Purines alkylation

SCHEME 7.3 Examples potential bioreductive alkylating purines reported by Skibo... 

The Suzuld-Miyaura cross-coupling reaction of 9-benzyl-6-chloropurine with boronic acids gives 6-alkylated purines in moderate to excellent yields. The reaction has been successfully... 

Mechanism of alkylation of DNA guanine. A bis(chloroethyl)amine forms an ethyleneimonium ion that reacts with a base such as N7 of guanine in DNA, producing an alkylated purine. Alkylation of a second guanine residue, through the illustrated mechanism, results in cross-linking of DNA strands. 

BID, Alkylated purines, Chinese hamster lung V79 cells in vitro... 

Likhachev, A. J., Margison, CP. Montesano, R. (1977) Alkylated purines in the DNA of various rat tissues after administration of 1,2-dimethylhydrazine. Chem.-biol. Interact, 18, 235-240... 

Such a catabolic reaction is indeed excluded in 6 alkyl purine derivatives. The parent compound of this group, 6-methylpurine, is known for its cytotoxicity its libera tion from the 2 -deoxyribonucleoside by purine nucleo side phosphorylases is used for detection of mycoplasma in cell cultures.19 It is highly potent and toxic to nonproliferating and proliferating tumor cells. Recently, the use of cytotoxic bases liberated by purine nucleoside phosphorylases such as 6-methylpurine was proposed as a novel principle in the gene therapy of cancer.20... 

Hirota, K. Kitade, Y. Kanbe, Y. Maki, Y. Convenient Method for the Synthesis of C-Alkylated Purine Nucleosides Palladium-Catalyzed Cross-Coupling Reaction of Halopurine Nucleosides with Trialkylaluminums. J. Org. Chem. 1992, 57, 5268-5270. 

Reagents A Convenient Route to sec- and tert- 6-Alkylpurines. Tetrahedron Lett. 1996, 37, 1285-1288. (c) Dvorakova, H. Dvorak, D. Holy, A. Synthesis of Acyclic Nucleotide Analogues Derived from 6-(sec- or tert-Alkyl) purines via Coupling of 6-Chloropurine Derivatives with Organocuprates. Collect. Czech. Chem. Commun. 1998, 63, 2065-2074. (d) Hocek, M. Holy, A. Perfluoroalkylation of 6-Iodopurines by Trimethyl(perfluoro-alkyl)silanes. Synthesis of 6-(Perfluoroalkyl)purine Bases, Nucleosides and Acyclic Nucleotide Analogues. Collect. Czech. Chem. Commun. 1999, 64, 229-241. 

The anticodon can be found in the middle of the unpaired anticodon loop (7 nucleotides) of tRNA ( 76 nucleotides) between positions 30 and 40 (at around position 35). The anitcodon is bordered by an unpaired pyrimidine, U, on the 5 side and often an unpaired alkylated purine on the 3 side. 

A more pronounced effect on the 77-electron structure is produced by N-alkylation than by C-substitution, replacing the ring nitrogen proton by alkyl groups restricts the number of anionic forms and of tautomeric structures. The alkylated purines can be stabilized toward base attack by anion formation, but if no proton is available then fission of one of the rings is likely. 

An anomalous result arose from the alkylation of purine-6-thione with 2-bromoethylamine. The product was not the S-alkylated purine (80) but the adenine derivative (79) which, on acid treatment, reverted... 

The S l reaction has been used in the synthesis of purine derivatives674,675. 6-Iodo-9-eth-ylpurine reacts with a variety of enolate anions in liquid ammonia to give C-6-alkylated purines, which may be converted to other functionalized purine systems. 

Traceless solid-phase synthesis of 2,6,9-trisubstituted purines from resin-bound 6-thiopurines <02T7911>, and microwave assisted solid-phase synthesis of 2,6,9-trisubstituted purines <02TL6169> have been described. A resin-capture and release strategy toward combinatorial libraries of 2,6,9-trisubstituted purines has been reported <02JCO183>. Alkylated purines chlorinated at the 6,8- or 2,6,8-positions can be captured onto a solid support and further elaborated by aromatic substitution or via palladium catalyzed crosscoupling reactions <02JA1594>. 

Unfortunately, the results of the mathematical treatment normally only reflect ground-state values of the molecules (75UC668) since it is difficult to find formulae which include all the various intrinsic environmental and extraneous factors such as solvent effects. Thus in the case of purine, CNDO calculations suggest that the IH tautomer should have a slightly lower energy value than the 9H form. In the solid state this appears to be the case (65AX573> but in solution there is ample chemical evidence of the equivalence of the IH and 9H forms. Thus alkylation of purine with vinyl acetate leads to equal amounts of the 7- and 9-vinylpurines (27) and (28), respectively, but with other purines the reaction is kinetically rather than thermodynamically controlled and normally only one alkylated purine is produced (75JOC3296) (see also Section 4.09.5.2.2). 

N-Alkylated purines, especially compounds such as quaternized caffeine with a positive charge in the imidazole ring, are readily reduced by sodium borohydride to produce dihydro derivatives, reduction occurring in the charged imidazole ring (76TL1199, 76joc2303). 

Further reactions leading to C-alkylated purines are given in Table 24. 

Careful kinetic studies of H or -> H exchange reactions on various substituted purines demonstrates that any factor that intensifies the positive charge on N7 facilitates proton abstraction at C8. Only a number of 3-alkylated purines exhibit anomalous behavior in that the proton removed first is that from C2 rather than C8. 

A few effective methods have been reported for the direct formation of 8-alkyl- or 8-(hydroxy-alkyl)purines from the parent purine. These reactions are mainly photoreactions of purines with alcohols, ethers, amines, and amino acids. For a review see ref 45. 

In particular, the process has been employed in the construction of benzo[c]phenanthridines and benzo[c]phenanthridones,of 3-benzazepines and 3-benzoxep-ines, and of functionalized 6-alkylated purines. ... 

Stumpf R, Margison GP, Montesano R, Pegg AE. 1979. Formation and loss of alkylated purines from DNA of hamster liver after administration of dimethylnitrosamine. Cancer Res 39 50-54. 

Where an imidazole nitrogen is substituted, as in 7- or 9-alkyl purines, the exchange rates for low and intermediate pH values are similar to those for purine. As pH increases, however, the rate of hydrogen abstraction does not decline, but accelerates dramatically (Fig. 2). Possible factors for this anomalous behavior are discussed in Section III,A,3. 

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