Epoxide and diol epoxide adducts of polycyclic aromatic hydrocarbons at the exocyclic amino group of deoxyguanosine

Zajc, Barbara; Lakshman, Mahesh K.; Sayer, Jane M.; Jerina, Donald M.

doi:10.1016/s0040-4039(00)92649-2

Cited by 49 publications

(43 citation statements)

References 10 publications

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“…O 6 -(2-Fluorobenzyl)-2′-deoxyguanosine. 3′,5′-O-Diacetyl-2′-deoxyguanosine (250 mg, 0.71 mmol) (24) was sonicated in 5 mL of dry dioxane for 30 min under nitrogen. Triphenylphosphine (465 mg, 1.78 mmol) and 2-fluorobenzyl alcohol (191 µL, 1.78 mmol) were added to the suspension, and the mixture was heated at 100 °C with stirring.…”

Section: Methodsmentioning

confidence: 99%

Substrate Specificity of Human O⁶-Methylguanine-DNA Methyltransferase for O⁶-Benzylguanine Derivatives in Oligodeoxynucleotides

Terashima

Kawate

Sakumi

et al. 1997

Chem. Res. Toxicol.

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To investigate the substrate specificity of human O6-methylguanine-DNA methyltransferase (MGMT) for O6-benzylguanine (6BG) derivatives incorporated in oligodeoxynucleotides, we prepared 25-mer lengths of sequences containing various 6BG derivatives and their related compounds and then measured the ability of these derivatives to inactivate MGMT in vitro. Oligodeoxynucleotides containing a 6BG, O6-(2-fluorobenzyl)guanine (2F-6BG), O6-(3-fluorobenzyl)guanine (3F-6BG), O6-(4-fluorobenzyl)guanine (4F-6BG), O6-benzylhypoxanthine (6BH), or O6-methylguanine (6MG) were all good substrates for MGMT, and no obvious differences were observed among them. Oligodeoxynucleotides containing N2-isobutyrylated 6BG and 6MG showed only a slightly reduced capacity for inactivating MGMT compared to N2-nonmodified forms of these derivatives. No obvious differences were observed in the corresponding double-stranded and single-stranded oligodeoxynucleotides. MGMT substrate specificity for the 6BG derivatives in the oligodeoxynucleotide was found to be quite different from that seen in our previous study [Mineura, K., et al. (1994) Int. J. Cancer 58, 706-712; (1995) Int. J. Cancer 63, 148-151. Kohda, K., et al. (1995) Biol. Pharm. Bull. 18, 424-430] and others [Moschel, R. C., et al. (1992) J. Med. Chem. 35, 4486-4491. Chae, M.Y., et al. (1994) J. Med. Chem. 37, 342-347] using the corresponding free bases. In brief, (i) 6BG, 3F-6BG, and 4F-6BG greatly inhibited human MGMT, whereas 2F-6BG, 6BH, and 6MG displayed much weaker activity; (ii) any modifications at the 2-amino group of the 6BG resulted in severe reductions in the ability to inactivate MGMT. These results obtained by the experiments using oligodeoxynucleotides and free bases suggest that human MGMT has low substrate specificity for 6BGs in oligodeoxynucleotides. Conformational changes in human MGMT which favor binding to oligodeoxynucleotides containing 6BG derivatives and the subsequent transfer of their benzyl groups may account for the difference in substrate specificity between the incorporated 6BG derivatives and their free base form.

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Section: Methodsmentioning

confidence: 99%

Substrate Specificity of Human O⁶-Methylguanine-DNA Methyltransferase for O⁶-Benzylguanine Derivatives in Oligodeoxynucleotides

Terashima

Kawate

Sakumi

et al. 1997

Chem. Res. Toxicol.

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“…However, only a few attempts have been made to prepare dGuo adducts of sterically crowded PAH such as B[a]P or B[c]Ph by total synthetic methods (32,33) because these methods have been plagued by low yields (32) on coupling of the hydrocarbon and nucleoside derivatives. Recently, our laboratory has developed a very convenient method for the synthesis of cis-and trans-opened N 2 -dGuo adducts of B[a]P DE in which the O 6 -position of the dGuo is blocked by the allyl protecting group (34).…”

Section: Introductionmentioning

confidence: 99%

O⁶-Allyl Protected Deoxyguanosine Adducts of Polycyclic Aromatic Hydrocarbons as Building Blocks for the Synthesis of Oligonucleotides

Kroth

Yagi

Sayer

et al. 2001

Chem. Res. Toxicol.

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We describe a synthetic strategy for the preparation of oligonucleotides using N(2)-alkylated and O(6)-allyl protected deoxyguanosine phosphoramidite building blocks derived from cis- and trans-opened (+/-)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene and from trans-opened (+/-)-3alpha,4beta-dihydroxy-1alpha,2alpha-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene. The appropriately blocked phosphoramidite building blocks were obtained as mixtures of the cis- and trans-opened diol epoxide adducts upon initial reaction of the diol epoxides with O(6)-allyl-3',5'-di-O-(tert-butyldimethylsilyl)-2'-deoxyguanosine. Key to the present approach is the removal of the O(6)-allyl protecting group utilizing a palladium catalyst prior to release of the constructed oligonucleotide with ammonia from the solid support. The methodology described enables a very convenient access to oligonucleotides containing cis- and trans-N(2)-deoxyguanosine adducts of polycyclic aromatic hydrocarbons in different sequence contexts.

