Molecular dissection

The observation that very significant parts of the cocaine molecule could be deleted from synthetic analogs without loss of biologic activity led to the search for the minimal structural feature consistent with activity. This exercise, sometimes referred to as molecular dissection, not only led to great simpli-fi cation of the structure of local anesthetics but resulted fi-tially in the preparation of active molecules that bear only the remotest structural relation to the prototype, cocaine. 

The relative inaccessibility of physostigmine led to molecular dissection studies to define the parts of the molecule necessary for activity. A surprisingly simple derivative of m-hydroxy-aniline, neostigmine (40), proved to have the same activity as the complex heterocyclic molecule. In addition, this drug has found use as a cholinsterase inhibitor in pathologic conditions such as myasthenia gravis, marked by insufficient muscle tone. Reaction of m-dimethylaminophenol (37) witn pnosgene affords tne... 

Gegg, C. V., Bowers, K. E., and Matthews, C. R. (1997). Probing minimal independent folding units in dihydrofolate reductase by molecular dissection. Protein Sci. 6, 1885-1892. 

Many years ago, doisynolic acid (39), a steroid degradation product, was shown to have such activity. Over the years many simple compounds have been synthesized following the idea of molecular dissection. One of these is fenesti-el (38). Hageman s ester (35) is alkylated to 36 by t-BuOK and ethyl-bromide. The regioselectivity observed is generally... 

A molecular dissection of the alkaloid vasicine (52) ultimately resulted in the expectorant and mucolytic agent bromhexine (54). The synthesis starts with displacement of halogen on 2-nitrobenzyl-bromide (53) by N-methyl cyclohexylamine, followed by Raney nickel and hydrazine reduction of the nitro group. Bromination in acetic acid then affords bromhexine. 

Extensive molecular dissection of the morphine molecule over the past several decades led to a host of molecules which showed narcotic analgesic activity even though they possessed but faint suggestion of the structural features present in morphine itself. Thus, both cyclic molecules such as meperidine (70) and alphaprodine (71), and acyclic Compounds such as methadone (72) were found to be effective analgesics. Common features of these compounds were formalized by the Beckett-Casy rule, which states as minimal required structural features (a) an aromatic ring attached to... 

One of the first pharmacological classes to be studied by medicinal chemists was local anesthetics. Many of the guiding principles which are used to this day, for example, molecular dissection, side chain substitution and inversion, and the like, were first developed in the course of those early researches. 

Bhattacharjee A et al. Molecular dissection of dimethylnitrosamine (DMN)-in-duced hepatotoxicity by mRNA differential display. Toxicol Appl Pharmacol 1998 150 186-195. 

Boileau, A. J., Kucken, A. M Evers, A. R and Czajkowski, C. (1998) Molecular dissection of benzodiazepine binding and allosteric coupling using chimeric gamma-aminobutyric acidA receptor subunits. Mol. Pharmacol. 53, 295-303. 

Applegate, M.L., Moore, M.M., Broder, C.B. et al. (1990). Molecular dissection of mutations at the heterozygous thymidine canise locus in mouse lymphoma cells. Proc. Nat. Acad. Sci. U.S.A. 87 51-55. 

An alternative approach for determining the relative pi electronic stabilization of two torsional isomers utilizes a molecular dissection into two open shell radical fragments. This approach is illustrated by examining torsional isomerism in butadiene and 1,3,5-hexatriene. The ir MO s of the conformational isomers of 1,3,5-hexatriene can be constructed from the union of the n MO s of two formal allyl radicals. The two regiochemical modes of union of interest will be designated cis and tram ... 

Andersen, O.M., Schmidt, V., Spoelgen, R., et al. (2006) Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LRl 1. Biochemistry, 45, 2618-2628. 

Pante N, Aebi U (1996) Molecular dissection of the nuclear pore complex. Crit Rev Biochem Mol Biol 31 153-199... 

Takahashi K, Kohno T, Matsumoto S et al. Clonal and parallel evolution of primary lung cancers and their metastases revealed by molecular dissection of cancer cells. Clin Cancer Res 2001 3 - 20. Findlay MP, Cunningham D, Morgan G et al. Lack of correlation between thymidylate synthase levels in primary colorectal tumours and subsequent response to chemotherapy. Br J Cancer 1997 75 903-909. 

Dekker PJ, Ryan MT, Brix J, Muller H, Honlinger A, Pfanner N (1998) Preprotein translo-case of the outer mitochondrial membrane molecular dissection and assembly of the general import pore complex. Mol Cell Biol 18 6515-6524 Delgadillo MG, Liston DR, Niazi K, Johnson PJ (1997) Transient and selectable transformation of the parasitic protist Trichomonas vaginalis. Proc Natl Acad Sci USA 94 4716-4720... 

Analysis of changes in in-vivo- and m-v/tro-synthesised proteins is a very descriptive approach to understanding the phenomenon of cold acclimation and cold tolerance. For a functional analysis a molecular dissection of the process is required. This will allow investigators to determine the level (transcriptional/translational) at which the appearance of the new mRNAs is regulated, and the sequence information of the cold-regulated genes should point to the biochemical features of the encoded proteins. 

Bang, M. L., Gregorio, C., and Labeit, S. (2002). Molecular dissection of the interaction of desmin with the C-terminal region of nebulin./ Struct. Biol. 137, 119-127. 

Flint, J. (2003) Animal models of anxiety and their molecular dissection. Semin Cell Dev BiolU, 37-42. 

Kumagai H., Chun K. T. and Simoni R. D. (1995) Molecular dissection of the role of the membrane domain in the regulated degradation of 3-hydroxy-3-methylglutaryl coenzyme A reductase. J. Biol. Chem. 270, 19107-19113. 

Luo J, Duggan DJ, Chen Y, Sauvageot J, Ewing CM, Bittner ML, Trent JM, Isaacs WB. Human prostate cancer and benign prostatic hyperplasia molecular dissection by gene expression profiling. Cancer Res 2001 61 4683-4688. 

Kannenberg, E.L., Rathbun, E.A., Brewin, N.J. Molecular dissection of structure and function in the lipopolysaccharide of Rhizobium leguminosarum strain 3841 using monoclonal antibodies and genetic analysis. Mol Microbiol 6(17) (1992) 2477-2487. 

Marzari R, Sblattero D, Florian F, Tongiorgi E, Not T, Tommasini A, et al. Molecular dissection of the tissue transglutaminase autoantibody response in celiac disease. J Immunol 2001 166 4170 -176. 

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