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Part IV: Basic Considerations of the Psoralens

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Part IV: Basic Considerations of the Psoralens CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector THE CHEMISTRY OF THE PSORALENS* W. L. FOWLKS, Ph.D. The psoralens belong to a group of compoundsfled since biological activity of the psoralens and which have been considered as derivatives ofangelicins has been demonstrated. They appear coumarin, the furocoumarins. There are twelveto have specific biochemical properties which different ways a furan ring can be condensed withmay contribute to the survival of certain plant the coumarin molecule and each of the resultingspecies. Specifically these compounds belong to compounds could be the parent for a family ofthat group of substances which can inhibit certain derivatives. Examples of most of these possibleplant growth without otherwise harming the furocoumarins have been synthesized; but natureplant (2, 3, 5). is more conservative so that all of the naturally It is interesting that it was this property which occurring furocoumarins so far described turnled to the isolation of the only new naturally out to be derivativesof psoralen I or angelicinoccuring furocoumarin discovered in the United II (1). States. Bennett and Bonner (2) isolated tharn- nosmin from leaves of the Desert Rue (Tham- n.osma montana) because a crude extract of this 0 0 plant was the best growth inhibitor found among /O\/8/O\/ the extracts of a number of desert plants sur- i' Ii veyed for this property, although all the extracts showed seedling growth inhibition. One could I II speculate as to the role such growth inhibition plays in the economy of those desert plants These natural derivatives of psoralen and angeli-when survival may depend upon a successful cm have one or more of the following substituentsfight for the little available water. The structure at the 5,8 or 5,6 positions respectively: hydroxy,of thamnosmin was determined by Crosby (4) methoxy, butanyloxy isoainyleneoxy, geranyloxyto be a derivative of angelicin namely 5- and substituted isoamyleneoxy derivatives such methoxy-6-(2 ,3-epoxyisopentanlyoxy-)angelicin. as epoxy, dihydroxy or esterified hydroxy. InRodighiero (5) has also shown that psoralen, addition derivatives of both psoralen and angeli-8-methoxypsoralen and angelicin inhibit seed cm are found with isopropyl or substituted iso- germination, root growth and seedling growth. propyl groups at the 5' position and some of Such findings suggest that further investiga- these derivatives have oxygen functions; keto,tion may reveal certain furocoumarins in the hydroxy or methoxy; at the 4' position. Alto-role of natural growth regulator of certain gether about two dozen furocoumarins have beenplants just like another coumarin derivative, isolated from natural sources. scopoletin, which Goodwin and others (6, 7) Although the first furocoumarin was isolatedhave shown regulates cell division in the root of over a hundred years ago, when in 1834 Kal-Avena sativa. This idea is strengthened if one brunner isolated bergapten (5-methoxypsoralen)recalls that the psoralens of Ammi majus, from bergamot oil, the biological importance of8-methoxypsoralen, 5-methoxypsoralen and 8- these compounds has not been known until veryisoamylenoxypsoralen (imperatorin) are found recent times. The fact that these compounds areconcentrated in the pericarp of the fruit (seed). found in various plant materials leads naturallyThe psoralen and angelicin of Psoralea corylifolia to teleological speculation as to what biologicalare also found in the pericarp of the fruit (28) function they fulfill. Such speculation was justi-and thus the germ of the seed is surrounded by *Fromthe Division of Dermatology, Uni-a tissue containing a germination inhibitor, versity of Oregon Medical School, Portland,which could regulate the time when sprouting Oregon. Presented at the Brook Lodge Invitationalwill occur by the rate at which it diffuses into Symposium on the Psoralens, sponsored by Thethe surrounding soil. Chakraborty, DasGupta, Upjohn Company, Kalamazoo, Michigan, March 27—28, 1958. and Bose (8) have very recently shown that out 249 250 THEJOURNAL OF INVESTIGATIVE DERMATOLOGY of seventeen natural eoumarin derivatives whichturned to paper chromatography as a means of they tested, the psoralens, including psoralenseparation and identification of furocoumarins. and imperatorin, were the most effective anti-The first effort along these lines was that of fungal agents tried. And thus the economy ofSvendsen (14) who reported the separation of nature would be beautifully demonstrated if thepimpinellin, isopimpinellin, bergapten, and iso- same compound acts as germination inhibitorbergapten from Pimpinella magna and P. saxi- and also decontaminates the soil by killing patho-fraga.Hechromatographed on paper the mic- genic fungi as it diffuses away. rosubhmates from the crude plant extracts Musajo (3) has mentioned some hitherto un- using petroleum ether (65—70° C.)