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“…Pfleiderer and colleagues developed the Mitsunobu reaction as a method to introduce the base-labile p-nitrophenylethyl group (Himmelsbach et al, 1984). This method was then modified and applied to the synthesis of silyl-protected, reactive nucleoside derivatives such as 2-fluoro-2deoxyinosine (Zajc et al, 1992), 2-bromo-2 -deoxyinosine (Harwood et al, 1999), 2-bromoinosine (Qian and Glaser, 2005), and 8-bromo-2 -deoxyguanosine (Meier and Gräsl, 2002). The protocol described herein is a bridge between the actual isolation of the reactive nucleoside derivatives and in situ formation of a reactive species that undergoes further transformation.…”

Section: 2611mentioning

confidence: 99%

“…Pfleiderer and colleagues developed the Mitsunobu reaction as a method to introduce the base‐labile p ‐nitrophenylethyl group (Himmelsbach et al, ). This method was then modified and applied to the synthesis of silyl‐protected, reactive nucleoside derivatives such as 2‐fluoro‐2′‐deoxyinosine (Zajc et al, ), 2‐bromo‐2′‐deoxyinosine (Harwood et al, ), 2‐bromoinosine (Qian and Glaser, ), and 8‐bromo‐2′‐deoxyguanosine (Meier and Gräsl, ).…”

Section: Commentarymentioning

confidence: 99%

Two‐Step, One‐Pot Synthesis of Inosine, Guanosine, and 2′‐Deoxyguanosine O⁶‐Ethers via Intermediate O⁶‐(Benzotriazol‐1‐yl) Derivatives

Kokatla

Lakshman

2012

CP Nucleic Acid Chemistry

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A simple method for the etherification at the O6-position of silyl-protected inosine, guanosine, and 2′-deoxyguanosine is described. Typically, a THF solution of the silylated nucleoside is treated with 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and Cs2CO3, under a nitrogen atmosphere. Conversion to the O6-(benzotriazol-1-yl) ethers occurs within about 10 minutes for inosine, and within about 60 minutes for guanosine and 2′-deoxyguanosine. Then, for reaction with alcohols, the reaction mixture is evaporated and the O6-(benzotriazol-1-yl) ether is treated with Cs2CO3 and an appropriate alcohol, at room temperature. On the other hand, for reaction with phenols, Cs2CO3 and the appropriate phenol are added to the reaction mixture without evaporation, and the reaction is carried out at 70°C. Subsequently, workup, isolation, and purification lead to the requisite O6-alkyl or -aryl ethers in good to excellent yields.

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Epoxide and diol epoxide adducts of polycyclic aromatic hydrocarbons at the exocyclic amino group of deoxyguanosine

Cited by 49 publications

References 10 publications

Substrate Specificity of Human O⁶-Methylguanine-DNA Methyltransferase for O⁶-Benzylguanine Derivatives in Oligodeoxynucleotides

Substrate Specificity of Human O⁶-Methylguanine-DNA Methyltransferase for O⁶-Benzylguanine Derivatives in Oligodeoxynucleotides

O⁶-Allyl Protected Deoxyguanosine Adducts of Polycyclic Aromatic Hydrocarbons as Building Blocks for the Synthesis of Oligonucleotides

Two‐Step, One‐Pot Synthesis of Inosine, Guanosine, and 2′‐Deoxyguanosine O⁶‐Ethers via Intermediate O⁶‐(Benzotriazol‐1‐yl) Derivatives

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Epoxide and diol epoxide adducts of polycyclic aromatic hydrocarbons at the exocyclic amino group of deoxyguanosine

Cited by 49 publications

References 10 publications

Substrate Specificity of Human O6-Methylguanine-DNA Methyltransferase for O6-Benzylguanine Derivatives in Oligodeoxynucleotides

Substrate Specificity of Human O6-Methylguanine-DNA Methyltransferase for O6-Benzylguanine Derivatives in Oligodeoxynucleotides

O6-Allyl Protected Deoxyguanosine Adducts of Polycyclic Aromatic Hydrocarbons as Building Blocks for the Synthesis of Oligonucleotides

Two‐Step, One‐Pot Synthesis of Inosine, Guanosine, and 2′‐Deoxyguanosine O6‐Ethers via Intermediate O6‐(Benzotriazol‐1‐yl) Derivatives

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Substrate Specificity of Human O⁶-Methylguanine-DNA Methyltransferase for O⁶-Benzylguanine Derivatives in Oligodeoxynucleotides

Substrate Specificity of Human O⁶-Methylguanine-DNA Methyltransferase for O⁶-Benzylguanine Derivatives in Oligodeoxynucleotides

O⁶-Allyl Protected Deoxyguanosine Adducts of Polycyclic Aromatic Hydrocarbons as Building Blocks for the Synthesis of Oligonucleotides

Two‐Step, One‐Pot Synthesis of Inosine, Guanosine, and 2′‐Deoxyguanosine O⁶‐Ethers via Intermediate O⁶‐(Benzotriazol‐1‐yl) Derivatives