Joumnal of Natural Products Review ough discussi in Figure S. we have not found any clinical trials reported on these of modifications of natural con ories used nds that are as follows tantino ar NBNadcot(thav vileged st may b time often found by random ates In overview of Results.Th zed in and onsubdivisions,the reader should ture a the adw ent in 2001 o red is the 30 years from 01/01/1981 to 12/31/2010: New roved drugs:With all source categories By sou of th (ue siPTK hibitors rated in the 2003 and have (Figure 3) er direc nhibit rces f small-molecule NCEs:By source/year N/NB/ND:By year (Figure 5) and trade names, nply produced by synth nd trade names,year d gr up for and source (Table 4) luct mimi dd co nsult the wHh20o9 tive drugs:All molecules,source,and number nd Anticancer drugs:Generic and trade names,year, cs of the sin II stn ng AT /AT照 tL-162313(3 sartans)into the (a pep udot ides lified by 4.which is nt（binding n and has a betre ll ha ng as repor products and structures derived from or reated tonatur the develop dd/0,1021/mp20os11e2012.75.11-35either in the tables or from the Supporting Information any reader who so desires may calculate their own particular variation(s) in Figure 5. As in our earlier reviews,1−3 the data have been analyzed in terms of numbers and classified according to their origin using the previous major categories and their subdivisions. Major Categories of Sources. The major categories used are as follows: “B” Biological; usually a large (>45 residues) peptide or protein either isolated from an organism/cell line or produced by biotechnological means in a surrogate host. “N” Natural product. “NB” Natural product “Botanical” (in general these have been recently approved). “ND” Derived from a natural product and is usually a semisynthetic modification. “S” Totally synthetic drug, often found by random screening/modification of an existing agent. “S*” Made by total synthesis, but the pharmacophore is/ was from a natural product. “V” Vaccine. Subcategory. “NM” Natural Product Mimic (see rationale and examples below). (For amplification of the rationales used for categorizing using the above subdivisions, the reader should consult the earlier reviews.1−3 ) In the field of anticancer therapy, the advent in 2001 of Gleevec, a protein tyrosine kinase inhibitor, was justly heralded as a breakthrough in the treatment of leukemia. This compound was classified as an “/NM” on the basis of its competitive displacement of the natural substrate, ATP, in which the intracellular concentrations can approach 5 mM. We have continued to classify PTK and other kinase inhibitors that are approved as drugs under the “/NM” category for exactly the same reasons as elaborated in the 2003 review2 and have continued to extend it to cover other direct inhibitors/ antagonists of the natural substrate/receptor interaction whether obtained by direct experiment or by in silico studies followed by direct assay in the relevant system. Similarly, a number of new peptidic drug entities, although formally synthetic in nature, are simply produced by synthetic methods rather than by the use of fermentation or extraction. In some cases, an end group might have been changed for ease of recovery. In addition, a number of compounds produced totally by synthesis are in fact isosteres of the peptidic substrate and are thus “natural product mimics” in the truest sense of the term. For further information on this area, interested readers should consult the excellent earlier review by Hruby,75 his 2009 “Perspective” review,76 and very recent work in the same area by Audie and Boyd77 and VanHee et al.78 in order to fully appreciate the potential of such (bio)chemistry. As an example of what can be found by studies on relatively simple peptidomimics of the angiotensin II structure, the paper of Wan et al.79 demonstrating the modification of the known but nonselective AT1/AT2 agonist L-162313 (2, itself related to the sartans) into the highly selective AT2 agonist 3 (a pep￾tidomimetic structure) led to the identification of short pseudopeptides exemplified by 4, which is equipotent (binding affinity = 500 pM) to angiotensin II and has a better than 20 000-fold selectivity versus AT1, whereas angiotensin II has only a 5-fold binding selectivity in the same assay,80 as reported in our 2007 review. The chemistry leading to these compounds was reported in 2007 in greater detail by Georgsson et al.,81 with a thorough discussion of the role of AT2 receptors in a multiplicity of disease states being published in 2008.82 To date, we have not found any clinical trials reported on these materials. In the area of modifications of natural products by combinatorial methods to produce entirely different com￾pounds that may bear little if any resemblance to the original, but are legitimately assignable to the “/NM” category, citations are given in previous reviews.8,83−90 In addition, one should consult the reports from Waldmann’s group91,92 and those by Ganesan,93,94 Shang and Tan,95 Bauer et al.,21 Constantino and Barlocco,96 Bade et al.,97 and Violette et al.,98 demonstrating the use of privileged structures as a source of molecular skeletons around which one may build libraries. Another paper of interest in this regard is the editorial by Macarron from GSK,15 as this may be the first time where data from industry on the results of HTS screens of combichem libraries versus potential targets were reported with a discussion of lead discovery rates. In this paper, Macarron re-emphasizes the fifth Lipinski rule, which is often ignored: “natural products do not obey the other four”. Overview of Results. The data we have analyzed in a variety of ways are presented as a series of bar graphs and pie charts and two major tables in order to establish the overall picture and then are further subdivided into some major therapeutic areas using a tabular format. The time frame covered is the 30 years from 01/01/1981 to 12/31/2010: New approved drugs: With all source categories (Figure 1) New approved drugs: By source/year (Figure 2) Sources of all NCEs: Where four or more drugs were approved per medical indication (Table 1), with listings of diseases with ≤3 approved drugs Sources of small-molecule NCEs: All subdivisions (Figure 3) Sources of small-molecule NCEs: By source/year (Figure 4) Percent N/NB/ND: By year (Figure 5) Total small molecules: By year (Figure 6) Antibacterial drugs: Generic and trade names, year, reference, and source (Table 2) Antifungal drugs: Generic and trade names, year, reference, and source (Table 3) Antiviral drugs: Generic and trade names, year, reference, and source (Table 4) Antiparasitic drugs: Generic and trade names, year, reference, and source (Table 5) Anti-infective drugs: All molecules, source, and numbers (Table 6) Anti-infective drugs: Small molecules, source, and numbers (Table 7) Anticancer drugs: Generic and trade names, year, reference, and source (Table 8; Figure 7) All anticancer drugs (very late 1930s−12/2010): Generic and trade names, year, reference, and source (Table 9; Figures 8, 9) Antidiabetic drugs: Generic and trade names, year, reference, and source (Table 10) The extensive data sets shown in the figures and tables referred to above highlight the continuing role that natural products and structures derived from or related to natural products from all sources have played, and continue to play, in the development of the current therapeutic armamentarium of Journal of Natural Products Review 316 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335