Cleavage agents

Active Raney nickel induces desulfurization of many sulfur-containing heterocycles thiazoles are fairly labile toward this ring cleavage agent. The reaction occurs apparently by two competing mechanisms (481) in the first, favored by alkaline conditions, ring fission occurs before desul-, furization, whereas in the second, favored by the use of neutral catalyst, the initial desulfurization is followed by fission of a C-N bond and formation of carbonyl derivatives by hydrolysis (Scheme 95). 

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... 

The use of periodate as a cleavage agent does have advantages, however. Unlike the use of cleavable crosslinkers that contain disulfide bonds which require a reductant to break the conjugate, cleavage of diol-containing crosslinks with periodate typically preserves the indigenous disulfide bonds and tertiary structure of proteins and other molecules. As a result, with most proteins bioactivity usually remains unaffected after mild periodate treatment. 

The most commonly utilized chemical cleavage agent is cyanogen bromide (it cleaves the peptide bond on the carboxyl side of methionine residues). V8 protease, produced by certain staphylococci, along with trypsin are two of the more commonly used proteolytic-based fragmentation agents. 

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. 

Few epoxidations have been accomplished with RuO since the reagent is a prime alkene cleavage agent (but see Fig. 3.1 below). Because of the intrinsic interest in, and need for, epoxidations many Ru complexes have been studied for the purpose, but generally only those which are effective (i.e. give good yields and selectivities), are catalytic and do not require forcing conditions are included. Some of those omitted here are mentioned in Ch. 1 and listed in 3.1.1.4 below. 

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. 

Most of our early work in this area centered on the complexes Ru(tpy)(L)OH22+, where L = bpy, phen, and dppz (Figure 1, tpy = 2,2, 2"-terpyridine) (7, 30, 33). These complexes cleave DNA upon oxidation to Ru(tpy)(L)OH2+ and Ru(tpy)(L)02+, which can be performed chemically or electrochemically. We have a number of other complexes in our laboratory with similar properties (39) however, we will begin here with a discussion of the binding and kinetics of the simple, achiral tpy complexes, which have provided a basis for the design of cleavage agents with other desirable properties. 

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