Libraries natural products

Abel U, Koch C, Speitling M, Hansske FG. (2002) Modern methods to produce natural-product libraries. Curr. Opin. Chem. Biol. 6 453-458. 

Another example in which literature results were reanalyzed in view of the PSSC concept concerns the development of ligands for the farnesoid X receptor. The farnesoid X receptor is a transcriptional sensor for bile acids, the primary products of cholesterol metabolism, and plays an important role in lipid homeostasis. The farnesoid X receptor was, until recently, an orphan receptor, which means that no specific ligands existed for this receptor. Selective ligands for this receptor have been found in natural product libraries described by Nicolaou et al. The group of Nicolaou developed solid phase synthesis methods to make combinatorial libraries based on a benzopyran core structure. " A 10,000-membered combinatorial library based on the benzopyran core structure was synthesized and screened for activity on the farnesoid X receptor. The first specific ligands for the... 

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. 

Sumiya, E., Shimogawa, H., Sasaki, H., Tsutsumi, M., Yoshita, K., Ojika, M., Suenaga, K., and Uesugi, M. (2011). Cell-morphology profiling of a natural product library identifies. ACS... 

Most inhibitors in this latter class were initially discovered by screening natural-products libraries or by structurebased de novo design. The most interesting examples of the nonpeptidic inhibitors from this group are the independently discovered but structurally... 

Janota, K. Carter, G. T. 1998. Natural products library screening using LC/MS and LC/MS/MS. Proc. 46th ASMS Conf. Mass Spectrom. and Allied Topics (Orlando, Florida), 557. 

Only recently the progress in solid-phase synthesis has met the demands of the intrinsic complexity of natural product library synthesis on solid support [10]. The aim of this chapter is to describe the different approaches followed in this science and to highlight these with notable examples demonstrating the current state of the art. 

Fig. 1. Examples of natural product libraries by modification of core structures.

For a recent and comprehensive review of solution-phase and solid-phase synthesis of natural product libraries, see a) D. G. Hall, S. Manku, F. Wang,/. Comb. Chem. 2001, 3, 125-150 b) L. Wess-[ohann, Curr. Opin. Chem. Biol 2000, 4, 303-309 c) L. J. Wilson in Solid-Phase Organic Synthesis , K. Burgess (Ed.), Wiley-Interscience New York, 2000 d) C. Watson, Angew. Chem. Int. Ed. 1999, 38, 1903-1908. 

GENERATING AND SCREENING A NATURAL PRODUCT LIBRARY FOR CYCLOOXYGENASE AND LIPOXYGENASE DUAL INHIBITORS... 

GENERATING NATURAL PRODUCT LIBRARIES BY HIGH THROUGHPUT TECHNOLOGY... 

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. 

Bradshaw et al. have disclosed a rapid and facile method for the dereplication of a purified natural product library [58]. The method integrates the molecular weight from low resolution MS data with the exact count of the number of methyl, methylene and methine groups obtained from ]H-13C NMR correlation data. Those structure properties were converted into a searchable text file that could be downloaded into a customized software program with chemical structure information in a specific format - SMILES. In the program, more than 120,000 unique structures were derived from commercial databases, such as Dictionary of Natural Products and Beilstein. 

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). 

But despite these limitations, the supplementation of phytochemical data with ethnopharmacological information has been demonstrated to lead to higher hit rates in both the virtual and the actual screening of natural product libraries.76... 

The preparation of prefractionated natural product libraries for drug discovery can be made more efficient by automation. Automation reduces manpower requirements, improves efficiency and increases productivity. In addition, human errors are reduced and reproducibility is improved. Overall, automation increases throughput and can produce larger and more diverse screening libraries. 

In terms of HTS campaigns, there has been a move toward screening purified natural products libraries.6,7 Although more chemical diversity can be sampled from crude extract libraries or partially purified natural product libraries, pure... 

---