Alkylated guanosines

The two O -alkylated guanosine derivatives (117) shown in Figure 28, do not demonstrate a perpendicularity of hydrocarbon and base, presumably because the hydrocarbon is much smaller. However, again the nucleoside has the syn-conformation. This perpendicularity, however, is found for the acetylamino fluorine derivative. 

Alkylation reactions are not only of use in structural studies but also provide the basis for the action of a large class of mutagenic compounds.528 Treatment of a nucleoside, nucleotide, or nucleic acid with an alkyl iodide or a dialkylsulfate converts residues of guanosine to an N7-alkyl-guanosine (Eq. 5-18). 

Post-synthesis modification may be used to introduce a number of O - alkylated guanosine derivatives into oligonucleotides. Using a 0 -methoxycar-bonylmethyl-dG phosphoramidite and different oligonucleotide deprotection conditions leads to a number of different alkylated guanosine derivatives. 

Guanine, 9-/3-D-ribofuranosyl-, 5, 536 Guanine, 6-thio-tautomerism, 5, 509 toxicity, 1, 141 Guanine, 8-trifluoromethyl-synthesis, 5, 574 Guanines, thio-synthesis, 5, 572 Guanosine arylation, 5, 538 dipole moment, 5, 522 free radical alkylation, 5, 543 hydrobromide... 

SCHEME 7.6 Catalytic reductive alkylation of guanosine with 13C at the C-10 position of WV-15. The inset shows generation of the iminium methide upon reduction. 

The primary binding site of adenine is N(9) but when this is blocked as in adenosine it becomes N(l). This makes the binding of metals to adenosine weaker than the binding to N(7) of guanosine. The N(7) of guanosine is a known major site of alkylation too. 

Very interesting information relevant to the stereochemical results of alkylation of DNA comes from studies of nucleosides alkylated by activated PAHs. Eight such structures have been reported (115-118). Three are products of the interaction of chloromethyl PAHs with N6 of adenosine XXX-XXXII, two with deoxyadenosine (XXXIII, XXXIV), two are para-substituted benzyl derivatives of guanosine, alkylated at 0-6 (XXXV, XXXVI) (117) and one is an acetyl aminofluorene derivative of guanosine, alkylated at C8 (XXXVII) (118). 

A more complex structure is that of leinamycin 45 (Scheme 15), a material with potent cytotoxic and antitumor properties, isolated from a Streptomyces sp. A 1,2 dithiolane-3-one ring is spiro fused to a complex macrolactam96 (and references therein). Leinamycin has the remarkable ability to cleave DNA. In brief, leinamycin reacts with a thiol and, after a profound rearrangement, forms an episulfonium ion. This ion alkylates the N7 position of guanosine residues in double stranded DNA an unstable adduct is depurinated by hydrolysis of the glycosidic bond between the alkylated base and a deoxyribose residue. Some structurally less complex l,2-dithiolane-3-one 1-oxides have a similar DNA cleaving ability.97... 

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-... 

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