Tandem base modifications

Tandem base modifications thymine hydroperoxides, 933 uracil hydroperoxides, 935, 936 Tantalum(V) complexes... 

The main oxidation reactions of the 2-deoxyribose of DNA are mediated by "OH that are able to abstract hydrogen atoms from most of the positions with the exception of the methylene group at C2, which is a poorly reactive site [12, 14, 112], An abundant literature is available on the degradation pathways that are derived from the reactions of osidic carbon-centered radicals and that lead in most cases to the formation of strand breaks [12, 14, 112], However, there is one major exception that concerns the chemical reactions of the CT radical that is the precursor of 2-deoxyribonolactone [113]. Here, emphasis is placed on reactions of C4 and C5 radicals that may lead to the formation of base modifications either as tandem lesions or clustered damage. 

The extremely high selectivity for tandem cycloaddition, the ease of manipulation of the nitroso acetals, and the release of the vinyl ether appendage in the hydrogenolytic cleavage constitute ideal features for asymmetric modifications of the cycloadditions with chiral vinyl ethers. As discussed in Section 8.3.2.1 (Inter [4+2]/inter [3+2] cycloadditions of nitroalkenes), the stereochemical course depends on the Lewis acids. The results are summarized in Scheme 8.38.179 The high levels and complementary selectivity with three chiral vinyl ethers and two kinds of Lewis acids (Ti- and Al-based Lewis acids) are presented in this scheme. 

Recently, Noort et al developed a procedure that is based on straightforward isolation of adducted BuChE from plasma by means of affinity chromatography with a procainamide column, followed by pepsin digestion and LC/electrospray tandem MS analysis of a specific nonapeptide containing the phosphonylated active site serine-198 residue (5). This method surpasses the limitations of the fluoride-reactivation method, since it can also deal with dealkylated ( aged ) phosphonylated BuChE. The method allowed the positive analysis of several serum samples of Japanese victims of the terrorist attack in the Tokyo subway in 1995. Furthermore, the method could be applied for detection of ChE modifications induced by, e.g., diethyl paraoxon and pyridostigmine bromide, illustrating the broad scope of this approach. This new approach... 

Nearly all modifications that have been detected on the model level (Chap. 10) are also found in free-radical damaged DNA. Obviously the DNA-bound lesions are much more difficult to detect, and there is an ongoing discussion as to the best procedure of their excision (Chap. 13.2 for a review on the excision and repair of base lesions in vivo see Wallace, 2002). Mechanistic details concerning the formation of the base lesions have been discussed in Chapters 10 and 11, and only some additional information will be given below and in the section on clustered lesions where the phenomenon of tandem lesions, two damaged bases that are formed side by side, is dealt with. The yields of damaged bases formed upon y-irradiation in aqueous solution, as has been determined by the GC-MS/SIM technique, are compiled in Table 12.5. 

A second group of reactions concerns rearrangements, occurring mostly in the cyclic Mannich base, which may generate deep structural modifications of the molecule. Due to its relevance in the synthesis of alkaloids, the tandem cationic ara-Cope reairangc-mcnt-Mannich cyclization (Fig. 68) is the most widely studied of this class of... 

Tandem mass spectrometry coupled to electrospray ion source allowed not only to identify proteins but also to characterize post-translational modifications of a protein (phosphorylation, acetylation, methylation, glycosylation, etc.). Indeed, the presence of such modifications induces an increase of the peptide molecular masses compared to the calculated masses based on the theoretical sequence, which often directly identifies the type of modification. In addition, tandem mass spectrometry allows in general precise localization of the modification at specific residue of the peptide. Analysis of modifications allows to understand biological mechanisms because several processes are controlled and/or induced by such modifications (Mann and Jensen 2003). Being... 

The Squibb team also worked back from their conception of the receptor s shape, based on their knowledge of details of the cleavage reaction it performed. Since the ACE protein had not itself been structurally defined, they developed a hypothetical model based on the active site of another enzyme that performed a similar cleavage reaction, and whose structure was known from x-ray crystallography. The research team crafted compounds to fit into the hypothetical active site of ACE and discovered a compound with inhibitory activity that was similar in shape to two amino-acids in tandem. They performed further chemical modifications of this molecule and eventually found a chemical amenable to oral administration that was 1,000 times more potent than their initial lead molecule. The synthetic drug had greater activity than the nine-amino-acid venom peptide. 

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