Telomerization mechanism

Mechanistic Aspects of the Telomerization Reaction 3.1 General Telomerization Mechanism... 

Scheme 9 Telomerization mechanism extended with the route that leads to phosphonium formation, adapted from [59]...

Scheme 10 Bimetallic telomerization mechanism proposed by Keim [65] for acetic acid or phenol telomerization, adapted from [25]...

Halocarbons including carbon tetrachloride, chloroform, bromotrichloroincthane6 (Scheme 6.7) and carbon tetrabromide have been widely used for the production of tclomcrs and transfer to these compounds has been the subject of a large number of investigations." Representative data are shown in Table 6.4. Telomerization involving halocarbons has also been developed as a means of studying the kinetics and mechanism of radical additions.66... 

Although sulfonyl chlorides add readily to unactivated olefins, with vinylic monomers telomeric and/or polymeric products were observed. This difficulty has been overcome by carrying out the addition in the presence of catalytic amounts of CuCl2, so as to provide a general and convenient synthesis of /5-chlorosulfones (Asscher-Vofsi reaction)63. For the copper-catalyzed system a redox-transfer mechanism has been suggested in which the... 

In order to explain the competitive formation of the 1 1 and 1 2 adducts and the formation of the 2,6-octadienyl rather than the 1,6-oc-tadienyl chain, a mechanism was proposed (62, 69) in which the insertion of one mole of butadiene to the Pd—H bond gives the 77-methallyl complex (68) at first, from which 1-silylated 2-butene is formed. At moderate temperature and in the presence of a stabilizing ligand, further insertion of another molecule of butadiene takes place to give C5-substituted n-allyl complex 69. The reductive elimination of this complex gives the 1 2 adduct having 2,6-octadienyl chain. In the usual telomerization of the nucleophiles, the reaction of butadiene is not stepwise and the bis-n--allylic complex 20 is formed, from which the l, 6-octadienyl chain is liberated. 

The scope of telomerization was outlined by Starks in 1974,8 and further developed by Gordon and Loftus.9 We recently reviewed such a reaction10,11 in which mechanisms and kinetics of radical and redox telomerizations were described. 

Colgin, L. M., and R. R. Reddel. 1999. Telomere maintenance mechanisms and cellular immortalization. Curr Opin Genet Dev 9(1) 97—103. 

Russo, I., A. R. Silver, A. P. Cuthbert, D. K. Griffin, D. A. Trott, and R. F. Newbold. 1998. A telomere-independent senescence mechanism is the sole barrier to Syrian hamster cell immortalization. Oncogene 17(26) 3417-26. 

Bryan TM, Englezou A, la-Pozza L, Dunham MA, Reddel RR. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat.Med. 1997 3 1271-1274. 

Telomeres are seqnences of six-nucleotide repeats found at the ends of the chromosomal DNA strands. Many thon-sands of repeat nnits (TTAGGG) may be present at the end of the 3 strand and (AATCCC) at the end of the 5 strand. These are present at the ends of the strands to overcome a problem posed by the semi-conservative mechanism of DNA replication, known as the end replication problem . Replication of the ends of the chromosomes presents par-ticnlar difficnlties, since DNA polymerase can only elon-... 

Positive results from the in vitro micronucleus test indicate that the test substance induces chromosome damage and/or damage to the cell division apparams, in cultured mammahan somatic cells. Immunochemical labehng (FISH fluorescence in sim hybridization) of kinetochores, or hybridization with general or chromosome specific centromeric/telomeric probes can provide useful information on the mechanism of micronucleus formation. Use of cytokinesis block facilitates the acquisition of the additional mechanistic information (e.g., chromosome nondisjunction) that can be obtained by FISH techniques. The micronucleus assay has a number of advantages over metaphase analysis performed to measure chromosome aberrations (see OECD TG 487 draft). 

The ends of a linear chromosome are not readily replicated by cellular DNA polymerases. DNA replication requires a template and primer, and beyond the end of a linear DNA molecule no template is available for the pairing of an RNA primer. Without a special mechanism for replicating the ends, chromosomes would be shortened somewhat in each cell generation. The enzyme telomerase solves this problem by adding telomeres to chromosome ends. 

Although the existence of this enzyme may not be surprising, the mechanism by which it acts is remarkable and unprecedented. Telomerase, like some other enzymes described in this chapter, contains both RNA and protein components. The RNA component is about 150 nucleotides long and contains about 1.5 copies of the appropriate CyKx telomere repeat. This region of the RNA acts as a template for synthesis of the T -G strand of the telomere. Telomerase thereby acts as a cellular reverse transcriptase that provides the active site for RNA-dependent DNA synthesis. Unlike retroviral reverse transcriptases, telomerase copies only a small segment of RNA that it carries within itself. Telomere synthesis requires the 3 end of a chromosome as primer and proceeds in the usual 5 —>3 direction. Having syn-... 

Scheme 5.23 Proposed mechanism for the Pd(0)-catalyzed telomerization of 1,3-butadiene with C02 (example with hemi-labile phosphino-nitrile ligands) [71].

The replication of a linear DNA molecule in a eukaryotic chromosome creates a problem that does not exist for the replication of bacterial circular DNA molecules. The normal mechanism of DNA synthesis (see above) means that the 3 end of the lagging strand is not replicated. This creates a gap at the end of the chromosome and therefore a shortening of the double-stranded replicated portion. The effect is that the chromosomal DNA would become shorter and shorter after each replication. Various mechanisms have evolved to solve this problem. In many organisms the solution is to use an enzyme called telom-erase to replicate the chromosome ends (telomeres). 

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