DNA cleavage agents

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... 

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... 

This approach was the first application of non-enediyne carbon centered radical mediated DNA cleavage agents that were not only capable of binding to DNA but could also be sequence specific. Further work is still needed to elucidate and confirm the sites of cleavage, nature of binding of these molecules and the mechanism of hydrogen abstraction from the nucleic acid backbone. 

Arya DP (2006) Diazo and Diazonium DNA Cleavage Agents Studies on Model Systems and Natural Product Mechanisms of Action. 2 129-152... 

The kinetics and mechanisms of the oxidation of DNA, nucleic acid sugars, and nucleotides by [Ru(0)(tpy)(bpy)] and its derivatives have been reported. " The Ru =0 species is an efficient DNA cleavage agent it cleaves DNA by sugar oxidation at the 1 position, which is indicated by the termini formed with and without piperidine treatment and by the production of free bases and 5-methylene-2(5//)-furanone. Kinetic studies show that the I -C— activation is rate determining and a hydride transfer mechanism is proposed. The Ru =0 species also oxidizes guanine bases via an 0x0 transfer mechanism to produce piperidine-labile cleavages. 

McPhee, M. M. Kern, J. T. Hoster, B. C. Kerwin, S. M, (2000) Propargylic sulfone-armed lariat crown ethers alkali metal ion-regulated DNA cleavage agents Bioorg. Chem. 8, 98-118. 

Biologically Active ge/w-Difluorocyclopropanes Anthracene-ge/n-Difluorocyclopropane Hybrids as DNA Cleavage Agents Switched on by Photoirradiation... 

Tosylates as well as alkyl halides can also cause A-alkylation of thiazoles and involve an Sn2 quartemization reaction. The thiazolium salt formation concept has been well utilized in medicinal chemistry. For example, Kerwin and co-workers at the University of Texas at Austin have reported the role of 2-alkynylbenzothiazolium component in DNA cleavage. They prepared a series of moderately potent A-propargyl-2-alkylbenzothiazolium aza-enediynes DNA cleavage agents, an example of which is shown below. Propargyl triflate was employed as the alkylating agent. 

Lariat ethers proved to be an effective vehicle for demonstrating alkali metal cation-7i interactions. When either Na" or is bound in the macroring, interactions are possible with neutral side arms. Indole, benzene, and phenol were studied, because these arenes are present on the side chains of tryptophan, phenylalanine, and tyrosine, respectively.Additional studies were reported of cation-x interactions between neutral double and triple bonds with these same alkali metal cations." Lariat ethers were also explored as ion-regulated DNA cleavage agents. Monomeric propargylic sulfone-armed lariat ethers were found to cleave DNA. Modest increases in DNA cleavage efficiency were observed in the presence of Na-" and... 

These types of DNA detection can also be applied to studies of antioxidative properties of various natural substances preserving DNA from damage [49, 50]. The detection scheme exploits quantification of the DNA portion that survives previous incubation of the biosensor in a mixture of the DNA cleavage agent and antioxidant/mixture of antioxidants under investigation. Using this approach, yeast polysaccharides, phenolic acids such as rosmarinic and caffeic acids, selected flavonoids, as well as aqueous plant extracts and tea extracts were studied [51]. 

Kumar et al. prepared aza-enediyne analogues by the incorporation of N-prop>argyl moiety to 2-alkynylbenzothiazolium salts (139) and the aza-enediynes (140) were proven to be the modest DNA cleavage agents. The mechanism probably involves the formation of an adduct (141) prior to cleavage of DNA. They also observed DNA cleavage with the N-methyl-2-alkynylbenzothiazolium salt, which lacks the aza-enediyne moiety (scheme-38) (Kumar et al. 2001). 

Scheme 38. N-propargyl alkynylbenzothiazolium salts as DNA cleavage agents...

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