Reduced pyrimidines

There is an admirable summary of the stereochemistry of barbiturates and di- to hexahydropyrimidines Further information on reduced pyrimidines is collected <70HC 16-81)322) and some examples of the use of proton NMR spectra in elucidating the conformations of hydropyrimidines is given elsewhere (Section 2.13.1.3.1), based on the general principles of such work <65QR426). 

The renaissance of the Biginelli MCR can be attributed to the obtained pyrimidine derivatives, which show remarkable pharmacological activity. A broad range of effects, including antiviral, antitumor, antibacterial, anti-inflammatory as well as antihypertensive activities has been ascribed to these partly reduced pyrimidine derivatives [96], such as 9-117 and 9-118 (antihypertensive agents) [97] and 9-119 (ala-adrenoceptor-selective antagonist) [98] (Scheme 9.24). Recently, the scope of this pharmacophore has been further increased by the identification of the 4-(3-hydroxyphenyl)-pyrimidin-2-thione derivative 9-120 known as monastrol [98], a novel cell-permeable lead molecule for the development of new anticancer drugs. Monastrol appears specifically to affect cell division (mitosis) by a new mechanism,... 

Additional information relative to dihydrouracils with anti-inflammatory activity is found in the section on reduced pyrimidines (hydropyrimidines). 

Reduced pyrimidines by adduct formation with organometallics... 

Reduced pyrimidines by radical ring-closure reactions... 

Reduced pyrimidines are much less stable toward hydrolysis than the fully conjugated analogs, and this is often used synthetically to produce amino acids and diamines. The BH3 reduction of cyclic amidines (1,4,5,6-tetrahydropyr-imidines) to hexahydropyrimidines, and their subsequent hydrolysis was mentioned above <1999JFIC105>, but there are many more examples. For instance, m-cyclobutane /5-amino acids 544 can be prepared from the cyclobutane derivatives 542 formed by the [2-F2] photocycloaddition reaction between uracil and ethylene <2002TL6177, 2004TL7095, 2006SL1394>. 

Labeled compounds have also been produced by the hydrolysis of reduced pyrimidine derivatives, and thus the basic hydrolysis of 5,5,6,6-tetradeuterouracil 547 (R = D) gave 2,2,3,3-tetradeutero-/5-alanine 548 (R=D) in 50% yield <2001JLR7>. 5,6,6-Trideuterothymine 547 (R = Me) behaved similarly to give 2,3,3-trideutero-3-amino-2-methylpropanoic acid 548 (R = Me), also in 50% yield <2001JLR7>. Similar procedures have been performed with tritiated uracil derivatives <2002MI295>. 

There are a variety of natural antibiotics which contain a pyrimidine or reduced pyrimidine ring <2005CBI1>, and several of these are used therapeutically for a number of different applications. Blasticidin S and the polytoxins were mentioned in the section on antifungals, but other examples include amicetin, capreomycin, gougerotin, and viomycin, as well as the bleomycins and phleomycins. 

DNA, laced with an intercalator characterized by a high electron affinity, is y-ir-radiated and observed by EPR. The one-electron reduced intercalator presents an EPR spectrum that is readily distinguishable from that of the DNA-trapped radicals. A key example is mitoxantrone (MX), with an electron affinity of 6.25 eV and a radical anion spectrum that is a sharp singlet. Charges are injected into the DNA by y-irradiation at a preselected temperature (4 130 K). Holding the temperature constant, the EPR spectrum changes as a function of time (0.5-30 h). Thereby, a direct measure of the rate of electron transfer from one-electron reduced pyrimidines (Pryre) to the intercalator, e.g., MX, is measured. The turmeling rate is observed to depend on the electron affinity (EA) of the... 

