DNA cleavage

It has been shown that polypyridyl Rh(III) complexes induce photo-cleavages of the sugar phosphate backbone of double-stranded DNA with a higher relative quantum yield than Ru(II) complexes of phen or DIP. Thus replacement of Ru(II) ions by Rh(III) in Tris(phen) complexes, increases the efficiency of DNA photo-cleavages. However, in contrast to the Ru(II) complexes, Rh(III) samples have to be illuminated in the UV because of the absence of absorption bands in the visible region. 

It would be interesting to test with other Rh(III) complexes, whether the direct oxidation of the base (by photo-electron transfer) could also be a primary step responsible for photocleavages. Indeed, as outlined before in Sect. 5, radiation studies have shown that the radical cation of the base can produce the sugar radical, itself leading to strand scission [122]. Moreover base release, as observed with the Rh(III) complexes, can also take place from the radical cation of the base [137]. Direct base oxidation and hydrogen abstraction from the sugar could be two competitive pathways leading to strand scission and/or base release. 

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Artificial endonucleases, ie, molecules able to cleave double-stranded DNA at a specific sequence, have also been developed. These endonucleases can be obtained by attaching a chemically reactive group to a sequence-specific oligonucleotide. When the oligonucleotide is bound to its complementary sequence, the activation of the reactive group results in double-stranded DNA cleavage. 

FIGURE 12.4 Maxam-Gilbert sequencing of DNA cleavage at purines uses dimethyl sulfate, followed by strand scission with piperidine. 

At present the synthetic importance of both the Bergman cyclization and the Myers reaction remains rather small. However, because of the considerable biological activity of the natural products mentioned above, there is great mechanistic interest in these reactions in connection with the mode of action of DNA cleavage. 

Cancer cells are killed by camptothecins as a result of the trapping of Topi-DNA cleavage complexes. Those... 

Camptothecins. Figure 3 Conversion of reversible Topi -DNA cleavage complexes into DNA damage by collision of a replication fork (the DNA polymerase complex is not shown). 

Topoisomerase enzymes control and modify the topologic states of DNA. The mechanisms of these enzymes involve DNA cleavage and strand passage through the break, followed by religation of the cleaved DNA. Two main forms of topoisomerase exist. The type... 

Bis(aminoalkyl)bithiazoles are useful as DNA cleavage agents. Bleomycin contains a 2,4 -bithiazole moiety which plays an important role in the interaction with double stranded DNA during the cleavage reaction. The 2,2 -bis(aminomethyl)-4,4 -bithiazole (70) has been synthesised by the condensation of l,4-dibromobutane-2,3-dione with Boc-glycinethioamide... 

To summarize, terminase inhibitors point the way toward a switch in strategy for developing HCMV inhibitors, with the aim of achieving a quality different from that of established DNA polymerase inhibitors. Intervention with viral DNA maturation arrests the replicative cycle at the DNA cleavage and packaging step, leading to an accumulation of empty procapsids and unprocessed concatemeric DNA. 

Beard PM, Duffy C, Baines JD (2004) Quantification of the DNA cleavage and packaging proteins UL15 and UL28 in A and B capsids of herpes simplex vims type 1. J Virol 78 1367-1374 Betz UA, Fischer R, Kleymann G, Hendrix M, Rubsamen-Waigmann H (2002) Potent in vivo antiviral activity of the herpes simplex vims primase-helicase inhibitor BAY 57-1293. Antimicrob Agents Chemother 46 1766-1772... 

Sheaffer AK, Newcomb WW, Gao M, Yu D, Weller SK, Brown JC, Tenney DJ (2001) Herpes simplex virus DNA cleavage and packaging proteins associate with the procapsid prior to its maturation. J Virol 75 687-698... 

This effect is particularly well documented for y - and -amino acid residues [217, 218] which in several natural products (bleomycin A2 [219], calyculins [220]) have been shown to play a substantial role in the pre-organization of the whole molecule into its bioactive conformation. For example, changes in the substitution pattern of the y-amino acid linker in bleomycin A2 result in reduced DNA cleavage efficiency [219]. In the case of y-peptides, changing the relative configuration like or unlike of y " -amino acids has been used as a strategy to generate different local conformations (Fig. 2.34) suitable either for the construction of helices [201] or turns ]202-204]. 

Although, as stated above, we wiU mostly focus on hydrolytic systems it is worth discussing oxidation catalysts briefly [8]. Probably the best known of these systems is exemphfied by the antitumor antibiotics belonging to the family of bleomycins (Fig. 6.1) [9]. These molecules may be included in the hst of peptide-based catalysts because of the presence of a small peptide which is involved both in the coordination to the metal ion (essential co-factor for the catalyst) and as a tether for a bisthiazole moiety that ensures interaction with DNA. It has recently been reported that bleomycins will also cleave RNA [10]. With these antibiotics DNA cleavage is known to be selective, preferentially occurring at 5 -GpC-3 and 5 -GpT-3 sequences, and results from metal-dependent oxidation [11]. Thus it is not a cleavage that occurs at the level of a P-O bond as expected for a non-hydrolytic mechanism. 

Fig. 6.3 Molecular model of the domains of the chimeric nuclease (constituted by an hybrid between a non-specific DNA cleavage domain and a zinc finger recognition domain) and DNA. The cleavage domain sits behind...

YAMASHITA Y, KAWADA s, NAKANO H (1990) Induction of mammalian topoisomerase II dependent DNA cleavage by non-intercalative flavonoids genistein and oroboL Biochem Pharmacol. 39 737-44. 

A series of 6-substituted 8,9-dimethoxy-2,3-methylenedioxy-6ff-dibenzo[c,h] [2,6] naphthyridin-5-ones (IX) was synthesized and evaluated for topo I-targeting activity as well as for cytotoxicity against different cell lines by Zhu et al. [53]. From the topo I-mediated DNA cleavage data of these compounds (IX), we developed Eq. 7 (Table 5) ... 

A series of 5H-indolo[2,3-b]quinoline derivatives (XVII) was synthesized by Kaczmarek et al. [70] as novel DNA topo II inhibitors. Using their data for topo Il-induced DNA cleavage by this compound series (XVII), Eq. 18 was derived (Table 14) ... 

Arya DP (2006) Diazo and Diazonium DNA Cleavage Agents Studies on Model Systems and Natural Product Mechanisms of Action. 2 129-152 El Ashry ESH, El KUany Y, Nahas NM (2007) Manipulation of Carbohydrate Carbon Atoms for the Synthesis of Heterocycles. 7 1-30 El Ashry ESH, see El Nemr A (2007) 7 249-285... 

Rajasinghe, H., Jayatilleke, E. and Shaw, S. (1990). DNA cleavage during ethanol metabolism, role of superoxide radicals and catalytic iron. Life Sci. 47, 807-814. 

Meng LH, Zhang JS, Ding J. Salvicine, a novel DNA topoisomerase II inhibitor, exerting its effects by trapping enzyme-DNA cleavage complexes. Biochem Pharmacol 2001 62 733-741. 

Adlakha RC, Ashom CL, Chan D, Zwelling LA. Modulation of 4 -(9-acridinyl-amino)methanesulfon m anisidide induced, topoisomerase ILmediated DNA cleavage by gossypol. Cancer Res 1989 49 2052-2058. 

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