Pathway stability

Pathway Stability as Reflected by Changes in Gene Expression Coherence... 

As described in Chapter 1, stress testing is the main tool that is used to predict stability-related problems, develop analytical methods, and identify degradation products and pathways. Stability-related issues can affect many areas, including the following ... 

Previous knowledge Although it may be obvious, information such as degradation product identity, degradation pathways, stability under various conditions, and the ability of analytical methods to determine degradation products is very valuable. Without this information, more extensive preliminary experiments will be required to understand degradation behavior and aid in the choice of appropriate stress conditions. 

Extrinsic pathway Intrinsic pathway Intrinsic pathway Extrinsic pathway Intrinsic pathway Intrinsic pathway Stabilizes fibrin... 

Samataro D, Campana V, Paladino S, Stomaiuolo M, Nitsch L, Zurzolo C. PrP(C) association with lipid rafts in the early secretory pathway stabilizes its cellular conformation. Mol Biol Cell. 2004 15(9) 4031-4042. 

The challenges for computational chernislry are to characteri/e and predict the structure and stability of chemical systems, to estimate energy differences between different states, and to explain reaction pathways and mechanisms at the atomic level. Meeting these challenges could eliminate tinie-consiini mg experiments. 

Accumulating evidence makes it increasingly clear that there is no single dominant Wittig transition state geometry and, therefore, no simple scheme to explain cis/trans selec-tivities. The conventional betaine pathway may not occur at all, the stabilized ylides, e,g., PhsP—CH —C02Et, can be ( )- or (Z)-selective, depending on the solvent and substrate (E. Vedejs, 1988 A, B, 1990). 

The sulfur atom stabilizes a-carbanions this has been used in the thiazole series to give a new synthetic pathway for various hydrocarbons (113) (Scheme 57) (281). 

Eor pesticides to leach to groundwater, it may be necessary for preferential flow through macropores to dominate the sorption processes that control pesticide leaching to groundwater. Several studies have demonstrated that large continuous macropores exist in soil and provide pathways for rapid movement of water solutes. Increased permeabiUty, percolation, and solute transport can result from increased porosity, especially in no-tiUage systems where pore stmcture is stiU intact at the soil surface (70). Plant roots are important in creation and stabilization of soil macropores (71). 

In the presence of aluminum, oxidative degradation or dimerization supply HCl for the formation of aluminum chloride, which catalyzes further dimerization to hexachlorobutene. The latter is decomposed by heat to give more HCl. The result is a self-sustaining pathway to solvent decomposition. Sufficient quantities of aluminum can cause violent decomposition, which can lead to mnaway reactions (1,2). Commercial grades of trichloroethylene are stabilized to prevent these reactions in normal storage and use conditions. 

Clearly, in the case of (66) two amide tautomers (72) and (73) are possible, but if both hydroxyl protons tautomerize to the nitrogen atoms one amide bond then becomes formally cross-conjugated and its normal resonance stabilization is not developed (c/. 74). Indeed, part of the driving force for the reactions may come from this feature, since once the cycloaddition (of 72 or 73) has occurred the double bond shift results in an intermediate imidic acid which should rapidly tautomerize. In addition, literature precedent suggests that betaines such as (74) may also be present and clearly this opens avenues for alternative mechanistic pathways. 

The catalytic triad consists of the side chains of Asp, His, and Ser close to each other. The Ser residue is reactive and forms a covalent bond with the substrate, thereby providing a specific pathway for the reaction. His has a dual role first, it accepts a proton from Ser to facilitate formation of the covalent bond and, second, it stabilizes the negatively charged transition state. The proton is subsequently transferred to the N atom of the leaving group. Mutations of either of these two residues decrease the catalytic rate by a factor of 10 because they abolish the specific reaction pathway. Asp, by stabilizing the positive charge of His, contributes a rate enhancement of 10. ... 

The soft-nucleophile-soft-electrophile combination is also associated with a late transition state, in which the strength of the newly forming bond contributes significantly to the stability of the transition state. The hard-nucleophile-hffld-elechophile combination inqilies an early transition state with electrostatic attraction being more important than bond formation. The reaction pathway is chosen early on the reaction coordinate and primarily on the basis of charge distributiotL... 

This compound is less stable than 5 and reverts to benzene with a half-life of about 2 days at 25°C, with AH = 23 kcal/mol. The observed kinetic stability of Dewar benzene is surprisingly high when one considers that its conversion to benzene is exothermic by 71 kcal/mol. The stability of Dewar benzene is intimately related to the orbital symmetry requirements for concerted electrocyclic transformations. The concerted thermal pathway should be conrotatory, since the reaction is the ring opening of a cyclobutene and therefore leads not to benzene, but to a highly strained Z,Z, -cyclohexatriene. A disrotatory process, which would lead directly to benzene, is forbidden. ... 

The haloform reaction of unsymmetrical perfluoroalkyl and co-hydroper-fluoroalkyl trifluororaethyl ketones gives the alkane corresponding to the longer alkyl chain [54] (equation 53) If the methyl group contains chlorine, the reaction can take different pathways, leading to loss of chlorine (equation 54), because of the variable stability of the chlorine-substituted methyl carbanions in alkali. 

Thermodynamically-Controlled Reaction. A reaction the product ratio for which is determined solely by the relative thermochemical stabilities of the different products (product formation must be reversible, or separate low-energy pathways interconnecting the products must exist). 

For the 2-1-2 pathway the FMO sum becomes (ab — ac) = a b — c) while for the 4 -I- 2 reaction it is (ab-I-ab) — a (2b). As (2b) > (b — c), it is clear that the 4 + 2 reaction has the largest stabilization, and therefore increases least in energy in the initial stages of the reaction (eq. (15.1), remembering that the steric repulsion will cause a net increase in energy). Consequently the 4 - - 2 reaction should have the lowest activation energy, and therefore occur easier than the 2-1-2. This is indeed what is observed, the Diels-Alder reaction occurs readily, but cyclobutane formation is not observed between non-polar dienes and dieneophiles. 

Two reaction mechanisms, such as SN1 and SN2 mechanisms, seem to be possible for explaining formations of 158a-c (Scheme 25). The former requires a resonance-stabilized indolyl cation 165 as an intermediate, while the latter indicates the presence of a transition state like 167. The introduction of a methoxy group into the 5 position of 165 should stabilize the corresponding cation 166, in which nucleophilic substitution on indole nitrogen would become a predominant pathway. 

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