Thymine preparation

DNA hydrolysis and TBDMS derivatization Salt-free DNA and internal standards ( N4-5-(P-H3]methyl)-cytosine and [m f/iyl- H3]thymine prepared as described in reference 355 and references therein) are transferred to 5 cm X 3 mm o.d. cleaned and silanized Pyrex tubes flamed-sealed at one end, and dried in vacuo. To each tube is then added 10 /il of 98% formic acid, and the tube is flame-sealed, then spun briefly at 12000 rpm to disperse any trapped air and heated at 180 °C for Ih. After hydrolysis, the formic acid is removed in vacuo. 

Thymine [65-71-4] M 126.1, m 326", pK 9.82. Crystd from ethyl acetate or water. Purified by preparative (2mm thick) TLC plates of silica gel, eluting with ethyl acetate/isopropanol/water (75 16 9, v/v Rp 0.75). Spot localised by uv lamp, cut from plate, placed in MeOH, shaken and filtered through a millipore filter, then rotary evapd. [Infante et al. J Chem Soc, Faraday Trans 1 68 1586 1973.]... 

A 12), 0-(thymin-l-yl)ethyldodecyldimethylamrnonium chloride), 25 (T12), j3-(theophyllin-7-yl)ethyldodecylammonium chloride, 26 (TH12), j3-(adenin-9-yl)-ethyloctadecyldimethylammonium chloride (A 18), and /3-(thymin-l-yl)ethylocta-decyldimethylammonium chloride (T18)47. These model compounds were prepared by the Menschutkin reaction of dodecyldimethyl amine or octadecyldimethylamine with chloroethylated bases. 

N -Fmoc serine benzyl ester 2, which could be prepared as shown or purchased commercially, was smoothly converted to the crystalHne O-methylthiomethyl (MTM) ether 3 in high yield via a Pummerer-Hke reaction using benzoyl peroxide and dimethyl sulfide in acetonitrile [39]. This common intermediate was used to synthesize both 5 and 8 [40]. Both Ogilvie [41] and Tsantrizos [42] had reported that I2 was an effective activator with similar MTM ether substrates. The H promoted nucleosidation reaction between O-MTM ether 3 and bis-silylated thymine 4 produced the nucleoamino acid 5 in 60% isolated yield (100% based on recovered 3). Hydrogenolytic deprotection of the benzyl ester with H2, Pd/C in MeOH gave the thymine-containing nucleoamino acid 6 in quantitative yield. 

Among the simplest compounds of this series are l-(2-deoxy-2-fluoro- -D-arabinofuranosyl)thymine (758, FMAU) and 1-(2-deoxy-2-fluoro-)S-D-arabinofuranosyl)-5-methylcytosine (749, FMAC). Later FIAU (757) and FMAU (758) were prepared in high yields (>95% the ratio of Plot an-omers being 7/1 and 4/1, respectively) by condensation using 743 and 2,4-bis(0-trimethylsilyl)-5-iodouracil (769), and 743 and 2,4-bis(0-trimethylsi-lyl)thymine (770), respectively. Likewise, 753, 757, 758, and 765 (this was described later) were prepared in high yields using pyrimidine derivatives... 

Deoxy-3 -fluorothymidine (813), a selective inhibitor of DNA synthesis, was prepared " in moderate yields from 3 -0-mesyl- or 3, 5 -di-O-mesyl-thymidine, through 2,3 -anhydro-1 -(2-deoxy- -D-t/2reopentofur-anosyl)thymine (808), by treatment with hydrogen fluoride (0.1% HF in l,4-dioxane-AlF3, 3.764 hf in DMF-AlFj, or 10% HF in DMF ),... 

Nucleosides containing deoxyfluoroglycopyranosyl residues were also prepared. 1-(6-Deoxy-6-fluoro-/ -D-gluco- and -galacto-pyranosyl)thymine (858 and 860) were obtained from l-/ -D-gluco- and -galacto-pyranosyl-thymine by the usual displacement reaction, or by the condensation method. 

Removal of the 2 -sulfonyloxy group of 859 in a basic medium, followed by reaction with metal halides (LiBr and Nal) or hydrogen halides (HCl-1,4-dioxane, HBr-acetone, or0.1% HFin l,4-dioxane-AlF3)gave, byway of the 2,2 -anhydro intermediate 861, the 2 -halo derivatives 862-865. The 2 -deoxy analog 866 and l-(6-deoxy-6-fluoro- ff-D-mannopyranosyl)thy-mine were also prepared from 864 (R = H) and 861 (R = H), respectively. l-(4-Deoxy-4-fluoro-y -D-glucopyranosyl)thymine was obtained by the condensation method. A different kind of nucleoside, 5-(5-deoxy-5-fluoro-2,3-0-isopropylidene-a-D-ribofuranosyl)-l,3-dimethyluracil has also been prepared. ... 

