6- Substituted-2-aminopurines

One important study on the regio- and stereoselectivity of the Pd(0)-catalyzed allylations of adenine 238 and the related 6-substituted 2-aminopurine derivatives 241 and 242 (Scheme 49) is that of Benneche and Undheim (92ACS761, 92TL1085). This group reported that adenine 238 is regioselectively allylated at N-9 both by allyl acetate and by rac-160 to afford 239 and rac-240 as the only isolated reaction products. However, when treated with allyl acetate, 241 and 242 afforded mixtures of N-allylation products at N-9 (243 and 244) and at N-7 (245 and 246). The ratios 243/245 and 244/246 indicate that the difference in reactivity between both positions is low. When both 241 and 242 were allylated with the more sterically demanding acetate rac-160, the ratio of N-9/N-7 allylation... 

The 2 -deoxy-0 -(pentafluorophenyl)guanosine 11 can be used as a synthon for the preparation of 6-substituted 2-aminopurine nucleosides, e.g. 12. ... 

Nucleophilic substitutions Aminopurines react with dilute nitrous acid to yield the corresponding hydroxy compounds. 

Methylsulfanyl)purines are good starting materials for the preparation of aminopurines. This method can be successfully employed in the synthesis of 6-substituted aminopurines, e.g. 1, and 2, from 6-(methylsulfanyl)purine and 8-(alkylamino)-2-hydroxypurines from 2-hy-droxy-8-(methylsulfanyl)purine, but presents some difficulties when the methylsulfanyl group is in the 2-position. 

The good activity of the kinetin-containing polymers is not imexpected since kinetin itself is a substituted aminopurine. Further, kinetin is known to directly interact with at least plant nucleic acids. 

Zeatm [6-(4-hydroxy-3-methyl-2-hu-tenyl) aminopurine] which occurs also as zeatin nucleoside and zeatin nucleotide also other 6-substituted aminopurines and related compounds yet to be identified. The synthetic substance, kinetin, is 6-furfurylaminopurine. 

Herschlag s group continued its study of structure-function relationships in the hammerhead ribozyme using a base-rescue biochemical method. This method substitutes other atoms or molecules for bases at critical catalytic or structural positions and tests whether catalytic activity is lost. If so, the RNA bases (U, A, G, C) or a modified base (for instance, deazaguanine or 2-aminopurine substituted for guanine) is added to the solution to ascertain... 

The result is surprising, as with the structurally quite similar adenine (6-aminopurine), N-substitution occurs only at the amino group 46) ... 

There are many examples of each of these possibilities (see figure 8.8). In the case of the 2 sugar position, most of the 2 -substititutions have been achieved with 2 -0-alkyl, 2 -amino, and 2 -fluoro replacements. Purine base substitutions have been performed with 2-aminopurine, xanthosine, and isoguanosine. Phosphodiester replacements have been effected using phosphorothioate substitutions. As for the non-nucleotide linkers, propanediol linkers have been employed. Using these various bioisosteric substitutions,... 

One way in which chemical compounds can induce base substitution mutation is through their incorporation into the structure of DNA itself. Thus, 5-bromodeoxyuridine (or bromouracil) can replace thymidine in DNA, where it serves as an efficient mutagenic agent.767 2-Aminopurine, an analog of adenine, pairs with thymine, just as does adenine when incorporated into DNA. 

Some heteroarylamines have been prepared by aromatic nucleophilic substitution of suitable support-bound arylating agents with amines (Table 3.27). This technique has been successfully employed in the synthesis of 2-(alkylamino)pyrimidines [507,508], 2-(arylamino)pyrimidines [509], aminopurines [510-512], and 1,3,5-triazines [513]. When the heteroarene is bound to the support as a thioether, nucleophilic clea-... 

Detailed work has been devoted to the elucidation of factors governing N-oxygenation of amino azaheterocycles. To this end, a series of substituted 2,4-diaminopyrimidines and 6-aminopurines was subjected to metabolic analysis8,16,64,65,147,148 Generapy5 P-450... 

Studies of tautomerism, in which the spectra of aminopurines and their substituted-amino analogs were compared, show clearly that the amino and not the imino form predominates.8 Confirmation has been supplied by infrared13 and by nuclear magnetic resonance studies on adenosine and guanosine.14,15 Alkylation of the pyrimidine ring nitro-... 

Fig. 15.1. The four bases found in the nucleic acids. Uracil occurs in RNA and is substituted by the analogous thymine (5-methyluracil) in DNA. Uracil is the keto tautomer of 2,4-dihydroxy pyrimidine with two donors N(1)H, N(3)H and two acceptors 0(2), 0(4). Cytosine is the keto tautomer of 4-amino, 2-hydroxy pyrimidine with three donors N(4)H2, N(1)H and two acceptors 0(2), N(3). Adenine is 6-aminopurine with three donors N(6)H2, N(9)H and three acceptors N(l), N(3), N(7). Guanine is the keto tautomer of 2-amino, 6-hydroxy purine with three donors N(2)H2, N(9)H and three acceptors, N(3), N(7), 0(6). In the nucleosides, pyrimidine N(l) and purine N(9) are substituted by ribose or deoxyribose (see Fig. 17.1)...

Alkylation of aminopurines normally leads almost exclusively to ring-substituted products (see Section 4.09.5.2.2(iii)). However, alkylation of adenine with formaldehyde probably produces the i -hydroxymethyl derivative (183) (64JCS792>, and the crystalline diadeninyl derivative (184) is also obtained from a mixture of equimolar amounts of adenine and formaldehyde in water, especially in acid solution (62MI40902). 

Cyclization of thioureidoimidazoles in the presence of sulfur-extracting agents such as mercury salts may favour 2-aminopurine formation. Thus 5-aminoimidazole-4-(iV-methyl)carboxamide (354) and some 2-substituted derivatives with phenyl isothiocyanate afforded the phenylthioureidoimidazole which when heated with mercury(II) salts produced 1,N-dimethylisoguanine and 8-substituted derivatives (355), respectively (Scheme 146) (50JCS1888). 

Substituted 3-aminopurines have also been best prepared by Traube syntheses from 3-(substituted amino)-4,5-diaminopyrimidines and triethyl orthoformate (63JOC1162). 

DNA polymerase incorporation of the mutagenic 2-hydroxy-dA has been examined and found to lead to GC- AT transition mutations." The synthesis, incorporation and repair of etheno-dA adducts have been reported." The use of a C2-alkaryl modified adenosine gave rise to enhanced stability towards a mutant UlA protein in which a conserved phenylalanine was substituted for alanine. ° 2-Aminopurine (2-AP) has been widely used because of its fluorescent properties. However, 2-AP dinucleotide also exhibits a distinct positive CD band at 326 nm, and this property has been used to probe changes in local conformation of ODNs containing (2-AP)2 by CD measurements." ... 

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