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Journal ArticleDOI

The Role of Natural Product Chemistry in Drug Discovery

23 Nov 2004-Journal of Natural Products (American Chemical Society)-Vol. 67, Iss: 12, pp 2141-2153
TL;DR: To continue to be competitive with other drug discovery methods, natural product research needs to continually improve the speed of the screening, isolation, and structure elucidation processes, as well addressing the suitability of screens for natural product extracts and dealing with issues involved with large-scale compound supply.
Abstract: Although traditionally natural products have played an important role in drug discovery, in the past few years most Big Pharma companies have either terminated or considerably scaled down their natural product operations. This is despite a significant number of natural product-derived drugs being ranked in the top 35 worldwide selling ethical drugs in 2000, 2001, and 2002. There were 15 new natural product-derived drugs launched from 2000 to 2003, as well as 15 natural product-derived compounds in Phase III clinical trials or registration at the end of 2003. Recently, there has been a renewed interest in natural product research due to the failure of alternative drug discovery methods to deliver many lead compounds in key therapeutic areas such as immunosuppression, anti-infectives, and metabolic diseases. To continue to be competitive with other drug discovery methods, natural product research needs to continually improve the speed of the screening, isolation, and structure elucidation processes, as well addressing the suitability of screens for natural product extracts and dealing with issues involved with large-scale compound supply.

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Citations
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Journal ArticleDOI
TL;DR: Curcumin, a spice once relegated to the kitchen shelf, has moved into the clinic and may prove to be "Curecumin", a therapeutic agent in wound healing, diabetes, Alzheimer disease, Parkinson disease, cardiovascular disease, pulmonary disease, and arthritis.

1,897 citations


Cites background from "The Role of Natural Product Chemist..."

  • ...[2] Butler MS....

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  • ...016 Medicines derived from plants have played a pivotal role in the health care of many cultures, both ancient and modern [1–5]....

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Journal ArticleDOI
TL;DR: While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs in the future.

1,760 citations


Cites background from "The Role of Natural Product Chemist..."

  • ...In contrast, pharmaceutical leads originating from synthetic libraries are usually comparably easy to generate and modify using simple chemical approaches (Butler, 2004; Henrich and Beutler, 2013; Li and Vederas, 2009)....

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Journal ArticleDOI
10 Jul 2009-Science
TL;DR: Untapped biological resources, “smart screening” methods, robotic separation with structural analysis, metabolic engineering, and synthetic biology offer exciting technologies for new natural product drug discovery.
Abstract: Historically, the majority of new drugs have been generated from natural products (secondary metabolites) and from compounds derived from natural products. During the past 15 years, pharmaceutical industry research into natural products has declined, in part because of an emphasis on high-throughput screening of synthetic libraries. Currently there is substantial decline in new drug approvals and impending loss of patent protection for important medicines. However, untapped biological resources, "smart screening" methods, robotic separation with structural analysis, metabolic engineering, and synthetic biology offer exciting technologies for new natural product drug discovery. Advances in rapid genetic sequencing, coupled with manipulation of biosynthetic pathways, may provide a vast resource for the future discovery of pharmaceutical agents.

1,683 citations

Journal ArticleDOI
TL;DR: Several compounds from tropical rainforest plant species with potential anticancer activity have been identified and several compounds, mainly from edible plant species or plants used as dietary supplements, that may act as chemopreventive agents are isolated.

1,591 citations


Cites background from "The Role of Natural Product Chemist..."

  • ...As such, many pharmaceutical companies have eliminated or scaled down their natural product research (Butler, 2004; Koehn and Carter, 2005)....

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  • ...Drug discovery from medicinal plants led to the isolation of early drugs such as cocaine, codeine, digitoxin, and quinine, in addition to morphine, of which some are still in use (Newman et al., 2000; Butler, 2004; Samuelsson, 2004)....

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  • ...Pharmacognosists, phytochemists, and other natural product scientists will need to continuously improve the quality and quantity of compounds that enter the drug development phase to keep pace with other drug discovery efforts (Butler, 2004)....

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  • ...Despite the recent interest in molecular modeling, combinatorial chemistry, and other synthetic chemistry techniques by pharmaceutical companies and funding organizations, natural products, and particularly medicinal plants, remain an important source of new drugs, new drug leads, and new chemical entities (NCEs) (Newman et al., 2000, 2003; Butler, 2004)....

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  • ...…chemistry, and other synthetic chemistry techniques by pharmaceutical companies and funding organizations, natural products, and particularly medicinal plants, remain an important source of new drugs, new drug leads, and new chemical entities (NCEs) (Newman et al., 2000, 2003; Butler, 2004)....