A series of ferrocenylmethyl nucleobases has been synthesized and the interactions with DNA in aqueous solution have been studied by electrochemistry (109,110). The neutral (rf— C5H5)Fe(r/5 — CgH4CH2-) derivatives were prepared by alkylation of the corresponding base with (rf — Cr>H5)Fe(rf— C5H4CH2N(CH3)J (110). For thymine and cyto-... 

In order to investigate the single electron donation process from a reduced flavin to a pyrimidine dimer or oxetane lesion, the photolyase model compounds 1-4 depicted in Scheme 4 were prepared [41, 42]. The first model compounds 1 and 2 contain a cyclobutane uracil (1) or thymine (2) dimer covalently connected to a flavin, which is the active electron donating subunit in photolyases. These model systems were dissolved in various solvents... 

Incorporation of a flavin electron donor and a thymine dimer acceptor into DNA double strands was achieved as depicted in Scheme 5 using a complex phosphoramidite/H-phosphonate/phosphoramidite DNA synthesis protocol. For the preparation of a flavin-base, which fits well into a DNA double strand structure, riboflavin was reacted with benzaldehyde-dimethylacetale to rigidify the ribityl-chain as a part of a 1,3-dioxane substructure [49]. The benzacetal-protected flavin was finally converted into the 5 -dimethoxytri-tyl-protected-3 -H-phosphonate ready for the incorporation into DNA using machine assisted DNA synthesis (Scheme 5a). For the cyclobutane pyrimidine dimer acceptor, a formacetal-linked thymine dimer phosphoramidite was prepared, which was found to be accessible in large quantities [50]. Both the flavin base and the formacetal-linked thymidine dimer, were finally incorporated into DNA strands like 7-12 (Scheme 5c). As depicted in... 

Polyamides containing thymine photodimer units in the main chain (17a,b) were prepared by polycondensation of thymine photodimer derivatives (15a,b), which were obtained by the photochemical reaction of the monomeric compound, and various diamines by the activated ester method (Figures 4 and 5) (17, 19). 

Photodissociation of the polyamides (Figures 4 and 5) was carried out in the solid films. Polymer films (1-2 U m) were cast onto quartz substrates and were exposed to monochromatic 250 nm light from a spectroirradiator. The dissociation of the thymine photodimers was followed by monitoring the absorbance at 270 nm. The results obtained for the polyamide prepared from the reaction of propane diamine and the isomers of the thymine photodimer (cis-syn(17a), cis-anti(17b), and... 

The derivatives of poly-L-lysine having pendant nucleic acid bases, that is, adenine, thymine and uracil were prepared as shown in the following scheme ... 

Various intermediates (uracil, thymine, pyrazoline, /S-carboline, and dihydroquinoline derivatives) have been prepared in this way [142-147]. 

Uracil and thymine are both reported to have electroshock anticonvulsant activity [371]. A series of 5- and 6-alkyl derivatives was prepared [373] and tested for electroshock as well as for metrazole protection [374]. It was found that most compounds of this type were active in the electroshock test. There is a trend toward increased activity with increased size of the alkyl groups, and introduction of 1,3-dimethyl substituents is also of benefit. Against metrazole-induced shock, however, there are no obvious structure-activity relationships. 

The complex [Ru(tpy)Cl3] binds to DNA, and is active as a cytostatic in L1210 leukemia cells. Its activity lies between those of cisplatin and carboplatin. Model complexes [Ru(tpy)L(H20)] + in which L = 9-ethylguanine or 9-methylhypoxanthine, have been prepared and characterized using NMR spectroscopy. " Proton NMR spectroscopy has been applied to a study of hydrogen bonding between 2, 3 -isopropylidine adenosine and [Ru(tpy)2] derivatives bearing a thymine group. 

Acyclonucleosides having a phenyl substituent on the C-T position as in 883 was prepared by condensation of the dioxolane 882 with bis(tri-methylsilyl)thymine in presence of SnCU (90GEP3906357). 

Dichlorobenzimidazole nucleosides of type 1.2 were prepared (94MI4). The thymine analog, upon selective protection, oxidation, and... 

The deoxy analogs of 2.1 were prepared by coupling l-benzyloxy-2-chloromethoxypropane with silylated thymine, 6-azathymine, uracil, and 6-azauracil to give the anticipated nucleosides 1194 in addition to minor quantities of benzyloxymethylated produce 1195 of type 5.1 (94MI15). None of the deprotected nucleosides exhibited significant activity against HIV. 

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