiological and photomedical investigations and the search for new compounds have continued to lead to a better understanding of the biological phenomena at the molecular level, as well as to a better understanding of complete remission. 4.1. Photochemotherapy Topical application or oral administration of a psoralen in a patient, followed by subsequent irradiation with UVA

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light (320–340 nm), can be used to carry out psoralen photochemotherapy [6,71]. This treatment is called PUVA therapy (psoralen + UVA) [6], and 8-methoxypsoralen (8-MOP), 5methoxypsoralen (5-MOP), and 4,5 ,8-trimethylpsoralen (TMP) are currently used in PUVA [24,88]. PUVA can treat a number of diseases, including psoriasis, mycosis fungoides, lichen planus, urticaria pigmentosa, polymorphous light eruption, alopecia areata, and vitiligo [50,71]. Several of these diseases, such as psoriasis, are characterized by hyperproliferative conditions; however, vitiligo manifests itself, because of the skin does not have the ability to produce pigment, which is due to the reduced proliferation of melanocytes [23,24,71,89,90]. In the hyperproliferative keratinocyte characteristic of psoriatic lesions, it was postulated that the formation of photoadducts between 8-MOP and DNA inhibits cell replication, therefore leading to an amelioration of the malady [59,60]. It appears that the genotoxic effects, as well as the therapeutically important antiproliferative effects, are due chiefly to their capacities to induce photoconjugation to DNA [34]. Such linkage of the strands in the DNA helix prevents the DNA from replicating [62]. With cross-link formation, the local helix twist is changed and the local DNA structure is distorted in both the mono-adduct and cross-link, returning to normal after three base pairs. There is no significant bend in the helix axis of either the mono-adduct or the crosslink. Nevertheless, there are significant changes in the local helix dynamics upon the cross-link formation, which cellular DNA repair enzyme systems may recognize [82]. 4.2. Photopheresis (extracorporeal photochemotherapy) Several authors have reviewed the details of photopheresis [71,91]. Cutaneous T-cell lymphoma (CTCL) and other infections connected with AIDS are treated with photopheresis [50,91–95]. Since the clinical aspects of photopheresis are beyond the scope of the present review, this section briefly summarizes CTCL treatment, which is a malignant clonal proliferation disease of helper T-cells. Extracorporeal photochemotherapy with 8-MOP is a harmless and effective therapeutic intervention for CTCL that involves the oral administration of 8-MOP. An adequate amount of blood is drawn from the patient and is separated by centrifugation into three components: erythrocytes, leukocytes, and plasma. The white cells and plasma are combined and then irradiated with high-intensity UVA sources. After irradiation, the combined components are retransfused into the patient [62,91]. Following photopheresis, the patient’s immune system mounts a specific suppressive response against the pathogenic T-cell clones. 4.3. Various psoralen derivatives for PUVA therapy Cross-links may be responsible for quite a few undesired side effects in photochemotherapy. It is therefore of interest to prepare and study new furocoumarin compounds that can behave purely as monofunctional agents in native DNA photobinding [96–98]. For this purpose, one approach is the use of angular psoralen (angelicins) [96,99]. 4,5 -Dimethylangelicin is an example of a monofunctional derivative that does not allow inter-

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Fig. 13. Molecular structure of psoralen analogs.

strand DNA cross-links for steric reasons. Another approach is to inhibit the photoreactive capacity of one of the two active sites of the psoralen molecule, the C3 C4 bond or the C4 C5 -bond, by introducing electron-accepting or electron-donating groups. For example, 3-carbethoxypsoralen (3-ethoxycarbonylpsoralen) photoreacts with DNA only with its 4 ,5 -double bond [74,100]. It exhibits lethal effects on yeast and a low mutagenicity, an absence of carcinogenicity, and therapeutic properties in psoriasis [101]. Pyridopsoralens that contain fused pyridine rings on the 3,4-positions have been found to be monofunctional [102]. A wide variety of compounds that retain the therapeutic benefits but lack the adverse effects have been synthesized and studied. Fig. 13 shows the structures of several psoralen derivatives that can be used in PUVA therapy. A number of substituted psoralens have larger extinction coefficients than that of unsubstituted psoralen. Similar therapeutic effects can be achieved by smaller doses of these drugs because of increased extinction coefficients, and they may exhibit less toxic effects when compared with simpler psoralens. The properties of pyrrolocoumarins, in particular, 4-methyl-N-ethylpyrrolo[3,2-g]coumarin, have been studied from photophysical, photochemical, and photobiological aspects [103]. Among the thieno-azacoumarins, 4,4 -dimethylthieno-8-azacoumarin has been found to be the most effective. It does not induce an erythematous reaction, one of the most commonly reported undesirable short-term side effects that follow phototherapeutic treatment with 8-MOP in PUVA therapy, even at a dose four times higher than that of 8-MOP. This drug displays an antiproliferative activity on human tumor cell lines [104]. Among other azapsoralens (furo[2,3-h]quinolin2(1H)-ones), 4,6,9-trimethylfuro[2,3-h]quinolin-2(1H)-one has

