ADVERTISEMENT RETURN TO ISSUEEditorialNEXTProfessor A. Douglas Kinghorn. A Lifetime Career Dedicated to Outstanding Service to Natural Product SciencesMarcy J. BalunasMarcy J. BalunasUniversity of Connecticut, Storrs, Connecticut, United StatesMore by Marcy J. Balunashttp://orcid.org/0000-0003-2374-4048, Gordon M. CraggGordon M. CraggNIH Special Volunteer, Gaithersburg, Maryland, United StatesMore by Gordon M. Cragg, Simon GibbonsSimon GibbonsUniversity of East Anglia, Norwich Research Park, Norwich, U.K.More by Simon Gibbons, and Rachel MataRachel MataNational Autonomous University of Mexico, Mexico City, MexicoMore by Rachel Matahttp://orcid.org/0000-0002-2861-2768Cite this: J. Nat. Prod. 2021, 84, 3, 549–552Publication Date (Web):March 26, 2021Publication History Published online26 March 2021Published inissue 26 March 2021https://pubs.acs.org/doi/10.1021/acs.jnatprod.0c01371https://doi.org/10.1021/acs.jnatprod.0c01371editorialACS PublicationsCopyright © Published 2021 by American Chemical Society and American Society of Pharmacognosy. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views11537Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (1 MB) Get e-AlertscloseSUBJECTS:Cancer,Pharmaceuticals,Plants,Students,Teaching and learning methods Get e-Alerts

In the last 20 or so years, the influence of endophytes and, quite recently, epiphytes of plants upon the compounds found in those plants, which were usually assumed to be phytochemicals produced by the plant for a variety of reasons, often as a defense against predators, is becoming more evident, in particular in the case of antitumor agents originally isolated from plant sources, though antibiotic agents might also be found, particularly from epiphytes. In this review, we started with the first report in 1993 of a taxol-producing endophyte and then expanded the compounds discussed to include camptothecin, the vinca alkaloids, podophyllotoxin, and homoharringtonine from endophytic microbes and then the realization that maytansine is not a plant secondary metabolite at all, and that even such a well-studied plant such as Arabidopsis thaliana has a vast repertoire of potential bioactive agents in its leaf epiphytic bacteria. We have taken data from a variety of sources, including a reasonable history of these discoveries that were not given in recent papers by us, nor in other papers covering this topic. The sources included the Scopus database, but we also performed other searches using bibliographic tools, thus, the majority of the papers referenced are the originals, though we note some very recent papers that have built on previous results. We concluded with a discussion of the more modern techniques that can be utilized to "persuade" endophytes and epiphytes to switch on silent biosynthetic pathways and how current analytical techniques may aid in evaluating such programs. We also comment at times on some findings, particularly in the case of homoharringtonine, where there are repetitious data reports differing by a few years claiming the same endophyte as the producer.

This review is an updated and expanded version of the five prior reviews that were published in this journal in 1997, 2003, 2007, 2012, and 2016. For all approved therapeutic agents, the time frame has been extended to cover the almost 39 years from the first of January 1981 to the 30th of September 2019 for all diseases worldwide and from ∼1946 (earliest so far identified) to the 30th of September 2019 for all approved antitumor drugs worldwide. As in earlier reviews, only the first approval of any drug is counted, irrespective of how many "biosimilars" or added approvals were subsequently identified. As in the 2012 and 2016 reviews, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions, and the designation "natural product botanical", or "NB", to cover those botanical "defined mixtures" now recognized as drug entities by the FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or synthetic variations using their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from 1946 to 1980, of the 75 small molecules, 40, or 53.3%, are N or ND. In the 1981 to date time frame the equivalent figures for the N* compounds of the 185 small molecules are 62, or 33.5%, though to these can be added the 58 S* and S*/NMs, bringing the figure to 64.9%. 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, though as can be seen in the review there are still disease areas (shown in Table 2) for which there are no drugs derived from natural products. 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 still able to identify only two de novo combinatorial compounds (one of which is a little speculative) approved as drugs in this 39-year time frame, though there is also one drug that was developed using the "fragment-binding methodology" and approved in 2012. We have also added a discussion of candidate drug entities currently in clinical trials as "warheads" and some very interesting preliminary reports on sources of novel antibiotics from Nature due to the absolute requirement for new agents to combat plasmid-borne resistance genes now in the general populace. We continue to draw the attention of readers to the 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"; thus we consider that this area of natural product research should be expanded significantly.

