Propano Adducts

Douki, T. and Ames, B.N. (1994) An HPLC-EC assay for l,N2-propano adducts of 2 -deoxyguanosine with 4-hydroxynonenal and other a, 3-unsaturated aldehydes. Chem. Res. Toxicol, 7, 511-518. 

In general, chiral propanoates providing simple diastereoselectivity (in favor of yyn-aldols), combined with a reasonable degree of auxiliary-induced stereoselectivity, are rare. Numerous terpenoid- and carbohydrate-derived propionates do not display satisfactory syn selectivity60. Similarly, the titanium(IV) chloride promoted aldol addition of the following JV-metbylephe-drine derived silylketene acetal leads to the formation of the. mi-adduct in the moderate diastereomeric ratio of 78 22 (syn-adduct sum of the other stereoisomers)61. 

A more effective control of both simple diastereoselectivity and induced stereoselectivity is provided by the titanium enolate generated in situ by transmetalation of deprotonated 2,6-dimethylphenyl propanoate with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene-a-D-glucofuranos-3-0-yl)titanium. Reaction of this titanium enolate with aldehydes yields predominantly the. yyw-adducts (syn/anti 89 11 to 97 3). The chemical yields of the adducts are 24 87% while the n-u-products have 93 to 98% ee62. 

To a stirred suspension of 2.3 mmol LDA in 20 mL of THF arc added at — 80 X under a nitrogen atmosphere 253 mg (1 mmol) of methyl 2-(2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylideneamino)propanoate and the mixture is stirred for a further 30 min. After the addition of 114 mg (1 mmol) of ethyl ( )-2-butenoate the mixture is stirred at — 80 °C until the reaction is complete (followed by TLC on silica gel). The mixture is poured into 70 mL of sat. aq NH4C1 and subsequently extracted three times with diethyl ether. The combined ether layers arc dried over Na2S04 and the solvent is evaporated. The crude adduct is purified by chromatography (silica gel. diethyl ether/hexane 66 34) yield 330 mg (90%). 

To a stirred solution of (1.5 mmol) of LDA in 3.5 mL of THF/hcxane (60 40) at — 78 C under a nitrogen atmosphere is added 198 mg (1.5 mmol) terf-butyl propanoate in 1.5 mL of HMPA. After 30 min 169 mg (1.5 mmol) of potassium rm-butoxide are added and the mixture is stirred for 10 min. Then 133 mg (0.5 mmol) of ethyl 6-iodo-2-hcxcnoatc in 1.5 mL of TI1F arc added and the mixture is stirred for an additional 0.5 h at — 78 C. The reaction is quenched by adding sat. aq NH4C1. Extraction with ethyl acetate, drying over Na,S04 followed by evaporation of the solvent and short-path distillation gives the adduct yield 135 mg (100%). 

A similar trend was observed in the reactions of the (/. (-lithium enolate of /cr/-butyl propanoate with (E)- and (Z)-l-nitropropene. The. yyn-adduct is favored when (E)-l-nitropropene is employed whereas (Z)-l-nitropropene favors the aw/t -adduet, although the product diastereose-lection in the latter case is poor1. 

Treatment of 2-(benzylideamino)propanoate with NEt3 and metal halides other than LiBr leads to N-metalated azomethine ylides (Scheme 11.11) (87). Although N-sodiated ylides generated by using Nal/NEta afford the Michael adduct as the major product in reactions with methyl crotonate, other metalated ylides produce... 

When 2-(benzylideneamino)propanoate is treated with methyl acrylate in the presence of LiBr/NEts in THF, the Michael adduct (18%) is formed as a minor product together with the cycloadduct (79%) as a major product in a stereoselective fashion (Scheme 11.15). 

Michael adducts are also formed from the reactions of pyrroles with ethyl propiolate and with but-l-yn-3-one. In addition to the expected acrylic ester, 1-methylpyrrole also yields ethyl 3,3-bis(l-methyl-2-pyrrolyl)propanoate in its reaction with ethyl propiolate (67MI30500, 67MI30501), whilst if both a -positions of the pyrrole ring are unsubstituted, a twofold Michael addition with but-l-yn-3-one occurs to give the 2,5-disubstituted pyrrole (76JHC1145). 

Figure 22.7. The major DNA lesions of the lipid peroxidation products. (A) DNA lesions produced by malondialdehyde. Mi denotes the monomeric form of malondialdehyde. Malo-ndialdehyde can polymerize to form dimers and trimers that can also react with DNA. The resulting lesions are designated as M2 and M3, respectively (c.g., M2G). These lesions, however, may not be significant in cells as polymerization of malondialdehyde is relatively slow at neutral pH. (B) The l,7V2-propano-dG DNA adducts produced by acrolein, crotonaldehyde, and 4-hydroxy-2-nonenal (HNE). Stereochemistry is not shown. The l.A -acrolcin-dG consists of three isomers. The 1, AAcrotonaldchyde-dG consists of two isomers. The FAAlINF-dGconsistsof four isomers. (C)EthenoDNAadductsproduced by 2,3-epoxy-4-hydroxynonenal. Further oxidation of 4-hydroxynonenal produces 2,3-epoxy-4-hydroxynonenal, which reacts with DNA to form the exocyclic etheno adducts.

In contrast, cyanoselenenylation of ketene acetals is either stereospecific or stereoselective. Thus, 1-ted-butyldimethylsilyloxy-l-methoxy-l-propene, obtained as a 7 3 mixture of Stereoisomers from the enolate anion of methyl propanoate, gives a single adduct 74 in 78% yield, whereas a cyclic ketene acetal affords two diastereomeric adducts 75 [d.r. (major/minor) 78 22]71. 

Many other guanosine lesions have been investigated, the majority of which are those derived from polyaromatic hydrocarbons (PAHs), though adducts with smaller reactive species are also reported. Reaction with aldehydes, such as acrolein and crotonaldehyde leads to the formation of propano-dG adducts such as (86) and its a- and y-hydroxy derivatives as well as ring-opened derivatives like (87). Derivatives (87) can further react with other nucleobases, particularly guanine, leading to crosslinking. The reaction with aldehydes is... 

Scheme 9 Acrolein adducts to deoxyguanosine to yield 1 AP-propano-2 -deoxyguanosme...

Douki, T., Odin, F., Caillat, S., Favier, A., and Cadet., J. (2004) Predominance of the l,N2-propano 2 -deoxyguanosine adduct among 4-hydroxy-2-nonenal-induced DNA lesions. Free Radio. Biol. Med., 37, 62-70. 

Smith, J., Harris, T.M., Lloyd, R.S., Rizzo, C.J., and Stone, M.P. (2006) Stereospecific formation of interstrand carbinolamine DNA cross-links by crotonaldehyde- and acetaldehyde-derived a-CH3-y-OH-l,N2-propano-2 -deoxyguanosine adducts in the 5 -CpG-3 sequence. Chem. Res. Toxicol, 19, 195-208. 

Implicit in the discussion of the chemistry of formation for DNA adducts in vitro is the generation of DNA adducts in vivo. The previously described pyrimidopuri-none, propano, and etheno adducts are found in human tissue samples and cultured human cell lines. The estimated levels of these adducts range from one to 10 adducts/108 bp DNA. Owing to the relatively low abundance of these lesions amid a preponderance of impurities, highly sensitive and specific analytical... 

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