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also been found to be extremely effective [88]. Bisagni has reviewed the syntheses of psoralens and analogs [29]. 4.4. Alternative approach for reducing side effects One of alternative ways to reduce the side effects of PUVA involves combination of psoralens linked to triplex-forming oligonucleotides and laser-induced two-photon excitation [105]. Spatial localization of sequence-specific DNA damage has been achieved by two-photon excitation. It has been suggested that this type of approach for targeting photochemical DNA damage has a potential for photochemotherapy in skin and other optically accessible tissues. The triple helix-forming oligonucleotides bind specifically to defined DNA sequences with purine-rich strands through the Hoogsteen base pairing method. When these triplex-forming oligonucleotides are linked to photochemically active compounds such as psoralens, they can react with DNA in a wellcontrolled way, because chromosomal DNA damage can occur in cells at a certain time due to irradiation with UVA light. It is to be noted that triplex-forming oligonucleotides are sitespecifically mutagenic. Multiphoton excitation is exploited in order to activate photodynamic molecules. Simultaneous multiphoton absorption occurs when a molecule is excited by two or more photons whose energies are individually insufficient to cause an electronic transition. Their combined energies do correspond to the energy separation between two electronic states. The probability of two-photon absorption in molecules is very small in comparison to one-photon absorption cross-sections, even though they are quadratically proportional to the incident light intensity. With the use of pulsed and focused laser beams, it becomes possible to employ multiphoton absorption to excite chromophores in a spatially restricted manner. Two-photon excitation can create psoralen adducts with DNA in cells, and the psoralen-triplex-forming oligonucleotide adducts can be targeted to specific DNA sequences. The triplexforming oligonucleotides can provide sequence specificity when linked to photodynamically active compounds, whereas multiphoton excitation of these reagents can provide spatial specificity. In order to optimize a therapeutic effect and to minimize the toxicity at the same time, it is important to develop the ability to selectively damage cells and tissues in both gene-specific and spatially specific manners. 5. Miscellaneous aspects of psoralen photochemistry Psoralens have been used in diverse ways, including as drugs and molecular probes. They are also utilized as irreversible nucleic acid cross-linking reagents and as ligands that can bind stereospecifically to nucleic acids [23]. These properties make them useful as agents in inactivating viruses and other pathogens [23,106,107] and as model compounds for mutagenesis and repair studies [23,108–110]. Psoralens in excited states can react with DNA pyrimidine bases to form cyclobutane rings in a sequence specific manner.

Fig. 14. Brominated 8-MOP derivative.

5.1. Sterilization of blood products Brominated psoralens have been employed for viral inactivation [111]. Fig. 14 shows the typical structure of an 8methoxypsoralen derivative with a bromine substituent at the C5 position. Molecular solubility in water is increased due to the presence of positively charged side chain. This derivative has improved the level of viral inactivation. The blood products can be used for therapeutic applications. In order to reduce the transmission risks of diseases such as AIDS and hepatitis, it is necessary to remove or inactivate the viral agents that may be present in the blood. The brominated 8-methoxypsoralen derivative shown in Fig. 14 has been used as a sterilization agent. The sensitizer is added to the blood products, and they are then irradiated with UV light in a reactor system. Blood platelets, erythrocytes, and plasma protein do not contain genomic nucleic acid, and the presence of these agents makes it possible to target chemical sensitizers to viruses. Photosensitization may provide a useful method for sterilizing blood products and safeguarding the integrity of the blood supply. 5.2. Covalent binding of DNA with psoralen derivatives A new-type of DNA-polymer conjugate has been synthesized in order to evaluate its application to an affinity precipitation separation of the TATA-box binding protein [112]. This conjugate is composed of a thermosensitive-fraction and a ligandfraction. The psoralen-terminated poly(N-isopropylacrylamide) (PNIPAAm) was first synthesized, and the DNA, psoralenterminated PNIPAAm, and water were then mixed and irradiated with an Hg lamp to form a covalent bond between the psoralen and DNA. The electrophoretic migration indicates that PNIPAAm-grafted DNA was formed. The migration degree of the DNA was almost the same as that of the DNA mixture with the psoralen-terminated PNIPAAm. After forming the covalent band, the DNA did not migrate at all because of the increase in its molecular weight according to the cross-linking reaction with PNIPAAm. Since PNIPAAm is known as a thermosensitive vinyl polymer, this can be called the thermosensitive part. The ligand fraction is a native double-stranded DNA containing a specific sequence (5 -TATAAA-3 ) called a TATA box. Its function is to recognize the target DNA-binding protein. A procedure for the covalent binding of DNA to a functionalized mica substrate has been described, and the bound DNA molecules can be directly observed with atomic force microscopy (AFM) [113]. The procedure for immobilization is as follows: first, a tetrafluorophenyl ester of trimethyl psoralen

