Leads from natural products

A Strategy for Rapid Identification of Novel Therapeutic Leads from Natural Products... 

These chemorational techniques have generated great interest in, and high expectations for, the acceleration of development of innovative pesticides. However, many purportedly successful appHcations of QSAR procedures have reHed on the quaHtative insights traditionally associated with art-based pesticide development programs. Retrospective QSAR analyses have, however, been helpful in identifying the best compounds for specific uses (17). Chemorational techniques have also found some appHcations in the development of pesticides from natural product lead compounds, the best known examples being the synthetic pyrethroid insecticides (19) modeled on the plant natural product, pyrethmm. 

Proponents of drugs from natural products argue that natural products provide a vast diversity of chemical compounds. These compounds with myriad chemical compositions and structures serve as reservoirs for many pharmacologically active lead compounds to be discovered. 

Matsui T, Matsumoto K. (2006) Anti-hypertensive peptides from natural resources. In Khan THM, Ather A. (eds). Lead Molecules from Natural Products Discovery and New Trends, pp. 255-271. Elsevier, Amsterdam. 

We have developed a rapid and systematic process for isolation and identification of biologically active components from natural products. The process reduces time and cost through application of advanced chromatographic instrumentation. It generates important activity and chemical information and also provides advanced active fraction(s) to accelerate isolation studies. As a result, lead prioritization, project management, and the cycle time of natural product lead discovery have been significantly improved. 

Rollinger JM, Langer T et al (2006) Strategies for efficient lead structure discovery from natural products. Curr Med Chem 13 1491-1507... 

Natural products are a reservoir of biologically active compounds. At the Natural Products Research Laboratories (NPRL) (Eshelman School of Pharmacy, University of North Carolina), our research focuses on the discovery of novel hits from natural products, followed by an extensive period of investigation whereby leads are identified and optimised, ultimately identifying new clinical trial candidates. 

Contributions by R. Joseph and P. Arya as well as M. A. Koch and H. Waldmann focus on synthetic aspects towards lead structures originating from natural product-derived scaffolds. R. Joseph and P. Arya refer to two complementary approaches, the synthetic access to focussed libraries around bioactive natural product cores, and diversity-oriented synthesis aiming at 3D scaffold diversity for hit generation, respectively. On the other hand, M. A. Koch and H. Waldmann emphasise the correlation of natural product-based library concepts with structural features of targeted protein domains, thus strengthening the privileged structure concept from a bioorganic viewpoint. 

Natural products have played a disproportionate role in the discovery of leads and the development of successful drugs. Close to 50% of the marketed drugs based on small molecules for the last 25 years have come from natural products, and the... 

Incremental innovation. This is a natural part of the continuous improvement process in corporations - traditional product development efforts leading from one product to its next generation. Here we can cite various specialty chemicals, such as de-watering agents, coating materials, or colorants whose product characteristics such as stabihty, color, and solubihty can be improved by further modification of the existing molecule or by mixing different substances. 

The traditional approach to drag discovery is based on rational drag design. Lead compounds, often structurally derived from natural products, are synthesized one at a time and are further optimized by a series of synthesis and screening steps. An important aspect is the structural characterization of reaction intermediates and end-products. MS and, given the nature of mai r of the compounds involved, LC-MS can play an important role in this. Often, molecular-mass determination with a soft ionization method leads to sufficient answers to the synthetic chemists. 

Exposure via dermal absorption and inhalation for hospital and veterinary personnel is common due to the use of DMSO in drugs. Industrial applications may lead to dermal and eye contact, and inhalation, with oral exposure a less likely route. The public may also be exposed via the use of DMSO in drugs, and to low levels via the environment (e.g., air and drinking water) via human uses and from natural productions (see below). 

Although serendipity is not a reliable source of new anticancer-drug leads, more molecules with interesting anticancer properties might still appear through chance in the future, especially from natural products. Second, synthetic chemistry has been used to modify drug leads discovered in plant material - the so-called semi-synthetic approach. 

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