Synthetic tractability

The chemical attributes of a lead series include knowing the chemical structure and purity of the hit(s). There are often cases where the activity of a screening sample cannot be confirmed when the compound is resynthesized and this can sometimes be traced to impurities in the original sample, and there are cases where the structure of the hit was not assigned correctly. In order to justify the resources required for lead optimization, it is important to know the structure of the lead. Synthetic tractability can... 

Cheminformatics methods are required to design screening libraries, enrich existing libraries, select diverse or focused subsets, and pre- or post-filter undesired or reactive compounds. At present more than 10 million unique compounds are commercially available for screening (http //www.emolecules.com/, http //www.chemnavigator.com) and the theoretical number of synthetically tractable compounds even with lead-like properties is enormous (Bleicher et al., 2003 Fink, Bruggesser, and Reymond, 2005). 

Fragment-based compound assembly tends to produce synthetically tractable structures. Purely atom-based construction has often resulted in molecules... 

Pfizer compound file Large pharma collection. Outsourced from ArQule, ChemRx, ChemBridge, and Tripos. > 2 X 10 U.S. 1 billion file enrichment program to expand diversity, dmg likeness, synthetic tractability, and rapid analog access. 15... 

Chlorophyll itself is rather unstable due to facile reactions at the 10 position. Pyropheophorbides, which lack substituents at this position, are much more stable and synthetically tractable. Thus, pyropheophorbide a, prepared from natural chlorophyll a, was used as the basis for triad 13 [58]. 

Most chemists will prioritize compounds based on potency and structure, the latter representing a combination of synthetic tractability and structural novelty. At this early stage, potency and structure may be all that s known about the confirmed hits anyway. They re certainly important because later on in the project compounds will need to be synthetically accessible, potent, and patentable. But that s just the start of the list. Plenty of other properties will be required too, including solubility, selectivity, stability, and cell permeability. An introduction to these properties and how one might begin to optimize for them is given in the following chapters. 

A few medicinal chemists in industry do their own modeling work. Some enjoy it, are proficient enough, and are willing to dedicate the time it takes. They might do this by choice or because they work for companies too small to have hired modelers yet. Most, however, do work with modelers. These valuable team members often have a background in organic synthesis so that they can tell which proposed structures are synthetically tractable and which aren t. 

Looked upon as a Cu-free click reaction with no apparent toxicity issues, the SPAAC reaction would appear to have a rich future. Still, the CuAAC reaction has the advantage of synthetic convenience due to the fact that terminal alkynes can be installed in biomolecules using simple building blocks, suh as commercially available alkynoic acids, while, in contrast, the synthesis of di uorinated cyclooctyne (DIFO) requires 12 steps and the overall yield is only about 1%. Synthetically tractable cyclooctynes having the reactivities of DIFO are therefore much needed in order to expand the use of this Cu free cUck reaction as an ef cient and biocompatible tool (Codelli et al., 2008). 

Alge, D.L., Azagarsamy, M.A., Donohue, D.F., Anseth, K.S. Synthetically tractable click hydrogels for three-dimensional cell culture formed using tetrazine-norbomene chemistry. Biomacromolecules 14,949-953 (2013)... 

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