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Photoreactivity of Coumaryl Compounds Toward Dna

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Photoreactivity of Coumaryl Compounds Toward Dna PHOTOREACTIVITY OF COUMARYL COMPOUNDS TOWARD DNA PYRIMIDINE BASES by DYNA KERNS McINTURFF, B.S. A THESIS IN CHEMISTRY Submitted to the Graduate Faculty of Texas Tech University in Partial Fulfillment of the Requirements for the Degree of MASTER OF SCIENCE Approved Accepted December, 1975 Hf<D I : u: It ACKNOWLEDGMENTS I am indebted to Professor Pill-Soon Song for his direction of this thesis and to the other members of my committee. Professors John A. Anderson and Ira C. Felkner, for their helpful criticism. I am also appreciative of early encouragement by Dr. W. J. Kerns and technical assistance by Dr. W. W. Mantulin. ii CONTENTS ACKNOWLEDGMENTS ii LIST OF TABLES iv LIST OF ILLUSTRATIONS v I. INTRODUCTION 1 Purpose and Scope of the Thesis 1 Review of the Literature 2 II. MATERIALS AND METHODS 15 Materials 15 Methods 16 III. RESULTS AND DISCUSSION 18 Results 18 Discussion 24 IV. CONCLUSIONS 30 REFERENCES 31 APPENDIX 34 11 LIST OF TABLES Table Page 1. Relative rates of the photoreaction between photosensitizers and 2 to 4 x 10~^M pyrimidine bases 20 2. Relative rates of the photoreaction between photosensitizers and 2 to 4 x 10 M pyrimidine bases 21 3. Effect of oxygen quenching on the photoreactions between photosensitizers and 2 to 4 x 10~^M pyrimidine bases 22 4. Relative rates of the photoreactions of the 5-methoxypsoralen, 5-hydroxypsoralen and 8-hydroxypsoralen systems studied. All pyrimidine bases are 2 to 4 x 10" M 23 IV LIST OF ILLUSTRATIONS 1. Structural formulas of coumarin, 8-methoxypsoralen, and benzodipyrones 8 2. Structural formulas of 5-methoxypsoralen, 5-hydroxypsoralen, and 8-hydroxypsoralen 10 3. Structural formulas of DNA pyrimidine bases and 5-fluorouracil 12 4. Suggested cross-linking of DNA strands through photocycloaddition to thymine bases 14 CHAPTER I INTRODUCTION Purpose and Scope of the Thesis Skin erythema and skin cancer are particularly common in the Southwest United States, which is characterized by abundant sun­ light containing near ultraviolet light and an arid environment with coumarin- and psoralen-producing plants such as Psoralea and Leguminosase species. Naturally-occurring coumarins are erythe- mogenic and carcinogenic in the presence of light. Thus such environmental conditions may stimulate skin cancer in animals (1,2), The purpose of this project is to study and compare the relative rates of the photoreaction between photosensitizing coumarins including psoralens and DNA pyrimidine bases including a fluoro-derivative. To characterize the skin-erythemogenic com­ pounds, their photoreactions with the pyrimidine bases have been followed spectroscopically. The present research project is aimed only at elucidating the relative photoreactivity of coumarins versus psoralens, but its implications may lead to other needed investigations such as correlation between photosensitizing potency and electronic prop­ erties of the excited-state carcinogens as well as the photoproduct study. Review of the Literature Psoralens exert various biological activities (3,4) which have long been well known. Furocoumarin 8-methoxypsoralen is known es­ pecially for its oxygen-independent photodynamic effect when irradiated with near ultraviolet light and is thus of special interest (5). The leaves and fruits of plants containing psoralens have been used in Egypt for centuries in the treatment of skin depigmentation (6). In addition, in 1955, both Musajo (7) and Fitzpatrick (8) reported increased skin pigmentation in individuals exposed to sunlight in the presence of psoralens. The best known and studied photosensitizing effect is erythema of human and guinea pig skin which appears after topical skin application of psoralens and exposure to near ultraviolet light or sunlight (4,9). Erythema, sometimes including edema and vesicles, appears after a latent period of several hours and lasts several days. It is succeeded also by dark pigmentation (10-14). Furthermore, 8-methoxypsoralen has been used for the treatment of the characteristic white spots of vitiligo. The compound may be applied to the epicutanea or given orally and following exposure to near ultraviolet light, a repigmentation of spots is found in many cases (15). Other photobiological effects of psoralens include killing of bacteria, mutant formation, and inactivation of tumor cells and some DNA viruses (4). Coumarin is generally considered in the literature as a com­ pletely ineffective photosensitizer. It has been studied in vivo and, in bacteria, is ineffective as either a photosensitizer or photomutagenic agent (16). Benzodipyrone has recently been studied and has, conversely, been shown to be active as a photo­ sensitizer. Both cis-benzodipyrone and trans-benzodipyrone have shown photomutagenic activity in bacteria upon near ultraviolet irradiation (17). Both hydroxypsoralens, 5-hydroxypsoralen and 8-hydroxypsoralen, are known to be inactive as skin sensitizers and 5-methoxypsoralen, although not inactive, is thought to have less skin photosensitizing activity than 8-methoxypsoralen (4). The