Depolymerization activity, effect

The causal relationship of PTX actin depolymerizing activity with i.p. toxicity in mice has not been demonstrated as well as its causal relationship with apoptosis induction in tumor and primary cells. Further research on PTXs mechanism of action is necessary to elucidate if actin depolymerization is responsible for in vivo and in vitro effects of PTX, if PTXs have other cellular targets, and which cell types are involved in the in vivo toxicity of PTXs. 

Some reports about the effect of the Sn-based catalyst on PLLA thermal degradation have been published. Noda [40] evaluated the activity of mono-, di-, tetraalkyl and aryl tin(IV) compounds as intramolecular transesterification catalysts and found that monobutyltin trichloride was the most active catalyst with some other compounds indicating almost the same depolymerization activity as Sn(Oct)2. Degee et al. [41] also reported that PLLA prepared with Sn(Oct)2 was less stable thermally than that prepared with Al alk-oxides based on TGA data. However, Cam and Mamed [33] found a contrary effect on thermal decomposition onset temperature in the order of Al > Zn > Sn. 

Polk et al. reported27 that PET fibers could be hydrolyzed with 5% aqueous sodium hydroxide at 80°C in the presence of trioctylmethylammonium bromide in 60 min to obtain terephthalic acid in 93% yield. The results of catalytic depolymerization of PET without agitation are listed in Table 10.1. The results of catalytic depolymerization of PET with agitation are listed in Table 10.2. As expected, agitation shortened the time required for 100% conversion. Results (Table 10.1) for the quaternary salts with a halide counterion were promising. Phenyltrimethylammonium chloride (PTMAC) was chosen to ascertain whether steric effects would hinder catalytic activity. Bulky alkyl groups of the quaternary ammonium compounds were expected to hinder close approach of the catalyst to the somewhat hidden carbonyl groups of the fiber structure. The results indicate that steric hindrance is not a problem for PET hydrolysis under this set of conditions since the depolymerization results were substantially lower for PTMAC than for die more sterically hindered quaternary salts. 

Ultrasound has proven effective in promoting a few heterogeneous nonmetallic reactions. As early as 1933 Moriguchi noted that the reaction of calcium carbonate and sulfuric acid was faster in the presence of ultrasound(4). In the same year Szalay reported that ultrasonic waves depolymerized starch, gum arabic and gelatin(50). Examples of synthetically useful applications are fewer than metallic systems but activity in this arena is increasing. 

First we consider the acyl sector of the epothilones, which proved to be intolerant of modification. For example, inversion of stereochemistry at C3 (S toR), or reduction at C5 results in serious arrest of activity. Analogs with functionality at C3, C5, C6, C7 and C8 removed demonstrate both diminished tubulin-binding activity and cytotoxidty (structures not shown). Ddetion of the single methyl group at C8 has a highly pronounced deleterious effect on activity. Removal of the C9 methylene group resulting in a 15-membered macrolide, 87, results in a major loss of activity in tubulin polymerization/depolymerization assays. 

The cause of the cell cycle specificity of the bisindole alkaloids may be associated with the ability of these compounds to interact with the protein tubulin and thereby inhibit the polymerization (and depolymerization) of microtubules (16,17). In this respect the cellular pharmacology of vinca alkaloids is similar to that of other cytotoxic natural products such as colchicine or podophyllotoxin. On closer inspection, however, Wilson determined that the specific binding site on tubulin occupied by vinblastine or vincristine is chemically distinct from the site occupied by the other natural products (18). Subsequent experiments have determined that the maytansinoids, a class of ansa-macrocycles structurally distinct from the bisindoles, may bind to tubulin at an adjacent (or overlapping) site (19). A partial correlation of the antimitotic activity of these compounds with their tubulin binding properties has been made, but discrepancies in cellular uptake probably preclude any quantitative relationship of these effects (20). 

The reduction in concentration of reactants, enzymes, and solute molecules can provide important information about kinetic systems. For example, one can readily differentiate a first-order process from a second-order process by testing whether the period required to reduce a reactant concentration to 50% of its initial value depends on dilution. First-order processes and intramolecular processes should not exhibit any effect on rate by diluting a reactant. In terms of enzyme-catalyzed processes, the Michaelis-Menten equation requires that the initial reaction velocity depends strictly on the concentration of active catalyst. Dilution can also be used to induce dissociation of molecular complexes or to promote depolymerization of certain polymers (such as F-actin and microtubules). 

The reactivity of metal ions is not always the same with DNA and RNA. One reaction that is exclusive to RNA is depolymerization of the polynucleotide structure by the cleavage of the phosphodiester bonds. This depolymerization reaction, as with other RNA hydrolyses, can be induced by metal hydroxides, Zn being one of the most effective. A simple mechanism is that the Zn" chelates to the phosphate group and the 2 -hydroxyl group of ribose (the 2 -group is absent in DNA). Electron withdrawal by the Zn ion then weakens the phosphodiester linkage. Such a mechanism, however, does not take into account the observed influence of the nature of the adjacent base and the formation of metal-dependent products. Pb is also an effective catalyst in site-specific depolymerization of tRNA. In this case the metal has been shown to bind to the bases with only weak interactions with phosphate groups. The catalytic action has been interpreted in terms of nucleophilic attack by a metal-bonded hydroxide ion.134 This may have implications for the mechanisms of other metal ions active in this reaction. 

Colchicine does not influence the renal excretion of uric acid or its concentration in blood. By virtue of its ability to bind to tubulin, colchicine interferes with the function of the mitotic spindles and causes depolymerization and disappearance of the fibrillar microtubules in granulocytes and other motile cells. This action is apparently the basis for the beneficial effect of colchicine, namely, the inhibition of the migration of granulocytes into the inflamed area and a decreased metabolic and phagocytic activity of granulocytes. This reduces the release of lactic acid and proinflammatory enzymes that occurs during phagocytosis and breaks the cycle that leads to the inflammatory response. 

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