Duplex adducts

Table 1. List of Interstrand and Intrastrand Duplex Adducts Studied by NMR Spectroscopy and Their Abbreviations and Sequences...

Very recently the trans- [Pt(NH3)2Cl2] isomer has been shown to promote the formation of some highly unusual multiple strand nucleic acid structures (28). A parallel-stranded DNA duplex, psPtDNA, has been prepared which incorporates a frarcs-Pt(NH3)2+ crosslink. The pla-tinated strands were synthesized through the series of reactions illustrated in Fig. 3. The initial mono-functional G N7 adduct is formed at pH 3.5 by addition of rans-[Pt(NH3)2(H20)Cl]+ to the pyrimidine-rich sequence 5 -d(T4CT4G). After the pH is increased, normal anti-parallel duplex formation occurs upon addition of the complementary purine-rich strand, 5 -d(A4GA4G). This intermediate anti-parallel stranded... 

While the critical role of intrastrand 1,2-crosslinks in the mechanism of action of the anti-tumor drug cis- [PtCl2(NH3)2] is well established, much less is known about the few frans-analogs that exhibit similar efficacy. A series of 1,3-adducts has been characterized with 3-mers generally involving purine N7 coordination (32-34), and either monofunctional or interstrand adducts are formed with duplex DNA (35). However, one of the most active compounds, frans-[PtCl2 ( )-HN = C(OMe)Me 2], (2), has been shown to form a 1,2-adduct with 2-mer ribonucleotide sequence r(AG) (36). Though the formation of the... 

Detection of the dA N1 and dC N3 adducts may not in one sense be particularly important for DNA based on their central position within the helical conformation and hydrogen bonding network.37,38 Still, the deoxynucleoside studies helped to focus attention on the reversibility of alkylation by QM and provided insight into the reactions of duplex DNA described below in Section 9.3. Reaction at the deoxynucleoside level also provided an essential system for developing a theoretical treatment of QM reaction.50-52 Computations based on density functional theory well rationalized the published results on d A and correctly anticipated the results on dG and dC reviewed above and described in more detail in Chapter 2 (Freccero). 

NU(C) base atoms (5) The stereoselectivity of the BPDEs during intercalative covalent binding in kinked DNA and (6) The possible reorientation of the complex to yield an externally bound adduct. The energetics for each of these processes will be presented to identify the important steps that influence the binding of specific isomers. It will be shown that the orientation of each diastereoisomer of BPDE about specific base atoms in kinked receptor sites in the duplex DNA during covalent bond formation is the determining factor in stereoselectivity. 

An example of the variation of energy of adduct formation with ring conformation and its influence on e and the entire pyrene moiety is given in Figure 7 For trans addition of BPDE l(+) to N2 on guanine in duplex DNA, the minimum occurs with the Cde (e=llU.7°)... 

From a structural point of view, there are two possible orientations for the externally bound adduct in duplex DNA. They are easiest to discuss for BPDE-N2(g) adduct formation. The first results from an anti - syn rotation of G about its glycosidic bond. The BPDE-N2(G) adduct is transferred to the major groove and the DNA... 

Further experiments focused therefore on [RuCl(en)(r 6-tha)]+ (12) and [RuCl(rj6-p-cym)(en)]+ (22), which represent the two different classes, and their conformational distortion of short oligonucleotide duplexes. Chemical probes demonstrated that the induced distortion extended over at least seven base pairs for [RuCl(rj6-p-cym)(en)]+ (22), whereas the distortion was less extensive for [RuCl(en)(rj6-tha)]+ (12). Isothermal titration calorimetry also showed that the thermodynamic destabilization of the duplex was more pronounced for [RuCl(r 6-p-cym)(en)]+ (22) (89). DNA polymerization was markedly more strongly inhibited by the monofunctional Ru(II) adducts than by monofunctional Pt(II) compounds. The lack of recognition of the DNA monofunctional adducts by HMGB1, an interaction that shields cisplatin-DNA adducts from repair, points to a different mechanism of antitumor activity for the ruthenium-arenes. DNA repair activity by a repair-proficient HeLa cell-free extract (CFE) showed a considerably lower level of damage-induced DNA repair synthesis (about six times) for [RuCl(en)(rj6-tha)] + compared to cisplatin. This enhanced persistence of the adduct is consistent with the higher cytotoxicity of this compound (89). 

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