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Journal ArticleDOI
TL;DR: A review of historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery, and a discussion of how natural product chemistry has resulted in the identification of many drug candidates are highlighted.
Abstract: Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Classical natural product chemistry methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. Many of these natural products have gone on to become current drug candidates. This brief review aims to highlight historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery. Furthermore a discussion of how natural product chemistry has resulted in the identification of many drug candidates; the application of advanced hyphenated spectroscopic techniques to aid in their discovery, the future of natural product chemistry and finally adopting metabolomic profiling and dereplication approaches for the comprehensive study of natural product extracts will be discussed.

1,282 citations


Cites background from "The Role of Natural Product Chemist..."

  • ...Doxorubicin (17) is used to treat acute leukaemia, soft tissue and bone sarcomas, lung cancer, thyroid cancer and both Hodgkins and non-Hodgkins lymphomas (Figure 5) [5,26]....

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  • ...Traditional medicinal practices have formed the basis of most of the early medicines followed by subsequent clinical, pharmacological and chemical studies [5]....

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  • ...Erythromycin (12) has broad spectrum activities against gram-positive cocci and bacilli and is used for mild to moderate, upper and lower respiratory tract infections [5,26]....

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  • ...The class of synthetic derivatives known as the bryologs, such as 53, are derived from bryostatin 1 (54), an antineoplastic compound isolated from the bryozoan, Bulgula neritina [5,113]....

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  • ...It is used for the treatment of severe infection and against susceptible organisms in patients hypersensitive to penicillin (7) [5]....

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References
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Journal ArticleDOI
TL;DR: An assessment of the number of molecular targets that represent an opportunity for therapeutic intervention is crucial to the development of post-genomic research strategies within the pharmaceutical industry.
Abstract: An assessment of the number of molecular targets that represent an opportunity for therapeutic intervention is crucial to the development of post-genomic research strategies within the pharmaceutical industry. Now that we know the size of the human genome, it is interesting to consider just how many molecular targets this opportunity represents. We start from the position that we understand the properties that are required for a good drug, and therefore must be able to understand what makes a good drug target.

3,037 citations

Journal ArticleDOI
TL;DR: From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well, and in the area of cancer, the percentage of small molecule, new chemical entities that are nonsynthetic has remained at 62% averaged over the whole time frame.
Abstract: This review is an updated and expanded version of a paper that was published in this journal in 1997. The time frame has been extended in both directions to include the 22 years from 1981 to 2002, and a new secondary subdivision related to the natural product source but applied to formally synthetic compounds has been introduced, using the concept of a “natural product mimic” or “NM” to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, the percentage of small molecule, new chemical entities that are nonsynthetic has remained at 62% averaged over the whole time frame. In other areas, the influence of natural product structures is quite marked, particularly in the antihypertensive area, where of the 74 formally synthetic drugs, 48 can be traced to natural product structures/mimics. Similarly, with the 10 antimigraine drugs, seven are bas...

2,985 citations

Journal ArticleDOI
TL;DR: Privileged substructures are believed to achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns.
Abstract: Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

2,620 citations

Journal ArticleDOI
17 Mar 2000-Science
TL;DR: The biotech industry is establishing itself as the discovery arm of the pharmaceutical industry, and in bridging the gap between academia and large pharmaceutical companies, the biotech firms have been effective instruments of technology transfer.
Abstract: Driven by chemistry but increasingly guided by pharmacology and the clinical sciences, drug research has contributed more to the progress of medicine during the past century than any other scientific factor. The advent of molecular biology and, in particular, of genomic sciences is having a deep impact on drug discovery. Recombinant proteins and monoclonal antibodies have greatly enriched our therapeutic armamentarium. Genome sciences, combined with bioinformatic tools, allow us to dissect the genetic basis of multifactorial diseases and to determine the most suitable points of attack for future medicines, thereby increasing the number of treatment options. The dramatic increase in the complexity of drug research is enforcing changes in the institutional basis of this interdisciplinary endeavor. The biotech industry is establishing itself as the discovery arm of the pharmaceutical industry. In bridging the gap between academia and large pharmaceutical companies, the biotech firms have been effective instruments of technology transfer.

2,551 citations

Journal ArticleDOI
17 Mar 2000-Science
TL;DR: Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are presented in this review.
Abstract: Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target. Target-oriented syntheses of these small molecules, individually or as collections (focused libraries), can be planned effectively with retrosynthetic analysis. Drug discovery can also involve screening small molecules for their ability to modulate a biological pathway in cells or organisms, without regard for any particular protein target. This process is likely to benefit in the future from an evolving forward analysis of synthetic pathways, used in diversity-oriented synthesis, that leads to structurally complex and diverse small molecules. One goal of diversity-oriented syntheses is to synthesize efficiently a collection of small molecules capable of perturbing any disease-related biological pathway, leading eventually to the identification of therapeutic protein targets capable of being modulated by small molecules. Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are presented in this review.

2,229 citations