ADVERTISEMENT RETURN TO ISSUEPREVEditorialNEXTSpecial Issue in Honor of Dr. Barbara N. TimmermannJohn H. Cardellina IIJohn H. Cardellina, IIReevesGroup, Virginia Beach, VirginiaMore by John H. Cardellina, II, Gordon M. CraggGordon M. CraggNIH Special Volunteer, Gaithersburg, MarylandMore by Gordon M. Cragg, David G. I. KingstonDavid G. I. KingstonVirginia Tech, Blacksburg, VirginiaMore by David G. I. Kingston, and David J. NewmanDavid J. NewmanNIH Special Volunteer, Wayne, PennsylvaniaMore by David J. NewmanCite this: J. Nat. Prod. 2019, 82, 3, 425–426Publication Date (Web):March 22, 2019Publication History Published online22 March 2019Published inissue 22 March 2019https://pubs.acs.org/doi/10.1021/acs.jnatprod.9b00008https://doi.org/10.1021/acs.jnatprod.9b00008editorialACS PublicationsCopyright © 2019 American Chemical Society and American Society of Pharmacognosy. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1262Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (1 MB) Get e-AlertscloseSUBJECTS:Cancer,Medicinal chemistry,Pharmaceuticals,Toxicology Get e-Alerts

The chapter on marine natural products with pharmacological properties covers molecules nominally produced by the organism from which they were first reported, with some overlap where it is now known that the actual producer is a microbe. Areas covered include toxins from Mollusca and Echinoderma, brominated compounds with antimicrobial activities, and antiviral compounds from Porifera including alkaloids and cyclic peptides, closing with a discussion of other pharmacological properties from marine invertebrates.

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTSpecial Issue in Honor of Professor Phil CrewsRobert H. Cichewicz, Gordon M. Cragg, Roger G. Linington, and Amy E. WrightView Author Information University of Oklahoma, Norman, Oklahoma, United States NIH Special Volunteer, Bethesda, Maryland, United States Simon Fraser University, Burnaby, British Columbia, Canada Harbor Branch Oceanographic Institute, Florida Atlantic University, Fort Pierce, Florida, United StatesCite this: J. Nat. Prod. 2017, 80, 3, 579–581Publication Date (Web):March 24, 2017Publication History Published online24 March 2017Published inissue 24 March 2017https://pubs.acs.org/doi/10.1021/acs.jnatprod.7b00161https://doi.org/10.1021/acs.jnatprod.7b00161editorialACS PublicationsCopyright © 2017 The American Chemical Society and American Society of Pharmacognosy. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1379Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (2 MB) Get e-AlertscloseSUBJECTS:Cancer,Molecular structure,Pharmaceuticals Get e-Alerts

In this review, we have attempted to describe all of the antibody–drug conjugates using a marine-derived compound as the “warhead”, that are currently in clinical trials as listed in the current version of the NIH clinical trials database (clinicaltrials.gov). In searching this database, we used the beta-test version currently available, as it permitted more specific search parameters, since the regular version did not always find trials that had been completed in the past with some agents. We also added small discussion sections on candidates that are still at the preclinical stage, including a derivative of diazonamide that has an unusual interaction with tubulin (DZ-23840), which may also be a potential warhead in the future.

