Journal of Natural Products Review tructural optimiza d high-throu bed bythe GSKoupbe byintere u ough combinatorial chemistry in one or more of its we to enc mpass all molecules ding biologic 54n being for drug ay,as c seen by inspect d 4 (s then in ely, research ngconducted by lopment as BAY-43-9006 and is a mu 。Shair Tan's,Waldr ann's,and Wipfs VEGFR-2,VEGFR-3,PDGFR-bet 3 of Chi by th other cou ntly,it is still in m tiple clinic once a drug is appr oved for an initial as ial svnthet I at the 1 in the a 2010 m ind N=135 NM.146.11 BB BN INB BND S ASNM BS ASINMI AF Figure 1.All new approved drugs d0g/n0.1021mp20o0as11 Nat Prod2012.75.311-355states that the first four rules do not apply to natural products nor to any molecule that is recognized by an active transport system when considering “druggable chemical entities”. 14−16 Recent commentaries on the “industrial perspective in regard to drug sources” 17 and high-throughput screening18 have been published by the GSK group and can be accessed by interested readers. Although combinatorial chemistry in one or more of its manifestations has now been used as a discovery source for approximately 70% of the time covered by this review, to date, we still can find only one de novo new chemical entity reported in the public domain as resulting from this method of chemical discovery and approved for drug use anywhere. This is the antitumor compound known as sorafenib (Nexavar, 1) from Bayer, approved by the FDA in 2005 for treatment of renal cell carcinoma, and then in 2007, another approval was given for treatment of hepatocellular carcinoma. It was known during development as BAY-43-9006 and is a multikinase inhibitor, targeting several serine/threonine and receptor tyrosine kinases (RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT, and FLT-3). It has been approved in Switzerland, the European Union, and the People’s Republic of China, with additional filings in other countries. Currently, it is still in multiple clinical trials in both combination and single-agent therapies, a common practice once a drug is approved for an initial class of cancer treatment. As mentioned by the present authors and others in prior reviews on this topic, the developmental capability of combinatorial chemistry as a means for structural optimization, once an active skeleton has been identified, is without par. An expected surge in productivity, however, has not materialized. Thus, the number of new active substances (NASs) from our data set, also known as new chemical entities (NCEs), which we consider to encompass all molecules, including biologics and vaccines, hit a 24-year low of 25 in 2004 (although 28% of these were assigned to the “ND” category), leading to a rebound to 54 in 2005, with 24% being “N” or “ND” and 37% being biologics (“B”) or vaccines (“V”), as we discuss subsequently. The trend to small numbers of approvals continues to this day, as can be seen by inspection of Figures 2 and 4 (see Discussion section below). Fortunately, however, research being conducted by groups such as Danishefsky’s, Ganesan’s, Nicolaou’s, Porco’s, Quinn’s, Schreiber’s, Shair’s, Tan’s, Waldmann’s, and Wipf’s, together with those of other synthetic chemists, is continuing the modification of active natural product skeletons as leads to novel agents. This was recently exemplified by the groups of Quinn19 and Danishefsky20 or the utilization of the “lessons learned” from studying such agents as reported by the groups of Tan21,22 and Kombarov23 to name just some of the recent publications. Thus, in due course, the numbers of materials developed by linking Mother Nature to combinatorial synthetic techniques should increase. These aspects, plus the potential contributions from the utilization of genetic analyses of microbes, will be discussed at the end of this review. Against this backdrop, we now present an updated analysis of the role of natural products in the drug discovery and development process, dating from January 1981 through December 2010. As in our earlier analyses,1−3 we have consulted the Annual Reports of Medicinal Chemistry, in this case from 1984 to 2010,24−50 and have produced a more comprehensive coverage of the 1981−2010 time frame through addition of data from the publication Drug News and Perspective51−71 and searches of the Prous (now Thomson￾Reuter’s Integrity) database, as well as by including information from individual investigators. As in the last review, biologics data prior to 2005 were updated using information culled from Figure 1. All new approved drugs. Journal of Natural Products Review 312 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335