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Fig. 16. Ferrocenyl psoralen derivative.

derivative is covalently bound and gives a redox activity to a DNA double helix, it would be more applicable for use as a redox-labeling agent in electrochemical gene sensor applications. 5.3. Photochemical bond formation with biomaterials other than nucleic acids

Fig. 15. Scheme of covalent binding of DNA to a functionalized mica substrate.

is synthesized, and it is then immobilized onto a functionalized aminopropyl mica surface. Finally, DNA molecules are cross-linked to a tetrafluorophenyl ester of trimethyl psoralen moieties by complex UV irradiation. Fig. 15 illustrates the scheme. After cross-linking, the DNA molecules withstand a thorough rinsing with SDS. This immobilization approach can be modified in such a way that covalent bonds are formed only at specific sequences. The immobilization of the sample is a key step toward the successful imaging of biological molecules with AFM. In comparison to double-stranded DNA, the sequencespecific tertiary and secondary structures of RNA are typically single-stranded in nature. They are very labile and are critically dependent on environmental conditions. This immobilization procedure of RNA molecules at a limited number of sites should be possible in an analogous manner that is comparable to that proposed for DNA. This may help facilitate the imaging of RNA with AFM, particularly in solution conditions. The possibility of covalently immobilizing DNA molecules opens realistic prospects for a number of important structural studies. A ferrocenyl derivative of psoralen has been found to bind to DNA [114]. Fig. 16 illustrates the structure of this derivative. The binding of the derivative to DNA was formed by irradiation with an Hg lamp. The results of gel electrophoresis showed that this binding occurred selectively with double-stranded DNA. For the diagnosis of genetic or infectious diseases, which include singlebase mismatches, it is important to discriminate the doublehelical DNA from the single-strand form. Since this psoralen

Psoralens have been found to have some reactivity with proteins and lipid membranes [23,115–120]. A possible mechanism of PUVA therapy was proposed to be the photoinduced damage of proteins with psoralen derivatives [60]. Psoralens form covalent DNA-protein cross-links [88,90]. However, there has not been much proof of psoralen photobinding to proteins or amino acids [34,120]. On the other hand, the photoproducts of psoralens and unsaturated fatty acids were isolated and characterized [34,121–123]. When acidic hydrogen is present in the substituents of psoralens, binding to the phospholipid membrane is favored over binding to the nucleic acid. Hydrogen bonding of a sensitizer is important in the binding of lipid membranes [111]. Although these reactivities are minor when compared to those for the reactions with nucleic acids [23], it is necessary to investigate further details of the reactions with proteins and the lipid membrane. 6. Crystal and molecular structures of furocoumarin derivatives determined by X-ray crystallographic analysis Since the successful structural analysis of xanthotoxin by Stemple and Watson [28] in 1972, there has been a compilation of crystal analysis data for a variety of furocoumarins. Table 1 lists furocoumarin derivatives whose crystal and molecular structures have been clarified by X-ray crystallographic analysis [124–144]. The systematic and conventional numberings of skeletal atoms in psoralen and derivatives have been employed for the compounds listed in Table 1. Fig. 17 illustrates molecular structures of typical psoralen derivatives listed in Table 1. Many of the furocoumarins in Table 1 are of medicinal interest except for bichromophoric chain species containing psoralen and thymine moieties [129,131] or a psoralen derivative of a monosubstituted 18-crown-6 ether [133]. The tricyclic furocoumarin system is generally planar except for small differences in overall planarity. In many cases, crystal cohesion is maintained chiefly by weak

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Table 1 Crystal and molecular structures of furocoumarin derivatives determined by X-ray analysis Compound name (Synonym)

