Selection methods, product-based

The compound selection methods described thus far can be used to select compounds for screening from an in-house collection, or to select which compounds to purchase from an external supplier. In combinatorial library design, however, it is necessary to select subsets of reactants for actual synthesis. The two main strategies for combinatorial library design are reactant-based selection and product-based selection. In reactant-based selection, optimized subsets of reactants are selected without consideration of the products that will result and any of the compound selection methods already identified can be used. An early example of reactant-based design is that already described by Martin and colleagues which is based on experimental design and where diverse subsets of reactants were selected for the synthesis of peptoid libraries [1]. 

In product-based selection, the properties of the resulting product molecules are taken into account when selecting the reactants. Typically this is done by enumerating the entire virtual library that could potentially be made. Any of the subset selection methods described previously could be used to select a diverse subset of products, however the resulting subset is very unlikely to represent a combinatorial subset. This process is known as cherry-picking and is synthetically inefficient as far as combinatorial synthesis is concerned. Synthetic efficiency is maximized by taking the combinatorial... 

Despite the greater computational complexity of product-based methods relative to reactant-based methods they can be more effective, especially when the aim is to optimise the properties of a library as a whole, such as diversity or the distribution of physicochemical properties [12,22,23]. In addition, product-based selection is usually more appropriate for focussed libraries which require consideration of the properties of the product molecules themselves. 

Many different methods have been developed both to measure diversity and to select diverse sets of compounds, however, currently there is no clear picture of which methods are best. To date, some work has been done on comparing the various methods however, there is a great need for more validation studies to be performed both on the structural descriptors used and on the different compound selection strategies that have been devised. In some cases, the characteristics of the library itself might determine the choice of descriptors and the compound selection methods that can be applied. For example, computationally expensive methods such as 3D pharmacophore methods are limited in the size of libraries that can be handled. Thus for product-based selection, they are currently restricted to handling libraries of tens of thousands of compounds rather than the millions that can be handled using 2D based descriptors. 

Figure 5.10 Virtual libraries product-based and reagent-based selection methods.

Figure 4 Schematic representation of a phage display-based selection method for directed enzyme evolution E enzyme, S substrate P product.

Product-based selection is much more computationally demanding than reagent-based selection. Typically, it requires the computational enumeration of the full virtual combinatorial library and calculation of the descriptors for all possible products, prior to the application of a subset selection method. Consider a three-component reaction with 100 reagents available at each substituent position and assume that the aim is to build a 10 x 10 x 10 combinatorial library. In reagent-based selection, this requires the calculation of descriptors for 300 compounds (100 + 100 + 100). In product-based design, however, the full library of 1 million compounds (100 x 100 x 100) must be enumerated and descriptors must be calculated for each product molecule. 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

In general, stabilizers function by reaction with proplnt decompn products. A number of methods have been described and a preliminary evaluation of these methods was conducted by several labs under a cooperative program. Based on results from these screening tests, the PicArsn spec tropho tome trie methods for available stabilizer and primary degradation products were selected for further study. The initial phase of this program was an attempt to standardize the necessary spectrophotometric factors. Significant differences with regard to the factors obtained... 

Sulfonic esters are most frequently prepared by treatment of the corresponding halides with alcohols in the presence of a base. The method is much used for the conversion of alcohols to tosylates, brosylates, and similar sulfonic esters. Both R and R may be alkyl or aryl. The base is often pyridine, which functions as a nucleophilic catalyst, as in the similar alcoholysis of carboxylic acyl halides (10-21). Primary alcohols react the most rapidly, and it is often possible to sulfonate selectively a primary OH group in a molecule that also contains secondary or tertiary OH groups. The reaction with sulfonamides has been much less frequently used and is limited to N,N-disubstituted sulfonamides that is, R" may not be hydrogen. However, within these limits it is a useful reaction. The nucleophile in this case is actually R 0 . However, R" may be hydrogen (as well as alkyl) if the nucleophile is a phenol, so that the product is RS020Ar. Acidic catalysts are used in this case. Sulfonic acids have been converted directly to sulfonates by treatment with triethyl or trimethyl orthoformate HC(OR)3, without catalyst or solvent and with a trialkyl phosphite P(OR)3. ... 

Sterilization of the finished drug delivery formulation is an important consideration often overlooked in the early design of lactide/glycolide delivery systems. Aseptic processing and terminal sterilization are the two major routes of affording an acceptably sterile product. Both of these methods are suitable for products based on lactide/glycolide polymers if proper care is exercised in processing or selection of the treatment procedures. 

Its major disadvantage is its selectivity it only detects endotoxin-based pyrogens. In practice, however, endotoxin represents the pyrogen that is by far the most likely to be present in pharmaceutical products. The LAL method is used extensively within the industry. It is used not only to detect endotoxin in finished parenteral preparations, but also in WFI and in biological fluids, such as serum or cerebrospinal fluid. 

Library design methods can be divided into reactant-based or product-based design. In reactant-based design, reactants are chosen without consideration of the products that will result. For example, diverse subsets of reactants are selected in the hope they will give rise to a diverse library of products. In product-based design, the selection of reactants is determined by analyzing the products that will be produced. 

Readers may note three imique features in this text. First, there is a substantial discussion of chemical reactions of all elements and many of their compounds, a practice abandoned nowadays by most modem reference and handbooks. Second, analytical methods are presented for identification and measurement of practically all entries. In many instances, the method is based on my own research and experience. Third, a preparation method is given for all entries. For most compoimds, more than one preparative method is presented, covering both laboratory and commercial production. Also, a brief history of the discovery and early production of selected elements is presented to serve as backgroimd against which modern methods may be judged and historical perspective maintained. 

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