Synthesis and biological activity of a new class of cytotoxic agents: N-(3-oxoprop-1-enyl)-substituted pyrimidines and purines

Johnson, Francis; Pillai, K. M. R.; Grollman, Arthur P.; Tseng, Linda; Takeshita, Masaru

doi:10.1021/jm00374a004

Cited by 49 publications

(22 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The 1 H NMR chemical shifts for the purine protons of both the N9-Bn and N3-Bn varied significantly in the three different solvents. The 1 H NMR shifts for N3-Bn in CDCl 3 were very similar to those for N9-Bn in DMSO-d 6 ; whereas the N3-Bn shifts in DMSO-d 6 were very similar to those of N9-Bn in CDCl 3 , having the C2-H and C8-H shifts reversed in both cases. The relative position of the C8 signal in the 13 C NMR spectra for N3-Bn in different solvents varied considerably showing a chemical shift range of 7.8 ppm.…”

Section: Resultsmentioning

confidence: 56%

“…N9‐alkyladenine derivatives, specifically N9‐benzyladenine derivatives, exhibit potent cyclic nucleotide phosphodiesterase (PDE) inhibition, with high selectivity for PDE‐4 . Other N9‐substituted adenine derivatives have antiviral activity for DNA viruses and retroviruses , and others are cytotoxic to tumor cell lines . N9‐substituted‐8‐oxoadenine derivatives have been shown to have interferon inducing activity and have been synthesized from N9‐substituted adenines, such as N9‐benzyladenine .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Solvent‐directed Regioselective Benzylation of Adenine: Characterization of N9‐benzyladenine and N3‐benzyladenine

Buyens

Mangondo

Cukrowski

et al. 2017

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

The preferred sites for the benzylation of adenine under basic conditions were proven to be the N9 and N3 positions. Formation of the N9‐benzyladenine product is favored in polar aprotic solvents, such as DMSO, whereas the proportion of N3‐benzyladenine formed increases as the proportion of polar protic solvents, such as water, increases. X‐ray crystal structures were obtained for both N9‐benzyladenine and N3‐benzyladenine. 1H‐13C HMBC NMR spectroscopy revealed diagnostic correlations used to assign the 1H and 13C NMR chemical shifts confirming that the solution structures in three different solvents were the same as the isolated crystals. 13C NMR assignment for N9‐benzyladenine, N3‐benzyladenine, and N7‐benzyladenine was confirmed by computation using ADF.

show abstract

Section: Resultsmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Solvent‐directed Regioselective Benzylation of Adenine: Characterization of N9‐benzyladenine and N3‐benzyladenine

Buyens

Mangondo

Cukrowski

et al. 2017

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

show abstract

“…Thymine propenal and cytosine propenal were synthesized according to a published method (15). Bleomycin and calf thymus DNA were purchased from Sigma.…”

Section: Methodsmentioning

confidence: 99%

Chemical and Biological Evidence for Base Propenals as the Major Sourceof the Endogenous M1dG Adduct in CellularDNA

