Revicw PRODUCTS pubs.acs.org/np Natural Products As Sources of New Drugs over the 30 Years from 1981to2010 David J.Newman*and Gordon M.Cragg napbaacCTeagoaCar Supporting Information f the ere pud the 八Ay December 2010 for all We 盈员星宝品西星器金金胃名是】 or entities by the FDA and simila struc ug entity,is ral pro or directly c ed the of nat ural pro t tures is quit structures alth ed as methods of ontim structures and have been very suc recognition t significan nce It was we al product researd ■INTRODUCTION pr the cdata be prtestand-lone It has been 14 years since the publication of our first,eight yn the very and four since our last of human although there have bee At tend was m areas ch a ioned in our 2003 review in that,though cance to pot e arti large libraries of com ds,the shift rom t an arge time has nued.with the phasis no on e the design of small n by ins his process. including rsity orie with elimi ies that crept into the d a fe authors from the National Can 6, Special Issue:Special Issue n Honor of Gordon M.Cragg ACS Publications 器诗58 311 20090%11A0d2012.75.311-35 Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010 David J. Newman* and Gordon M. Cragg Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute−Frederick, P.O. Box B, Frederick, Maryland 21702, United States *S Supporting Information ABSTRACT: This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003, and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from January 1, 1981, to December 31, 2010, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2010 for all approved antitumor drugs worldwide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions and have added a new designation, “natural product botanical” or “NB”, to cover those botanical “defined mixtures” that have now been recognized as drug entities by the FDA and similar organizations. 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, over the time frame from around the 1940s to date, of the 175 small molecules, 131, or 74.8%, are other than “S” (synthetic), with 85, or 48.6%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are able to identify only one de novo combinatorial compound approved as a drug in this 30-year time frame. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the “host from whence it was isolated”, and therefore we consider that this area of natural product research should be expanded significantly. ■ INTRODUCTION It has been 14 years since the publication of our first,1 eight years since the second,2 and four years3 since our last full analysis of the sources of new and approved drugs for the treatment of human diseases, although there have been intermediate reports in specific areas such as cancer4,5 and anti-infectives,6 together with a more general discussion on natural products as leads to potential drugs.7 All of these articles demonstrated that natural product and/or natural product structures continued to play a highly significant role in the drug discovery and development process. That Nature in one guise or another has continued to influence the design of small molecules is shown by inspection of the information given below, where with the advantage of now 30 years of data, the system has been able to be refined. We have eliminated some duplicated entries that crept into the original data sets and have revised a few source designations as newer information has been obtained from diverse sources. In particular, as behooves authors from the National Cancer Institute (NCI), in the specific case of cancer treatments, we have continued to consult the records of the FDA and added comments from investigators who have informed us of compounds that may have been approved in other countries and that were not captured in our earlier searches. As was done previously, the cancer data will be presented as a stand-alone section from the beginning of formal chemotherapy in the very late 1930s or early 1940s to the present, but information from the last 30 years will be included in the data sets used in the overall discussion. A trend was mentioned in our 2003 review2 in that, though the development of high-throughput screens based on molecular targets had led to a demand for the generation of large libraries of compounds, the shift away from large combinatorial libraries that was becoming obvious at that time has continued, with the emphasis now being on small focused (100 to ∼3000 plus) collections that contain much of the “structural aspects” of natural products. Various names have been given to this process, including “diversity oriented syntheses”, 8−12 but we prefer to simply refer to “more natural product-like”, in terms of their combinations of heteroatoms and significant numbers of chiral centers within a single molecule,13 or even ”natural product mimics” if they happen to be direct competitive inhibitors of the natural substrate. It should also be pointed out that Lipinski's fifth rule effectively Special Issue: Special Issue in Honor of Gordon M. Cragg Received: November 14, 2011 Published: February 8, 2012 Review pubs.acs.org/jnp This article not subject to U.S. Copyright. Published 2012 by the American Chemical Society 311 dx.doi.org/10.1021/np200906s | J. Nat. Prod. 2012, 75, 311−335