From the yields of 5,6-dihydropyrimidine radicals, we predict reduction product yields of 0.04-0.06 pmol/J for 5,6-dihydrouracil and 0.03-0.05 pmol/J for 5,6-dihydro-thymine for B-form DNA hydrated to 9 waters per nucleotide. With respect to oxidation products, we predict strand-break yields —0.10 pmol/J. A very surprising prediction of this model is that the yield of damaged guanine is nil. Half the damage is oxidized sugar products and the other half is reduced pyrimidines. 

The method ZC3Z + C is used for the preparation of reduced pyrimidines, oxazines and thiazines as well as for dioxanes, dithianes and oxathianes as mentioned above (e.g. 258 — 257, 259 Z, Z = NH, O, S). The Prins reaction yields 1,3-dioxanes (77S661) it involves the acid-catalyzed condensation of alkenes with aldehydes with 1,3-diols as intermediates. 

Enzymes present in mammalian liver are capable of the catabolism of both uracil and thymine. The first reduces uracil and thymine to the corresponding 5,6-dihydro derivatives. This hepatic enzyme uses NADPH as the reductant, whereas a similar bacterial enzyme is specific for NADH. Similar enzymes are apparently present in yeast and plants. Hydropyrimidine hydrase then opens the reduced pyrimidine ring, and finally the carbamoyl group is hydrolyzed off from the product to yield /3-alanine or /3-aminoisobutyric acid, respectively, from uracil and thymine (see fig. 23.23). 

Naturally occurring pterin derivatives have existed in 3 oxidation states pterin (4 aromatic), dihydropterin (e.g., 5-8) and tetrahydropterin (9). In the present review, we do not refer to reduced pterin derivatives with reduced pyrimidine structures. The reduced pterin derivatives, dihydropterin and tetrahydropterin are readily oxidized to the corresponding aromatic form (4) under aerobic conditions. Based on the location to which hydrogen atoms are added, 4 kinds of dihydropterin have been defined 7,8-dihydropterin (5), quinonoid dihydropterin (6), 5,6-dihydropterin (7) and 5,8-dihydropterin (8). Of these, only 7,8-dihydropterin derivatives can be stored for long periods under non-aerobic conditions. Indeed, several 7,8-... 

The foregoing suggests that the structure of the reduction product is a dimer, as shown in Scheme 22, and supported by comparison with the dimer reduction product of pyrimidone-2 (Scheme 2), since the reduced pyrimidine rings in both dimers should be similar. The foregoing interpretation is confirmed by the results of earlier studies on 1 1 photoadducts of alcohols to purine 156157> the products were identified as substituted 1,6-dihydropurines, and the site of addition of the alcohols was readily established as C(6) on the basis of the 1H NMR spectra prior to, and following, selective deuteration at C(6) or C(8) 156,157). 

Whole-cell biocatalytic reactions are most often used when the biotransformation to be conducted requires the input of energy. In biological systems this usually takes the form of reduced pyrimidine nucleotides or ATP but can be many of a number of reduced cofactors or modified reaction components. Using the whole cell allows the technologist to take advantage of the intact, preformed cellular machinery to efficiently provide the required cofactors or components. In order to provide the energy to catalyze these reactions a source of reducing power is usually required. The cooxidation of an oxidizable substrate such as... 

At a pressure of two atmospheres uracil III is reduced nearly quantitatively in aqueous solution to hydrouracil IV by action of hydrogen gas in presence of colloidal platinum. For example, when six grams of this pyrimidine were agitated in the reductor at a temperature of 75-85° C. and at a pressure of two atmospheres the reduction was complete at the end of seven hours, and almost a theoretical amount of hydrogen had added to the pyrimidine. The reduced pyrimidine melted at 272° C. and corresponded in all its chemical and physical properties witli hydrouracil prepared by application of Hoffmann s reaction to sucdnimide.4 It did not respond to Wheeler and Johnson s test for uracil 5 We are now engaged in determining whether hydrouradl can be reduced still further by our catalytic method to the cyclic urea derivative of syn-trimethylenediamine V. 

Spectroscopic properties of reduced pyrimidines are discussed in Section 6.02.6.1.1. 

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