Natural product libraries compounds

Natural Product Inspired Compound Library Synthesis... 

Modern drug discovery approaches involve HTS, where, applying full automation and robotics, hundreds of molecules can be screened using several assays within a short time, and with very little amounts of compounds. In order to incorporate natural products in the modern HTS programmes, a natural product library (a collection of dereplicated natural products) needs to be built. Dereplication is the process by which one can eliminate recurrence or re-isolation of same or similar compounds from various extracts. A number of hyphenated techniques are used for dereplication, e.g. LC-PDA (liquid chromatography-photo-diode-array detector). 

While in the recent past it was extremely difficult, time consuming and labour intensive to build such a library from purified natural products, with the advent of newer and improved technologies related to separation, isolation and identification of natural products the situation has improved remarkably. Now, it is possible to build a high quality and chemically diverse natural product library that can be suitable for any modern HTS programmes. Natural product libraries can also be of crude extracts, chromatographic fractions or semi-purified compounds. However, the best result can be obtained from a fully identified pure natural product library as it provides scientists with the opportunity to handle the lead rapidly for further developmental work, e.g. total or partial synthesis, dealing with formulation factors, in vivo assays and clinical trials. 

Stewart et al. have also reported the efforts at Molecular Nature Ltd. to generate a pure natural product library [41], Compounds for this library were isolated utilizing parallel, normal phase column chromatography followed by C-18 and/or ion exchange chromatography. To be accepted into the library, the compounds must be > 90% pure with structural verification via a combination of HPLC, NMR, MS and GC/MS. 

A partial list of companies that sell natural products can be found at http //www.rechemical. com/natural-compounds. Several such companies have entered agreements with the same large pharmaceutical companies that were so eager to abandon in-house natural product groups. Such deals usually involve the supply of natural product samples or the provision of certain screens and targets as identified by the large companies against their natural products libraries to find new and novel natural product leads (Bouley, 2007 Rouhi, 2003). 

The selection and quality of a screening library with drug-like and lead-like structures is a critical endeavour. The features of drug-like and lead-like structures continue to be better defined, at the same time as the diversity of drug-like and lead-like molecular space continues to be explored and categorised. Other areas of development focus on the discovery of small molecules suitable for modulating protein-protein interactions, with a greater focus on natural product-like compounds. 

Natural Product-derived Compound Libraries and Protein Structure Similarity... 

The first part of the chapter covers several examples of stereoselective solution and solid-phase approaches to obtaining natural product analogs. The examples discussed here represent focused strategies to library generation that are based on specific bioactive natural products. These libraries have often served as natural product analogs in searches for better biological responses than those exhibited by the parent natural products. The generation of libraries of natural product-like compounds by solution and solid-phase synthesis methods is discussed in the second half. 

Fig. 17.13 The use oftetrahydroaminoquinoline and aminoindoline scaffolds in the library generation of natural product-like compounds and in silico testing of these two libraries as small molecule binders to Bcl-2/Bcl-XL...

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