Telomerization, inhibition

Rezler EM, Bearss DJ, Hurley LH (2003) Telomere inhibition and telomere disruption as processes for drug targeting. Annu Rev Pharmacol Toxicol 43 359-379... 

Telomere Inhibition and Telomere Disruption as Processes for Drug Targeting... 

TELOMERE INHIBITION AND TELOMERE DISRUPTION AS PROCESSES FOR DRUG TARGETING... 

Zhang, X., Mar, V., Zhou, W., Harrington, L., and Robinson, M.O. (1999). Telomerer shortening and apoptosis in telomere-inhibited human tumor cells. Genes Dev. 13, 2388-2399. 

Herbert B. S., Pitts A. E., Baker S. I., Hamilton S. E., Wright W. E., Shay J.W., Corey D.R. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc. Natl Acad. Sci. USA 1999 96 14276-14281. 

NAASANI I, SEIMIYA H and TSURUO T (1998) Telomerase inhibition, telomere shortening, and senescence of cancer cells by tea catechins , Biochem Biophys Res Commun, 249 (2), 391-6. 

The d-lactone (Scheme 38.11) can be efficiently obtained by the telomerization of butadiene and C02. Its biphasic hydrogenation with an in-situ-prepared Rh/ mtppts catalyst yields 2-ethylidene-6-heptenoic acid (and its isomers) [136]. Note, that the catalyst is selective for the hydrogenolysis of the lactone in the presence of two olefmic double bonds this is probably due to the relatively large [P] [Rh] ratio (10 1) which is known to inhibit C = C hydrogenations with [RhCl(wtppms)3]. The mixture of heptenoic acids can further be hydrogenated on Pd/C and Mo/Rh catalysts to 2-ethylheptanol which finds several applications in lubricants, solvents, and plasticizers. This is one of the rare examples of using C02 as a Cl building block in a transition metal-catalyzed synthetic process. 

The results from Zhou et al. revealed that the introduction of electron-donating groups such as substituted amino groups at the C-ll position of the quindoline significantly enhanced the ability of the molecule to inhibit telomerase activity (IC50 > 138 iM for quindoline, 0.44-12.3 iM for quindoline derivatives 1-10). The quindoline derivatives not only stabilized the G-quadruplex structure but also induced the G-rich telomeric repeated DNA sequence to fold into a quadruplex [31]. 

The process of transcription can also occur in reverse, from RNA to DNA, when the sequence coded in RNA is transcribed into antisense DNA by reverse transcriptase enzymes first discovered by Temin and Mizutani [18] and Baltimore [19]. Further integrase enzymes insert the DNA sequence into the native DNA. This is the mechanism by which viruses infect their host organisms and can be stopped by antiviral drugs, such as azidothymine (AZT) that inhibits F1IV reverse transcriptase. Other processes such as the extension of telomeres at the ends of chromosomes by telomerase, to control programmed cell death, use the same mechanism. 

Cyclohexane. It is the purpose of the present paper to discuss a unique modifier for the reaction which very markedly inhibits the telomerization and results in the formation of ethylcyclohexane as the principal single reaction product together with some butylcyclohexane and diethylcyclohexanes. 

The pathway by which the hydrogen chloride inhibits the telomerization and thus produces mono-ethylcyclohexane was supported by use of a solution of deuterium chloride (38%) in heavy water (99% deuterium oxide) as promoter under the standard conditions. The reaction mixture included 1.15 mols of cyclohexane and... 

Applications of cyclised oligonucleotides are varied. They have been used to produce artificial human telomeres by rolling circle DNA synthesis/as inhibitors of viral replication in influenza virus and as structural motifs for quadruplex formation.A further form of cyclic oligonucleotide figures in a recently described method in which a self-complementary oligonucleotide, e.g., a hairpin structure, is denatured and allowed to re-anneal in the presence of circular DNA such as a plasmid (7). The effect is that the short oligonucleotide traps the plasmid in what has been termed a padlock. Such structures have been successfully used to inhibit transcription elongation reactions based on triple helix formation of the padlock structure. 

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