This chapter describes the reader through recent applications of synthesis and the variations of synthetic biology and of synthetic chemistry blended with synthetic biology. It uses the two abbreviations Chem and Bio; the former refers to a chemical synthesis or partial chemical synthesis while the latter describes a biosynthesis or biological step. The chapter looks particularly at approaches that may be utilized to enable access to a series of analogues of natural products, with particular focus on natural products with antibiotic activities. Natural products are made by biomolecules and therefore naturally predisposed to interact with biomolecules; thus, as discussed above, they make an excellent starting point for drug discovery. Mutasynthesis enabling expansion of substrate scope is probably most clearly demonstrated for PKS and nonribosomal peptide synthetase biosynthetic pathways. Combinatorial biosynthesis, often referred to now as the synthetic biological modification of biosynthetic gene clusters, is the genetic manipulation of biosynthetic enzymes within or into a pathway.

This chapter provides the compounds as well as their activities in both enzyme inhibitory assays and orthogonal cell-based assays. It also provides a profile of Berkeley Pit Lake (BPL) and a brief history of its evolution from an abandoned mine into a dynamic ecosystem. However, when colleague Bill Chatham discovered green algae growing on a piece of wood floating just below the surface of BPL less than one mile from our laboratory, we were intrigued by the possibility that other microorganisms might be found in this acid lake. BPL is ground zero for the largest Environmental Protection Agency (EPA) Superfund site in North America. Despite its low pH, high oxidation potential (Eh), and high metal concentration, it harbors a population of extremophilic microbes that have yielded a collection of bioactive natural products with promising drug-like properties. The chapter focuses on microbes that could be isolated from waters and sediment of the Pit and grown in the laboratory in submerged culture.

Natural products possess unrivaled chemical and structural diversity and, correspondingly, a wide range of biological activities. Combinatorial biosynthesis is traditionally defined as the generation of natural product analogues through the use of genetic engineering of biosynthetic pathways. Platensimycin (PTM) and platencin (PTN) are a new class of promising antibiotic and antidiabetic drug leads. They are effective against a wide range of gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Mycobacterium tuberculosis. Complementary to chemical synthesis, combinatorial biosynthesis provides an alternative to generating natural product structural diversity. Natural product discovery has had a profound impact on modern human health and has inspired both biology and drug therapy. Discovery-based combinatorial biosynthesis can supplement the knowledge-based approach by discovering novel natural products, biosynthetic gene clusters, and enzyme functions. The power of combinatorial biosynthesis by discovery is the ability to probe Nature for a desired structural motif while allowing the rest of the natural product scaffold to change.

This chapter describes the reader through recent applications of synthesis and the variations of synthetic biology and of synthetic chemistry blended with synthetic biology. It uses the two abbreviations Chem and Bio; the former refers to a chemical synthesis or partial chemical synthesis while the latter describes a biosynthesis or biological step. The chapter looks particularly at approaches that may be utilized to enable access to a series of analogues of natural products, with particular focus on natural products with antibiotic activities. Natural products are made by biomolecules and therefore naturally predisposed to interact with biomolecules; thus, as discussed above, they make an excellent starting point for drug discovery. Mutasynthesis enabling expansion of substrate scope is probably most clearly demonstrated for PKS and nonribosomal peptide synthetase biosynthetic pathways. Combinatorial biosynthesis, often referred to now as the synthetic biological modification of biosynthetic gene clusters, is the genetic manipulation of biosynthetic enzymes within or into a pathway.

This chapter provides an overview of successful examples that highlight the power of the one strain many compounds (OSMAC) approach or of microbial cocultivation for an elicitation of bioactive fungal natural products that resulted either in an enhanced accumulation of constitutively present compounds, and/or in an accumulation of new natural compounds missing in axenic control cultures. The OSMAC concept is applied to explore changes of microbial metabolite profiles influenced by changing fermentation conditions, such as different media, different temperature regimes, different culture vessels, and other factors. Another approach that has proven highly successful in triggering the activation of silent biosynthetic gene clusters is the cocultivation of two or more different microbes together in one culture vessel rather than maintaining pure cultures. This strategy mimics the natural microbial ecosystem, defined as microbiome, where the microorganisms interact with each other in synergistic and/or antagonistic relationships, which are the driving ecological forces for triggering secondary metabolite biosynthesis.