Disassembly pathways

FIGURE 5.31 Disassembly pathway of second-generation dendritic molecule 34 triggered by enzymatic activation of PGA. 

The disassembly pathway of molecular probe 39 is initiated by catalytic cleavage of phenylacetic acid by PGA, elimination of azaquinone methide, decarboxylation, and cyclization to release dimethylurea derivative and phenol 40 (Fig. 5.38). The latter rapidly undergoes double quinone methide elimination to release the two reporter units and by-product 41. The output of these cascade... 

FIGURE 5.38 Disassembly pathway of AB2 self-immolative dendritic molecule 39. 

Sollner T, Bennett MK, Whiteheart SW, Scheller RH, Rothman JE (1993) A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion. Cell 75 409 18. 

SollnerTH, Bennett MK, Whiteheart SW, Scheller RH, Rothman JE (1993 b) A protein assembly-disassembly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation, and fusion. In Cell 75 409-18 Stecher B, Weller U, Habermann E, Gratzl M, Anhert-Hilger G (1989) The light chain but not the heavy chain of botulinum A toxin inhibits exocytosis from per-meabilized adrenal chromaffin cells. In FEBS Lett. 255 391 -4... 

Fandrich, M., Tito, M.A., Leroux, M.R., Rostom, A.A., Hard, F.U., Dobson, C.M., Robinson, C.V. (2000) Observation of the Noncovalent Assembly and Disassembly Pathways of the Chaperone Complex MtGimC by Mass Spectrometry. Proc. Natl. Acad. Sci. USA 97 14151-14155. 

Scheme 11 Proposed disassembly pathway of 2,6-bis(hydroxymethyl)-p-cresol-based den-drons...

Scheme 12 Proposed disassembly pathway of 2-(4-aminobenzylidene) propane-1,3-diol-based dendrons...

Scheme 13 Proposed disassembly pathway of 2,4-bis0iydroxymethyl)phenol-baseddendrons...

In recent years, several model complexes have been synthesized and studied to understand the properties of these complexes, for example, the influence of S- or N-ligands or NO-releasing abilities [119]. It is not always easy to determine the electronic character of the NO-ligands in nitrosyliron complexes thus, forms of NO [120], neutral NO, or NO [121] have been postulated depending on each complex. Similarly, it is difficult to determine the oxidation state of Fe therefore, these complexes are categorized in the Enemark-Feltham notation [122], where the number of rf-electrons of Fe is indicated. In studies on the nitrosylation pathway of thiolate complexes, Liaw et al. could show that the nitrosylation of complexes [Fe(SR)4] (R = Ph, Et) led to the formation of air- and light-sensitive mono-nitrosyl complexes [Fe(NO)(SR)3] in which tetrathiolate iron(+3) complexes were reduced to Fe(+2) under formation of (SR)2. Further nitrosylation by NO yields the dinitrosyl complexes [(SR)2Fe(NO)2], while nitrosylation by NO forms the neutral complex [Fe(NO)2(SR)2] and subsequently Roussin s red ester [Fe2(p-SR)2(NO)4] under reductive elimination forming (SR)2. Thus, nitrosylation of biomimetic oxidized- and reduced-form rubredoxin was mimicked [121]. Lip-pard et al. showed that dinuclear Fe-clusters are susceptible to disassembly in the presence of NO [123]. 

The basics of the technique of disconnection is illustrated by considering the synthesis of the local anaesthetic benzocaine. The most appropriate disconnections are the ester and amine groups. At this point it is a matter of experience as to which disassembly route is followed. The normal approach is to pick the synthons that give rise to reagents that can most easily be reformed into the product. Consequently, in this case the ester disconnection would appear to be the most profitable pathway, as ester formation is relatively easy, but it is notpossible to directly introduce a nucleophilic amino group into a benzene ring. 

Scheme 10.3 Free radical retrosynthetic disassembly of bond d in 7. Advantages it does not necessitate the construction of a functionalised medium-sized ring. It forms the bicyclooctane ring system by a favourable 5-exo-trig pathway. Conformational and steric bias will allow the stereochemistry of the methyl a to the ketone to be controlled.

If amyloid fibrils and other self-assembling polypeptide systems are to be developed as new materials and components for nanotechnology and biomedicine, it is important that we understand the pathways and kinetics of their assembly. It will also be desirable to be able to control this assembly and any subsequent disassembly. 

Scheme 3 Scheme of the two possible reassembly pathways following disassembly of the J aggregates formed for interaction with A-[Ru(phen)3]2+ but in the presence of an excess of A-[Ru(phen)3]2+. Modified from [51]... 

Vinca alkaloids (vincristine, vinblastine, vinorelbine) are derived from the periwinkle plant (Vinca rosea). These agents work by binding to tubulin at a site different than colchicine or paclitaxel. They block polymerization, which prevents the formation of the mitotic spindle, and are used as antineoplastic agents. Taxanes produce a stabilization of microtubules similar to colchicine, but by a different mechanism, and also halt cells in metaphase. Paclitaxel (taxol) is the taxane used clinically. It is derived from the bark of the pacific yew. Taxol disrupts several microtubule-based functions as completely as inhibitors of polymerization, emphasizing the importance of assembly/disassembly balance in microtubule function. Recently, it has been found that paclitaxel also binds to and inhibits the function of a protein called bcl-2, an inhibitor of one or more pathways involved in mediating apoptosis. PaclitaxeTs interference with this function promotes apoptosis in addition to its microtubule-related inhibition of cell division. 

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