A-thiouracil

Whittaker, J. R. Biosynthesis of a thiouracil pheomelanin in embryonic pigment cells exposed to thiouracil. J. Biol. Chem. 1971, 246, 6217-6226. 

Table 8 collects the information on the interaction features of the Watson-Crick A-U and A-thiouracils base pairs. As follows from its last column, the total energies of the A-U and A-2TU base pairs after ZPVE correction are nearly identical and differ from each other by 0.4 kcal/mol. In this Table we separate the deformation energies of adenine and uracil or thiouracil under the corresponding base pairing. We find then that both uracil and thioracils experience more substantial deformations compared to adenine. These deformations are also indicated in Figures 6 and 7. 

Table 8. Interaction of the Watson-Crick A U and A-thiouracils base pairs.

A-Thiouracil 5-(M ethoxycarbonylmethyl)- 5-(Methoxycarbonyl-uracil methyl)-2-thiouraci I... 

Induction of atherosclerosis in dogs by a thiouracil free semi-synthetic diet, containing cholesterol and hydrogenated coconut oil. In Progress in Biochemical Pharmacology, vol. 4, p. 482. 

The best direct synthetic route to uracil is probably the classical procedure from malic acid and urea in concentrated sulfuric acid (26JA2379), despite efforts to use maleic acid, urea and polyphosphoric acid (71S154) or propiolic acid, urea and a little concentrated sulfuric acid (77JOC2185) to achieve the same result. However, the most convenient source (apart from purchase) is to convert 2-thiouracil (937 X = S) into uracil by boiling with aqueous chloroacetic acid (52MI21300) or perhaps by oxidation with DMSO in strong sulfuric acid (74S491). 

Hyperthyroidism may be treated in several ways. One of these is interference with the synthesis of the thyroid hormones, possibly by removal of iodine. Thiourea and cyclic thioureas have this effect and of such cyclic compounds, thiouracil (1030 R = H), its 6-alkyl derivatives (1030 R = Me or Pr) and thiobarbital (1031) are effective thyroid drugs. Today only propylthiouracil (1030 R = Pr) is widely used, probably because it has fewer side effects than the others (71MI21302). The thiouracils are made by the Principal Synthesis from a /3-oxo ester (1032 R = H, Me, Pr, etc.) and thiourea (45JA2197) their fine structures are experimentally based (64AF1004). 

The reaction involves an electrophilic attack into the 5-position of the pyrimidine ring and thus only those pyrimidines that are activated toward electrophilic substitution by the presence of electron-donating substituents at the 2- and 4-positions undergo cyclization. 2,4,6-Triaminopyrimidine, 6-aminouracil, 6-amino-2-thiouracil, 4-amino-2,4 dimercaptopyrimidine, 2,4-diaminopyrimidin-6(l/I)-one, and various 4-amino-vV-alkyl and aryl pyriinidones have all been converted into pyrido[2,3-[Pg.160]

Alkylthio, arylthio, and thioxo. The thioxo group in pyrimidine-2,4-dithione can be displaced by amines, ammonia, and amine acetates, and this amination is specific for the 4-position in pyrimidines and quinazolines. 2-Substitution fails even when a 5-substituent (cf. 134) sterically prevents reaction of a secondary amine at the 4-position. Acid hydrolysis of pyrimidine-2,4-dithione is selective at the 4-position. 2-Amination of 2-thiobarbituric acid and its /S-methyl derivative has been reported. Under more basic conditions, anionization of thioxo compounds decreases the reactivity 2-thiouracil is less reactive toward hot alkali than is the iS-methyl analog. Hydrazine has been reported to replace (95°, 6 hr, 65% 3deld) the 2-thioxo group in 5-hexyl-6-methyl-2-thiouracil. Ortho and para mercapto- or thio- azines are actually in the thione form. ... 

The deprotonation of 132 is favored at Ni and the coordination of 135 occurs preferentially at 82- A second entity of 135 coordinates at N3. A computational study of thiouracil derivatives of the tungsten(O) hexacarbonyl shows that the sulfur-bound thiouracil is serving as a ir-donor during the CO dissociation (Scheme 91) [99IC4715]. DFT calculations show that 137 is significantly stabilized with respect to the alternative reaction product 138. 

A) Preparation of 1-(2,3,5-Tri-0-Acetyl- -D-Arat>inofuranosy/)-4-Thiouracil A mixture of 1.85 g (5.0 mmol) of 1-(2,3,5-tri-0-acetyl-(3-arabinofuranosyl)uracil, 1.23 g (5.55 mmol) of phosphorus pentasulfide, and 30 ml of pyridine was heated under gentle reflux for 2.5 hours with exclusion of moisture. The reaction mixture was cooled, and the supernatant solution was transferred by means of a pipette into a mixture of crushed ice and water. 

