Activation—synthesis hypothesis

On to the activation-synthesis hypothesis, according to which dreams are caused by a cholinergically activated forebrain, anticholinergic medications and damage to cholinergic forebrain structures should produce decreased fre-... 

According to a hypothesis launched by Larionov et al in the 1960s, some new nitrogen mustard derivatives were developed. They contain metabolites and heterocyclic structures as carriers of the cytotoxic chloroethylamine groups. By this way the synthesis of aliylating metabolites started melphalan (sarcolysine) as L- or DL-phenylalanine derivative prospidine with a tricyclic piperazine moiety and chlorambucil as butyric acid derivative. It was proven that each alkylating metabolite has its own spectrum of selective antitumor activity. 

The situation was that as medicinal chemists pursued an SAR, calculations by the computational chemists might suggest a structure worthy of synthesis. Maybe the design had the potential of being more active. But the computational chemist was totally dependent on the medicinal chemist to test the hypothesis. Suddenly, the medicinal chemist saw himself going from being the... 

Reactions (1) and (2) have been quite actively pursued from the early nineties [4] and a possible connection between the M° nanoclusters size produced inside the swollen resin and the nanoporosity of the macromolecular support was discovered in 2000. This amazing observation led us to develop an operational hypothesis for what was appearing as an unprecedented means for the synthesis of size-controlled metal nanoclusters. 

Co-expression of the human a- and p-subunits in the yeast Pichea pastoralis produces only trace amounts of active tetramer, with the majority being present in an unassembled form. Co-expression with human type III collagens, however, increases this assembly level tenfold. This indicates that collagen synthesis and the formation of an active prolyl 4-hydroxylase complex are mutually dependent processes (Vuorela et al, 1997). A similar observation has been noted for baculovirus encoded enzymes in insect cells (Lamberg et al, 1996). These findings support the hypothesis that this unusual control mechanism may be a common feature of collagen synthesis in all cell types. 

The Li+-induced inhibition of the production of the HSV virus may be related to its actions upon viral DNA polymerase production and activity. Li+ reduces both the synthesis of DNA polymerase in tissue culture and the activity of DNA polymerase in vitro, each by about 50%. It has been proposed that Li+ reduces the biosynthesis of viral polypeptides and nucleic acids, and hence inhibits viral DNA replication by competition with Mg2+, a cofactor of many enzymes [243]. However, the inhibitory effect of Li+ on HSV replication in tissue culture is not affected by Mg2+ levels. A more likely hypothesis is the alteration of the intracellular K+ levels, possibly modifying levels of the high-energy phosphate compounds by replacement of either Na+ or K+ in Na+/K+-ATPase [244]. In tissue culture, HSV replication has been shown to be affected by the... 

Catalytic asymmetric cyanide addition to imines constitutes an important C—C bondforming reaction, as the product amino nitriles may be converted to non-proteogenic a-amino acids. Kobayashi and co-workers have developed two different versions of the Zr-catalyzed amino nitrile synthesis [73]. The first variant is summarized in Scheme 6.22. The bimetallic complex 65, formed from two molecules of 6-Br-binol and one molecule of 2-Br-binol in the presence of two molecules of Zr(OtBu)4 and N-methylimidazole, was proposed as the active catalytic species. This hypothesis was based on various NMR studies more rigorous kinetic data are not as yet available. Nonetheless, as depicted in Scheme 6.22, reaction of o-hydroxyl imine 66 with 5 mol% 65 and 1—1.5 equiv. Bu3SnCN (CH2C12, —45 °C) leads to the formation of amino nitrile 67 with 91 % ee and in 92 % isolated yield. As is also shown in Scheme 6.22, electron-withdrawing (— 68) and electron-rich (—> 69), as well as more sterically hindered aryl substituents (— 70) readily undergo asymmetric cyanide addition. 

An anomaly associated with citrulline that became evident when detailed kinetic studies were made in the 1950s (R.B. Fisher and J.R. Bronk) was the irreproducibility of its catalytic activity in liver slices on the formation of urea, despite the clear evidence from Ratner and Petrack of its importance in arginine synthesis. Initially the discrepancy in catalytic activity between ornithine and citrulline was ascribed to the possible impermeability of the liver cell plasma membrane to the latter intermediate, a hypothesis which was rapidly disproved experimentally. Only recently has it been shown that ornithine transcarbamylase is clearly associated with the ornithine/... 

These ideas are readily testable and therefore can constitute a research enterprise. For example, the hydrolysis of polyphosphates to monomeric phosphate is relatively fast in weak aqueous acid and warm temperatures. [129, 205] Curiously, however, the same acidity would promote thermal polyphosphate synthesis under the dehydrating conditions of the heated subterranean mineral pores within a hydrothermal system. Measurement of the stability of polyphosphates in microscopic environments where the activity of water might be low would test the phosphate-polyphosphate conjecture made above. If polyphosphates are not stabilized relative to bulk water solutions, as dissolved within micron-sized mineral pores or within vesicles, perhaps in the presence of dissolved organics, then this hypothesis is in danger. Additionally, the proposed production and delivery of polyphosphates by hydrothermal systems can be tested in an appropriate laboratory setting. 

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