Random Discovery

In practice there are different approaches to the development of new MCRs. These are random discovery or chance, combinatorial chemistry, rational and computer-assisted design and the concept of unions of MCRs, and these will be described in the following sections. 

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Random, Discovery, or Prospecting Libraries - the Quest for the Universal Scaffold... 

In the Pacific Northwest, at least four thousand mushroom species have been identified, with more than a dozen of these containing psilocybin. About three-quarters as many have been reported in Europe thus far. Mexico is the richest in psilocybin mycoflora. In fact, I have yet to find a single temperate or tropical habitat with high annual rainfall that lacks psilocybin mushrooms. But without some form of guidance, the random discovery of a psilocybin mushroom is, frankly, remote. In any region of the world, psilocybin mushrooms are greatly outnumbered by toxic mushrooms. 

In the absence of any external influence such as a catalyst which is biased in favor of one configuration over the other, we might expect structures [VIII] and [IX] to occur at random with equal probability as if the configuration at each successive addition were determined by the toss of a coin. Such, indeed, is the ordinary case. However, in the early 1950s, stereospecific catalysts were discovered Ziegler and Natta received the Nobel Prize for this discovery in 1963. 

Examination of the various classified listings of herbicides provides iasight iato the processes and approaches that lead to the discovery of new pesticides. The four principal development approaches are random screening, imitative chemistry, testing natural products, and biorational development. 

Historically, the discovery of one effective herbicide has led quickly to the preparation and screening of a family of imitative chemicals (3). Herbicide developers have traditionally used combinations of experience, art-based approaches, and intuitive appHcations of classical stmcture—activity relationships to imitate, increase, or make more selective the activity of the parent compound. This trial-and-error process depends on the costs and availabiUties of appropriate starting materials, ease of synthesis of usually inactive intermediates, and alterations of parent compound chemical properties by stepwise addition of substituents that have been effective in the development of other pesticides, eg, halogens or substituted amino groups. The reason a particular imitative compound works is seldom understood, and other pesticidal appHcations are not readily predictable. Novices in this traditional, quite random, process requite several years of training and experience in order to function productively. 

Commercial processes Commercial electroless nickel plating stems from an accidental discovery by Brenner and Riddell made in 1944 during the electroplating of a tube, with sodium hypophosphite added to the solution to reduce anodic oxidation of other bath constituents. This led to a process available under licence from the National Bureau of Standards in the USA. Their solutions contain a nickel salt, sodium hypophosphite, a buffer and sometimes accelerators, inhibitors to limit random deposition and brighteners. The solutions are used as acid baths (pH 4-6) or, less commonly, as alkaline baths (pH 8-10). Some compositions and operating conditions are given in Table 13.17 . 

Radioactivity The ability possessed by some natural and synthetic isotopes to undergo nuclear transformation to other isotopes, 513 applications, 516-518 biological effects, 528-529 bombardment reactions, 514-516 diagnostic uses, 516t discovery of, 517 modes of decay, 513-514 nuclear stability and, 29-30 rate of decay, 518-520,531q Radium, 521-522 Radon, 528 Ramsay, William, 190 Random polymer 613-614 Randomness factor, 452-453 Raoult s law A relation between the vapor pressure (P) of a component of a solution and that of the pure component (P°) at the same temperature P — XP°, where X is the mole fraction, 268... 

Tang Herbal, 147 Target-based drug discovery biological targets, 180-184 chemical end point in, 180 chemical tools, 178-179 definition of, 5 description of, 175-177 linear approach, 176 orphan receptors, 180 preclinical process in, 176-177 random variation in gene expression, 178... 

Combinatorial chemistry, a new chapter of organic synthesis, is now developing rapidly. This new approach to synthesizing large designed or random chemical libraries through application of solid phase synthetic methods, promises to revolutionize the process of drug discovery in the pharmaceutical industry.24... 

In drug discovery, a chemist usually begins by investigating compounds that have already shown medicinal value. A fruitful path is to find a natural product, an organic compound found in nature, that has been shown to have healing characteristics. Nature is the best of all synthetic chemists, with billions of chemicals that fulfill as many different needs. The challenge is to find compounds that have curative powers. These substances are found in different ways random or blind collection of samples that are then tested, or collection of specific samples identified by native healers as medically effective. 

The recently developed methodology for enzyme discovery that is based on random DNA isolation and subsequent screening (metagenome mining) is... 

The discovery that the 4-heteroarylpiperazine-l-carboxyanilide template can generate potent TRPVl antagonists was independently reported by three groups [76-79]. Most of the published work on this class of compounds was carried out by Purdue Pharma, and is focused on the optimization of (13a), a lead compound that had emerged from random screening of a chemical... 

The discovery of two new elements started a frenetic race to find more. Actinium was soon unearthed (Debierne 1900) and many other substances were isolated from U and Th which also seemed to be new elements. One of these was discovered somewhat fortuitously. Several workers had noticed that the radioactivity of Th salts seemed to vary randomly with time and they noticed that the variation correlated with drafts in the lab, appearing to reflect a radioactive emanation which could be blown away from the surface of the Th. This Th-emanation was not attracted by charge and appeared to be a gas, °Rn, as it turns out, although Rutherford at first speculated that it was Th vapor. Rutherford swept some of the Th-emanation into a jar and repeatedly measured its ability to ionize air in order to assess its radioactivity. He was therefore the first to report an exponential decrease in radioactivity with time, and his 1900 paper on the subject introduced the familiar equation dN/dt = - iN, as well as the concept of half-lives (Rutherford 1900a). His measured half-life for the Th emanation of 60 seconds was remarkably close to our present assessment of 55.6 seconds for °Rn. 

A joint research project between Lummus Technology and the Delft University of Technology led to the discovery of a new mesoporous material, named TUD-1 (8). TUD-1 is a three-dimensional amorphous structure of random, intercoimecting pores. The original emphasis was on the silica version, which has since been extended to about 20 chemical variants (e.g., Al, Al-Si, Ti-Si, etc.). 

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