A small amount of undissolved material collected on the filter and it was washed with chloroform. The chloroform solution (filtrate plus washings) was washed three times with ice-water, twice with ice-cold 3N sulfuric acid, twice with ice-cold saturated aqueous sodium bicarbonate solution, twice with ice-water, and then dried over anhydrous sodium sulfate. The chloroform was removed under reduced pressure at a bath temperature of about 40°C, leaving a yellow, somewhat gummy residue. This yellow residue was dissolved in absolute methanol which was then evaporated at reduced pressure at about 40°C, and the residue was then held for 2 hours at 0.5 to 2.0 mm pressure and a bath temperature of about 50°C. There was thus obtained 1.69 g of T(2,3,5-tri-0-acetyl-(3-D-arabinofuranosyl)-4-thiouracil. 

B) Preparation of 1-0-D-Arabinofuranosylcytosine In a glass liner, a mixture of 1.16 g (3.0 mmol) of 1-(2,3,5-tri-0-acetyl-(3-D-arabinofuranosyl)-4-thiouracil prepared in (A) and about 60 ml of absolute methanol which had been saturated with anhydrous ammonia at 0°C was heated in a steel bomb at 98° to 105°C for 35 hours. After cooling to about 25°C and venting the bomb, the dark solution was filtered into a round-bottom flask. The methanol and excess ammonia were then removed under reduced pressure at about 25°C. The residual syrup was dissolved in absolute methanol, and the methanol was removed under reduced pressure at a bath temperature of about 40°C. This procedure of dissolving in absolute methanol and removing the solvent was repeated, and the residue was held under reduced pressure at a bath temperature of 45°C for 12 hours. 

As pointed out previously, the 6-iodo-2-thiouracil is carefully dried, preferably in a vacuum over PjOs. 

PNA targeting of duplex DNA is not limited to homopurine sequences. Under special circumstances (high negative superhelical stress) mixed purine-pyrimidine PNA-peptide conjugates can bind by duplex invasion (Fig. 4.7) [31], but such complexes are of limited stability. However, using a set of pseudo-complementary PNAs containing diaminopurine-thiouracil substitutions, very stable double duplex invasion complexes can be formed (Fig. 4.4) and the only sequence requirement is about 50% AT content. Very recently, it was also demonstrated that reasonably stable helix invasion complexes can be obtained with tail-clamp PNA comprising a short (>six bases) homopyrimidine bis-PNA clamp and a mixed sequence tail extension [32] (Fig. 4.7). 

Selective N-alkylation of 6-amino-2-thiouracil with different halides has been performed efficiently by use of MW-assisted methods in the presence of small amounts of DMF to improve energy transfer (Eq. 34 and Tab. 5.12). No reaction was observed under the same conditions in a thermoregulated oil bath. 

Solid-phase synthesis of dihydropteridinones has been achieved from 4,6-dichloro-5-nitropyrimidine <00TL8177>. A series of ethyl 7-aminopteridine-6-carboxylate derivatives has been prepared in one step from the reaction of vicinal diamines as 13-dialky 1-5,6-diamino-2-thiouracils with diethyl ( )-2,3-dicyanobutenedioate <99JHC1317>. The relative binding affinities to human dihydrofolate reductase of new 2,4-diaminopteridine derivatives... 

Finally, the most complex synthetic reaction clearly catalysed by RNA molecules generated by in vitro selection is the formation of the C-N bond of a nucleoside (Scheme 7), from 4-thiouracil and most of the natural substrate for the natural (uracil phos-phoribotransferase) reaction.1461. (Thiouracil was used because it is easily tagged by alkylation on sulfur.) The catalytic RNAs produced by 11 rounds of selection required Mg++ cations and had kcat as high as 0.13 min-1,with kcaJKM at least 107 times greater than the (undetectable) uncatalyzed reaction. Once again these systems are convincing, rather efficient enzyme mimics. 

Abstract This presentation is a brief review on the resnlts of our work on iodine interaction with thioamides, selenoamides and amides. The thioamides, benzothia-zole-2-thione (BZT) (1), 6-n-propyl-2-thiouracil (PTU) (2), 5-chloro-2-mercap-tobenzothiazole (CMBZT) (3), N-methyl-benzothiazole-2-thione (NMBZT) (4), benzimidazole-2-thione (BZIM) (5), thiazolidine-2-thione (TZD) (6), 2-mercapto-pyridine (PYSH) (7), 2-mercapto-nicotinic acid (MNA) (8), 2-mercapto-benzoic acid (MBA) (9) and 2-mercapto-pyrimidine (PMT) (10) react with producing three type of complexes of formulae [(HL)IJ(l2) (HL= thioamide and n= 0, 1), [(HL) [I3 ] and [(HL-L)]+[l3 ]. The interaction of seleno-amides, derived from, 6-n-propyl-2-thiouracil (RSelJ) (R= Me- (11), Et- (12), n-Pr- (13) and i-Pr- (14)) with I, have also been studied and produced the complexes [(RSeU)IJ of spoke structure. These complexes are stable in non-polar solvents, but they decompose in polar solvents, producing dimeric diselenide compounds or undertake deselenation. 

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