Structure searching history

His main current complaints are that he cannot look for structures in WOS. He would like to have a plug-in that would retrieve all the full text of articles that he has located in a WOS search. Currently it takes lots of effort and clicks to go from the citations discovered in a search to pull in all the articles, and when they are downloaded, they have cryptic filenames. He feels it would be useful to have available a history of his search activities along with the search terms that would be automatically stored as the day went along. The ability to call up a previous search history in the rare instance that he would want to find again something he had a hard time locating earlier would be useful. 

The structural modification of natural products is useful in several ways. The known pharmacology of bisindole alkaloids is enriched by the diversity of chemical structures that are made available by structure modification and total synthesis. These molecules have served as biochemical probes in several areas of biology, especially in those of microtubule assembly and drug resistance. The most elusive prize, however, has remained the discovery of new compounds with clinical activity. In recent years several compounds have been evaluated in clinical trials, but vinblastine and vincristine remain the only bisindole alkaloids approved for the treatment of cancer in the United States. These compounds are joined by vindesine in Europe, and at least two new derivatives are the subject of ongoing clinical trials. Considering the breadth of chemical research in this area, the overall yield as measured by new compounds with clinical activity has been relatively low, but this observation is not unique in history of analog development in cancer research. Nevertheless, the search continues, and this chapter details the chemical endeavors to discover a new bisindole alkaloid with clinical activity. 

Any theoretical study of applied molecular evolution needs information on the fitnesses of the molecules in the search space, as it is not possible to characterize the performance of search algorithms without knowing properties of the landscape being searched [63], Since the ideals of sequence-to-structure or sequence-to-function models are not yet possible, it is necessary to use approximations to these relationships or make assumptions about their functional form. To this end, a large variety of models have been developed, ranging from randomly choosing affinities from a probability distribution to detailed biophysical descriptions of sequence-structure prediction. These models are often used to study protein folding, the immune system and molecular evolution (the study of macromolecule evolution and the reconstruction of evolutionary histories), but they can also be used to study applied molecular evolution [4,39,53,64-67], A number ofthese models are reviewed below. 

The early history of the search for non-Kekulean benzenoid systems (= systems for which no Kekule structural formula can be written = systems for which K = 0) is described elsewhere (see pp. 62-66 in [3]). Some time was needed for theoretical chemists to recognize that for large benzenoids it is not quite simple to decide whether K > 0 (Kekuleans) or K = 0 (non-Kekuleans). 

This subblock of the Heat Capacity Data Bank contains empirical as well as theoretical prediction calculations of the heat capacity which are continuously updated. Based on the chemical structure (back-bone, side-chain) as well as on the physical state (glass, crystal, mesophase, liquid, semicrystalline, equilibrium, history), a heat capacity is retrieved. The Prediction Scheme subblock can also be searched for its base, i.e., the precise assumptions which go into the prediction, with documentation to the 1iterature. 

F. Suppe, The Search for Philosophic Understanding of Scientific Theories , in F. Suppe (ed.). The Structure of Scientific Theories (Urbana, IL University of Illinois Press, 1974), pp. 3-232, p. 3. A more complete documentation of the issues covered in this chapter can be found in J. G. McEvoy, Positivism, Whiggism and the Chemical Revolution A Study in the Historiography of Science , History of Science, 35 (1997), pp. 1-33. 

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic drugs came this century when the two World Wars interrupted the supply of cinchona bark to the combatants. A structurally related 4-quinolinemethanol is mefloquine (65, Lari am [51773-92-3]), which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this drug such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

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