Reference

8-Methoxypsoralen (Xanthotoxin, 8-MOP) 5-Methoxy-8-((2,3-epoxy-3-methyl)butoxy)furo[3,2-g]coumarin ((±)-Byak-angelicol) 5,8-Dimethoxypsoralen (Isopimpinellin) Furo[3,2-g]coumarin (Psoralen) Furo[2,3-f]coumarin (Allopsoralen) 8-Methoxyfuro[3,2-g]coumarin (8-MOP) 9-(1-Thyminylbutoxy)psoralen Ethyl furo[3,2-g]coumarin-3-carboxylate 9-(5-Thyminylpentoxy)furo[3,2-g]coumarin 5-((2,3-Epoxy-3-methyl)butoxy)furo[3,2-g]coumarin Trimethylpsoralen containing 18-crown-6 4-Hydroxy-7H-furo[3,2-g]benzopyran-7-one (Bergaptol) 6-Methoxyangelicin 4-[(2,4,4,-Trimethyl-1-cyclohexen-1-yl)methoxy]-7H-furo-[3,2-g][1]benzopyran-7-one (Archangelin) 9-(1,1-Dimethyl-2-propenyl)-4-hydroxy-7H-furo[3,2-g]benzopyran-7-one 4-[(3,3-Dimethyloxiranyl)methoxy]-7H-furo[3,2-g][1]benzopyran-7-one 4-[[3-(4,5-Dihydro-5,5-dimethyl-4-oxo-2-furanyl)-butyl]oxy]-7H-furo-[3,2-g][1]benzopyran-7-one 4-(3-Methyl-2-butenyl)oxy-7H-furo[3,2-g]benzopyran-7-one (Isoimperatorin, 5-Isoamylenoxypsoralen) 2,5,9-Trimethyl-7H-furo[3,2-g][1]benzopyran-7-one (Trioxsalen) 9-(3-Methylbut-2-enyloxy)-7H-furo[3,2-g]chromen-7-one (Imperatorin, 8-Isoamylenoxypsoralen) 4-Methoxy-9-(3-methylbut-2-enyloxy)-7H-furo[3,2-g]chromen-7-one (5-methoxyimperatorin, Phellopterin) 5,8-Dimethoxypsoralen (Isopimpinellin) 9-(3-Methylbut-2-enyloxy)-7H-furo[3,2-g]chromen-7-one (Imperatorin)

[28] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [142] [143] [144]

intermolecular hydrogen bonds C H· · ·O [132]. There may be two kinds of furocoumarin crystals. The first case is classified as furocoumarin crystals in which intermolecular ␲–␲ interactions are clearly observed [134], and the second case with no definite stacking interactions [129]. 6.1. Average geometry of aromatic rings in furocoumarins The furano-condensation with coumarin may give rise to changes in molecular geometry, in particular, distortion of the aromatic rings in furocoumarins. The furano-condensation effect can be analyzed by comparing changes in bond angles and lengths on going from bicyclic coumarins to tricyclic furocoumarins. Fig. 18 shows that numerical (1–6) and alphabetical (a–f) symbols are assigned to the bond angles and aromatic carbon–carbon bonds, respectively. The same symbols are also applied to the benzene ring in bicyclic coumarins. The average

Fig. 17. Molecular structures of psoralen derivatives.

Fig. 18. Numbering of bond angles and alphabetical assignment of bond length in aromatic ring in psoralen.

N. Kitamura et al. / Journal of Photochemistry and Photobiology C: Photochemistry Reviews 6 (2005) 168–185 Table 2 Average geometry of aromatic rings in bicyclic coumarins (BC) and tricyclic furocoumarins (TF) 1