Zhou

Taghizadeh

Dedon

2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

The endogenous DNA adduct, M 1 dG, has been shown to arise in vitro in reactions of dG with malondialdehyde (MDA), a product of both lipid peroxidation and 4-oxidation of deoxyribose in DNA, and with base propenals also derived from deoxyribose 4-oxidation. We now report the results of cellular studies consistent with base propenals, and not MDA, as the major source of M 1 dG under biological conditions. As a foundation for cellular studies, M 1 dG, base propenals, and MDA were quantified in purified DNA treated with oxidizing agents known to produce deoxyribose 4-oxidation. The results revealed a consistent pattern; Fe 2؉ -EDTA and ␥-radiation generated MDA but not base propenals or M 1 dG, whereas bleomycin and peroxynitrite (ONOO ؊ ) both produced M 1 dG as well as base propenals with no detectable MDA. These observations were then assessed in Escherichia coli with controlled membrane levels of polyunsaturated fatty acids (PUFA). ONOO ؊ treatment (2 mM) of cells containing no PUFA (defined medium with 18:0/stearic acid) produced 6.5 M 1 dG/10 7 deoxynucleotides and no detectable lipid peroxidation products, including MDA, as compared with 3.8 M 1 dG/ 10 7 deoxynucleotides and 0.07 g/ml lipid peroxidation products with control cells grown in a mixture of fatty acids (0.5% PUFA) mimicking Luria-Bertani medium. In cells grown with linoleic acid (18:2), the level of PUFA rose to 54% and the level of MDA rose to 0.14 g/ml, whereas M 1 dG fell to 1.4/10 7 deoxynucleotides. Parallel studies with ␥-radiation revealed levels of MDA similar to those produced by ONOO ؊ but no detectable M 1 dG. These results are consistent with base propenals as the major source of M 1 dG in this model cell system.

show abstract

“…Adenine propenal [9-(3-oxoprop-1-enyl)adenine], cytosine propenal [1-(3-oxoprop-1-enyl)cytosine], thymine propenal [1-(3-oxoprop-1-enyl)thymine], and uracil propenal [1-(3-oxoprop-1-enyl)uracil] were synthesized by published procedures (22). All other chemicals were standard commercial products.…”

Section: Methodsmentioning

confidence: 99%

Detoxication of base propenals and other alpha,beta-unsaturated aldehyde products of radical reactions and lipid peroxidationby human glutathione transferases.

Berhane

Widersten

Engström

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

398

224

View full text Add to dashboard Cite

Radiation and chemical reactions that give rise to free radicals cause the formation of highly cytotoxic base propenals, degradation products of DNA. Human glutathione transferases (GSTs; RX:glutathione R-transferase, EC 2.5.1.18) of classes Alpha, Mu, and Pi were shown to promote the conjugation of glutathione with base propenals and related alkenes. GST P1-i was particularly active in catalyzing the reactions with the propenal derivatives, and adenine propenal was the substrate giving the highest activity. The catalytic efficiency of GST P1-i with adenine propenal (kat/K. = 7.7 x 105 M-1's-) is the highest so far reported with any substrate for this enzyme. In general, GST Al-i and GST Mi-i, in contrast to GST P1-i, were more active with 4-hydroxyalkenals (products of lipid peroxidation) than with base propenals. The adduct resulting from the Michael addition of glutathione to the alkene function of one of the base propenals (adenine propenal) was identified by mass spectrometry. At the cellular level, GST P1-i was shown to provide protection against a,4-unsaturated aldehydes. GST Pi-i added to the culture medium of HeLa cells augmented the protective effect of glutathione against the toxicity of adenine propenal and thymine propenal. No protective effect ofthe enzyme was observed in the presence of the competitive inhibitor S-hexylglutathione. GST Pi-i introduced into Hep G2 cells by electroporation was similarly found to increase their resistance to acrolein. The results show that glutathione transferases may play an important role in cellular detoxication of electrophilic a,.-unsaturated carbonyl compounds produced by radical reactions, lipid peroxidation, ionizing radiation, and drug metabolism.

show abstract

Synthesis and biological activity of a new class of cytotoxic agents: N-(3-oxoprop-1-enyl)-substituted pyrimidines and purines

Cited by 49 publications

References 0 publications

Solvent‐directed Regioselective Benzylation of Adenine: Characterization of N9‐benzyladenine and N3‐benzyladenine

Solvent‐directed Regioselective Benzylation of Adenine: Characterization of N9‐benzyladenine and N3‐benzyladenine

Chemical and Biological Evidence for Base Propenals as the Major Sourceof the Endogenous M1dG Adduct in CellularDNA

Detoxication of base propenals and other alpha,beta-unsaturated aldehyde products of radical reactions and lipid peroxidationby human glutathione transferases.

Contact Info

Product

Resources

About