electronic properties of coumarin, methoxypsoralens, hydroxypsoralens and benzodipyrones show the following differences and similarities. Coumarin absorbs in the near ultraviolet at approximately 313 nm and fluoresces at approximately 380 nm (18), 8-methoxypsoralen absorbs around 345 nm and fluoresces at 440 nm (18), cis-benzodipyrone absorbs at 354 nm and fluoresces at 371 nm (19) and trans-benzodipyrone absorbs at 383 nm and fluoresces at 413 nm (17). Also, 5-methoxypsoralen absorbs at 335 nm and fluoresces at 425 nm, 5-hydroxypsoralen absorbs at approximately 345 nm and fluoresces at 442 nm (19) and 8-hydroxypsoralen absorbs at 310 nm and fluoresces at about 450 nm (25). It should be noted, however, that the 0-0 phosphorescence energy has been found to be essentially invariant in all these compounds (19,25). It is known that pyrimidine bases always react at the 5,6 double bond. Psoralens, however, may have two reactive sites. Luminescence spectroscopy has indicated that the lowest triplet excitation (Tr,iT*) is highly localized in the pyrone 3,4 double bond and that this is the potential reaction site. This is further substantiated by the isolation of photoadducts (20). The second possible reaction site is the 4',5' double bond in the furan moiety. In other studies, it has been proposed as the photore- active site (21). In coumarin, the lowest triplet excitation state has also been shown to localize in the pyrone 3,4 double bond (22). The excita­ tion decreases the electron density at the 3 position, giving it a relatively positive charge and increases the electron density at the 4 position, giving it a relatively negative charge (23). This may explain the orientation specificity of some coumarin photo- addition reactions. The benzodipyrones are interesting because they possess, in their molecular structures, two reactive pyrone 3,4 double bonds. The luminescence characteristics of the benzodipyrones are similar to 8-methoxypsoralen. In the hydroxypsoralens, on the other hand, the reactive state is suggested to be a triplet (IT,IT ), but it is less populated than in its 8-methoxypsoralen analogue because of inefficient singlet-to-triplet intersystem crossing. The apparent base-assisted hydroxyl proton dissociation in the excited singlet state competes with the intersystem crossing to the triplet state, making the anion less photoreactive than the unionized hydroxy- psoralen (25) . Previous work and calculations have shown that the lowest excited singlet and triplet states of psoralen are of the (•ir,TT ) type and on the basis of molecular orbital calculations, the triplet state can be predicted to be more reactive than the singlet state (22). Bevilacqua and Bordin showed that the presence of oxygen in the irradiated solution of psoralen and thymine has a quenching effect on the rate of the photoreaction between psoralen and thymine (24). Furthermore, the oxygen quenching effect can be explained in terms of triplet energy transfer to oxygen, generating singlet oxygen, thus quenching the excited photoreactive triplet state of psoralen. The photocycloaddition of psoralens to DNA pyrimidine bases has been studied with intact nucleic acids. Musajo et al. deter­ mined the reactive sites in DNA to be pyrimidine derivatives giving a cyclobutane ring (1,26). It has also been shown that native DNA may react with both the 3,4 and 4',5' double bonds giving photo­ adducts of one molecule of psoralen and two molecules of pyrimidine base (27). A study using poly d(A-T) and poly d(A-T) as substrates has shown that the former is not favorable to the photoreaction whereas the latter is highly favorable (28). Several researchers have suggested that the psoralens are intercalated between two adjacent base pairs of the DNA double helix to form interstrand cross-linkages (28-32). The biological activity of psoralens and their photoreactivity with DNA pyrimidine bases have been corre­ lated. Furthermore, from photoproduct studies, it has been suggested that, although there may be products other than cross­ links, they are the only biologically important ones (34). Recent studies iji vivo on mouse epidermis after application of 8-methoxypsoralen indicate that photoaddition of psoralen occurs to the pyrimidine bases of DNA and to a much lesser extent, to RNA (35). Investigation is also under way concerning the possibility of a singlet state reaction of the resulting adduct after the first addition of pyrimidine base to the psoralen furan moiety (36). 8 COUMARIN 0. 2 /O 8-METHOXyPSORALEN o\^° cis-BENZODIPYRONE 0^-^ trans-BENZODIPYRONE o^^^o 10 ^^'^ 5-METHOXYP SORALEN 5-HYDROXYPSORiVLEN 8-HYDROXYP SORALEN 11 12 3 CH HN 5 THYMINE 6 i N H H HN URACIL H HN 5-FLUOROURACIL H 13 14 XZ TiX CHAPTER II MATERIALS AND METHODS Materials Crystalline puriss grade coumarin (1,2-benzopyrone) was ob­ tained from Matheson Coleman and Bell. It was previously found to be free of impurities to a desired sensitivity (19) and was used as received. Xanthotoxin (8-methoxypsoralen), pfs grade, Sigma Chemical Co., was used as received. Cis-benzodipyrone (benzoIl,2-b:4,5-b']dipyran-2,8-dione) was previously synthesized by improvements in the reported synthetic sequence (17).
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