2

3

4

5

6

Bond angle/degree (BC) Average 117.7 S.D. 1.5

120.7 1.1

119.9 0.9

120.9 0.8

118.0 1.0

122.8 1.3

Bond angle/degree (TF) Average 118.8 S.D. 0.5

118.3 1.2

125.3 1.1

114.6 1.1

123.5 1.0

119.5 0.8

b

c

d

e

f

Bond length/pm (BC) Average 140.3 S.D. 1.2

137.1 1.1

139.7 1.0

138.6 1.3

138.2 0.9

139.1 0.9

Bond length/pm (TF) Average 140.5 S.D. 1.4

139.0 1.3

140.2 1.0

137.8 1.3

138.3 1.1

140.6 1.0

a

structure of aromatic ring in the furocoumarin moiety was evaluated on the basis of crystallographic data from references cited in Table 1. The calculated results (average values and standard deviations) are given in Table 2. Crystallographic data for 20 bicyclic coumarins (unsubstituted coumarin, 7-OH and 7-OR derivatives, and so forth [145–163]) were collected from the literature, and the average geometry was calculated in a similar manner. The results are also shown in Table 2. Because the quality of crystallographic data is not homogeneous, only considerable changes may be mentioned. Bond angles 3 and 5 are increased, while the angle of 4 is decreased on going from the bicyclic to the tricyclic coumarins. The aromatic bond length is less sensitive to the condensation with furan. 6.2. Structures of photoadducts In several cases, photoadducts formed between psoralens and nucleic acid bases or oligonucleotides have been determined by the X-ray crystallographic method. Land et al. [164] published a short communication describing the structure of a mono-adduct obtained by UV-irradiation of a mixture of 8-methoxypsoralen and thymine in a frozen icemethanol matrix in the presence of a triplet sensitizer, benzophenone. Although this adduct was formed under non-biological conditions, with no structural constraints of the double-helical DNA [165], the structure is the same as the photoadduct formed with DNA. The configuration of the photoproduct is cis-syn with respect to the cyclobutane ring and substituents in the alkoxypsoralen and thymine moieties (see Fig. 10). It is to be noted that the cyclobutane is formed between the C5 C6 bond of thymine and the C4 C5 -bond in furan ring (see the numbering system in Fig. 1). On the other hand, cis-anti configuration was observed for photocycloaddition of bichromophoric chain species containing thymine and furocoumarin moieties [166,167]. In this case, photocycloaddition takes place between the C5 C6 -bond of thymine and the C3 C4 -bond in the pyrone ring (see the numbering system in Fig. 1). In the solid state,

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8-[5-(1-thyminylpentoxy)]psoralen undergoes a specific photocyclization involving two C3 C4 -bonds in the pyrone moiety, which yields a furocoumarin dimer with a trans-head-to-tail configuration (see Fig. 6) [131]. By means of X-ray diffraction [168], two different types of Holliday junctions have been clarified in single crystals where two different DNA sequences with thymine bases are covalently cross-linked across the complementary strands by 4 hydroxymethyl-4,5 ,8-trimethylpsoralen (HMT). One decamer d(CCGCTAGCGG) forms a HMT-dependent Holliday junction, while the other decamer d(CCGGTACCGG) forms a sequencedependent junction. In both junctions, the DNA duplex is highly distorted at the thymine base linked to the pyrone ring of HMT. The psoralen cross-link defines the intramolecular interaction of HMT-induced junctions. In contrast, the sequence-dependent structure is nearly identical to the native Holliday junction of the second decamer d(CCGGTACCGG) observed in the absence of HMT [169]. The difference in HMT- and sequence-dependent interactions is responsible for the two types of Holliday junction structures, which may be important in elucidating a role for psoralen in the mechanism to initiate DNA repair.

7. Summary Coumarins and furocoumarins are heterocyclic aromatic compounds that are present in numerous plants throughout the world. Psoralens, typical furocoumarins, are photosensitizers of UVA in the 320–380 nm range, a range where cellular nucleic acids and proteins exhibit weak absorption bands. The intrinsic photochemical reactivity of furocoumarins is mainly determined by the nature of the lowest excited states (S1 and T1 ␲–␲* states). This photochemical property has been exploited by the ancient Egyptians in their popular medicine for the treatment of depigmented skin. Photobiological actions have been interpreted in terms of photochemical primary processes that occur in aqueous and non-aqueous media. Photochemical and photophysical properties have been elucidated over several decades in order to clarify the photobiology of furocoumarins at the molecular level. After irradiation with UVA, the furocoumarins bind to DNA by way of the C3 C4 and C4 C5 bonds of the pyrone and furan moieties. The DNA reacts with both sites, resulting in the formation of cross-links. The development of mono- and di-adduct depends on the structure of the furocoumarins, the light doses, the solvents, and several other factors. The poly[dA-dT]·poly[dA-dT] sequence in DNA is the most favorable site for photoaddition. It can be concluded that the interstrand cross-links are responsible for the undesirable side effects in the photobiological actions. Furocoumarin with added UVA photochemotherapy is called PUVA. Extracorporeal photochemotherapy (photopheresis) can be applied in the treatments of cutaneous T-cell lymphoma and certain AIDSconnected infections. Several brominated furocoumarins have been used for the sterilization of blood products. On the basis of results obtained in the fields of molecular photochemistry, photobiology, and X-ray crystallography, furocoumarins will be utilized over a wider range as drugs and molecular probes.

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