—benzene—95 % reported results of Dolcher, Rodighiero andmethanol (5:4:2) to develop the ehromatograms. Caporale who described the mutagenic propertiesAt about the same time in 1952 Riedl and of five furocoumarins and found 5-methoxy-Neugcbauer (15) also published a chromato- psoralen and psoralen to be almost as effectivegraphic method for the isolation and identifica- as the most effective mutagcnic agent known,tion of coumarins from plant sources. They used trypafiavin, when tested on onion root tips.a paper that had been presprayed with glycol Psoralen at 5.6 x10M. and 5-mcthoxy-(ethylene or propylene) and was developed with psoralen at 5.0 x10M. induced 40% of mitosisbenzene at 10°C. for their separation. Swain (16) with chromosome mutations when incubatedstudied a number of solvent systems for the with the onion roots for 4 hours at 20°C. Atseparation of a wide variety of naturally occurring higher concentrations there was total inhibitioncoumarins including three furocoumarins. Rodig- of mitosis. Chromosome aberrations noted werehicro, Caporale and Ragazzi (17) reported the agglutinization of chromosomes and liquificationidentification of psoralen and bergapten from of the chromosome surface (stickiness effect). ItRuta graveolens using chromatographic separation is not reported if these experiments were per-on paper developed with methanol-pyridine- formed in the absence of light which could havewater (18:1 :1) solution. They determined the caused these effects due to photosensitization inRf. of a number of different furocoumarins in the the presence of the furocoumarins (29). Themcthanol-pyridine-water solvent and also in photoscnsitizing properties of several of themethanol-phenol-water (45:4:1). Chakraborty psoralens have been described elsewhere (3, 9). and Bose (18) have made the most extensive study of the paper chromatographic separation 5EPAEATION OF FUEOcOUMAEIN5 of natural coumarins. They studied the separa- With new discoveries of the biological ac-tion of 12 representative coumarin derivatives, tivities of the several furocoumarins which haveincluding furocoumarins, in 21 different solvent appeared in recent years there has also been asystems. Unlike other investigators they also renewed activity concerning the chemistry andattempted the separation of a mixture of their physical properties of these compounds. Incoumarin derivatives and discovered that most particular a number of investigators have soughtspots contained more than one compound and ways of isolating, identifying and quantitativelywhen a single compound was separated from the determining the furocoumarins in general andmixture its Rf. was usually altered sufficiently so certain of them in particular. that positive identification was rarely possible. There is no simple quantitative method for theThe author has confirmed these observations of isolation of the furocoumarins of plant origin.difficulties with the chromatographic separation The usual methods which have been employedof mixtures and also that the best separations on for the isolation of numerous natural productspaper arc obtained with solvent mixtures con- have been used for the furocoumarins namely:taining 85% or more water. It is our observation extraction with lipid solvents or alcohol followedthat the addition of up to 15% of solvents such by partition between immiscible solvents withas acetic acid or methylethyilcetone to the water or without the use of acids or alkalies, thenincreased the capacity of the system and usually further purification by repeated recrystalliza-sharpens the separation somewhat. Paper chro- lions or combinations of sublimation and re-matography alone can not be relied upon for the crystallization. Such methods are not suitablyseparation and identification of furocoumarins quantitative, nor are they technically satisfac-unless a preliminary purification has first been tory. carried out. A number of investigators have therefore The separation of a number of furocoumarins CHEMISTRY OF THE PSORALENS 251 using paper eleetrophoresis (19) on a circular disk apparatus has also been reported. Difficulties are encountered with this method in mixtures. — Psornien Preliminary separations of eoumarins from 5 —Methnsy Psnrnlen 8—Methney Pso,alen natural sources using aluminum oxide column 5,8—Diniethnsy Psornien chromatography has been reported (20—22) but in general pure compounds have not been ob- tained. ANALYTICAL EEACTION5 The analytical determination of the furoeou- marins remains a problem. One might expect from general considerations that furoeoumarins & would be quite reactive or at least undergo reactions
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