Psoralen reactions

Modified oligonucleotides can be used to cross-link DNA sequences via a reactive group tethered to an oligonucleotide. When irradiated with uv light, psoralens (31) reacts with thymine bases, and the reaction yields a cross-link if the thymine residues are adjacent to each other on opposite strands. Psoralen linked to oligonucleotides have been shown to induce site-specific cross-links in vitro (51). 

JOC6503>, and new pyridazino-psoralens 15 were prepared via a furan ring expansion reaction <05T4805>. The reaction of 3-acetylcoumarins with alloxan followed by NH2NH2 easily produced 3-(2-oxo-2//-chromen-3-yl)-6//,8//-pyrimido[4,5-c]pyridazine-5,7-diones <05JHC1223>. Furano- and pyrano[2,3-c]pyridazines 17 and 18a,b as well as substituted quinolines were conveniently prepared from pyridazinone 16 and vinyl- and allyltriphenyl-phosphonium salts <05HAC56>. 

Psoralens can react by two different routes upon photoactivation (Parsons, 1980 Pathak, 1984). The first route is through the well-known photoreaction mechanism that principally involves intercalation within double-stranded DNA or RNA with the formation of adducts with adjacent thymine bases. The furan-side and pyrone-side rings in psoralen both can form cycloaddition products with the 5,6-double bond of thymine to create a crosslink between two DNA strands (Reaction 57) or to a lesser extent, within double-strand regions of RNA. 

Pathak, M.A. (1984) Mechanisms of psoralen photosensitization reactions./. Natl. Cancer Inst. Monogr. 66, 41-46. 

In the oxygen-independent Type III reactions the excited/sensi-tized psoralen donates its excitation energy directly to, or reacts with, the target compound. This occurs if the substrate and the target compound (e.g., DNA) are already in close proximity or intercalated. The reactions will proceed very rapidly via the excited singlet state, and are, typically, cyclization reactions or electron-transfer between the sensitizer and the target. In addition, the psoralen can be ionized, either directly or via the excited state, and react with the target compound in the form of a radical cation. Furocoumarins are also employed in treatment of cutaneous T-cell lymphoma and some infections connected with AIDS, by so-called photopheresis processes [71, 74-76]. In this case, peripheral blood is exposed to, e.g., photoactivated (sensitized) 8-methoxypsoralen (8-MOP) in an extracorporeal flow system. This... 

Oxygen-free reactions of psoralens, when in close proximity to the target, proceed via the first excited states in which the 3,4-and the 4, 5 7r-bonds of the pyrone and furan moieties, respectively, can undergo C4-cyclization reactions with, e.g., unsaturated bonds of lipids, or the C5=C6 double bonds of thymine in DNA. In reactions with DNA the psoralen is believed to intercalate with DNA in the dark. Subsequent irradiation at 400 nm usually leads to furan-side 4, 5 -monoadduct formation, whereas irradiation at 350 nm increases the formation of crosslinks in which the furan and pyrone rings form C4 cycloadducts to thymines on opposite strands [95], Subsequent irradiation of the 4, 5 -monoadducts at 350 nm leads to formation of crosslinks and conversion into pyrone-side 3,4-monoadducts. Shorter wave-... 

Pseudowollastonite, 19 12 PSI F-ionones, 24 562-563 PSII complex, 13 288—292 plastoquinones in, 13 293 PSII reaction center, 13 292—293 PSI transport processes, 13 288 PSMAA ionomers, 14 465 PSMALi ionomer, 14 477 PSMANa ionomers, 14 466, 468, 470-473 diethylbenzene in, 14 479 Psoralens, 17 636, 637 Psoriasis... 

Analysis of excreta samples indicated that both psoralen and Isopsoralen are metabolized extensively by polyxenes caterpillars, primarily by the same furan ring cleavage reactions observed in our earlier studies with xanthotoxin (Figure 3). 

Diels-Alder reactions of benzo[fc]furan-43-diones and benzo[b]furan-4,7-diones have been reported <99H(50)1137>. The activation of a C-0 bond in a Mn(C0>3 complexed benzo[i>]furan was examined <99AG2343>. The enzyme-catalyzed dealkylation of (+)-marmesin to the phototoxic psoralene (and acetone) has been investigated <99AG413>. A hi yielding synthesis of bidentate bisoxazoline DBFOX/Ph [(R,R)-4,6-dibenzofutandiyl-2 2 -bis(4-phenyloxazoline)] was developed. DBFOX/Ph was subsequently tested in enantio-selective conjugate radical additions onto 3-(3-phenyl-2-propenoyl)-2-oxazolidinone <99TA2417>. 

With the acetonyl ether of 7-hydroxycoumarin (73), the reaction gives 3-methylpsoralene cyperaquinone (63) is synthesized by the same method.211 Polysubstituted psoralenes have also been obtained from polyalkylated acetonyloxycoumarins, for instance, 6-ethy 1-3,5,9-tri-methylpsoralene from 7-acetonyloxy-4,8-dimethyl-3-ethylcoumarin.76... 

Chemically modified DNAs can also be used as hybridization probes, provided that the modification does not interfere with the formation of hybrid DNA molecules. A psoralen biotin label has also been developed. Psoralen is a photoactivable agent that can intercalates into single- or double-stranded nucleic acids. On irradiation at 365 nm, it will covalently bind to the probes. This labeling reaction is simple and straightforward. However, the reagents for labeling and detection are only available in a kit format. 

The facility of these reactions was attributed to the favorable geometry of the allenyl ether for intramolecular Diels-Alder reactions, compared with that of the propargyl ether. These methodologies were used in a new synthesis of a naturally occurring furocoumarin, psoralen 308, which is of interest because of its unique photoreactions with DNA and its utility as a phototherapeutic agent. 

The last major group of reagents are the psoralens which have earlier been exploited to form crosslinks in double-stranded DNA and RNA (Song and Tapley, 1979 Parsons, 1980 Hearst, 1981). Reaction occurs primarily by 2 + 2 addition to pyrimidines but also with purines (Fig. 2.9). 

Berdahl, D.R. and Wasserman, H.H. (1983) The reaction of psoralens and related benzofurans with singlet oxygen. An account of current research. Israel Journal of Chemistry, 23 (4), 409—414. 

An improved procedure to synthesize the scaffold of psoralen was developed by addition of an aldehyde to a NaOH solution at reflux. A mechanistic interpretation was provided, though the exact mechanism of the reaction is still not clear and no intermediate was isolated... 

The use of fused heterocyclic enaminones in the reaction with dichloroketene leads to unstable furobenzopyranones which are dehydrochlorinated and aromatized to give 4-amino-3-chloroangelicinic acid and its 7-thioisoster in high yield277,278 (equation 203). The products exhibit interesting photobiological activity, similar to that of psoralenes. 

The reaction of benzodifuran 113 with 3,6-dimethoxycarbonyl-l,2,4,5-tetrazine 114 proved to be an efficient way to make pyridazino-psoralen-based aromatic polycycles such as 115 through a reaction sequence illustrated in Scheme 57 <2005T4805>. 

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