David J Newman

• D.Phil.
• Retired at National Cancer Institute (USA), National Institutes of Health

The phytochemical investigation of the rainforest plant Croton argyratus (Euphorbiaceae) led to the isolation of two halimane-type diterpenes, crotargyolides A (1) and B (2), with an uncommon γ-lactone ring at C-5 and C-9, together with a crotofolane-type diterpene, 3-hydroxylated crotofolin C (3, crokocrotogenoid A), and the known clerodane diterp...

A large proportion of the current pharmacopoeia can trace its origin back to nature. Biodiversity in the Earth’s largest habitat, the ocean, is greater than that on land, suggesting a huge potential for new bioactive chemistry. Compounds isolated from marine organisms have novel structures and modulate human disease targets with novel mechanisms of...

Eight vilasinin-class limonoids, including the unusually chlorinated rubescins K–M (1–3), the 2,3-epoxylated rubescin N (4), and rubescins O–R (5–8), were newly isolated from Trichilia rubescens. The structures of the isolated compounds were determined through spectroscopic and spectrometric analyses, as well as ECD calculations. The natural occurr...

Purpose of Review A discussion of the role of natural products as drugs and/or following partial or complete chemical synthesis, have been approved human use drugs in at least one country, or alternatively is/are the source of inspiration for further investigation. Recent Findings The blister beetle toxin pederin and the multiple structurally simi...

This review covers the recent history of a series of very important natural products and their derivatives that are currently in use or under evaluation in the areas of anti-infectives, important cancer treatments that include antibody drug conjugates, followed by a discussion of type 2 diabetes (T2DM) drugs and angiotensin converting enzyme inhibi...

Objective: Marine organisms continue providing significant chemical biodiversity that contributes to both the global preclinical and clinical pharmaceutical pipelines. A recently (2021) redesigned website www.marinepharmacology.org allows for easier and more frequent updates, thus highlighting the continuous progress in this area of marine pharmac...

Drug discovery from natural sources is going through a renaissance, having spent many decades in the shadow of synthetic molecule drug discovery, despite the fact that natural product-derived compounds occupy a much greater chemical space than those created through synthetic chemistry methods. With this new era comes new possibilities, not least th...

Due to the lack of new antibiotics with efficacy against the ESKAPE and other resistant microbes, coupled to the demise of major pharmaceutical company antibiotic discovery programs, due to a number of factors but mainly ROI calculations and the lack of efficacy of combinatorial chemistry as a substitute, the search for novel antibiotics may well h...

Drug discovery from natural sources is going through a renaissance, having spent many decades in the shadow of synthetic molecule drug discovery, despite the fact that natural product-derived compounds occupy a much greater chemical space than those created through synthetic chemistry methods. With this new era comes new possibilities, not least th...

Marine environments are underexplored terrains containing fungi that produce a diversity of natural products given unique environmental pressures and nutrients. While bacteria are commonly the most studied microorganism for natural products in the marine world, marine fungi are also abundant but remain an untapped source of bioactive metabolites. G...

For a significant number of years, scientists of many persuasions have assayed natural product materials, ranging from crude extracts to pure compounds, in a multitude of assays causally related to some biological processes. However, in a very significant number of submitted and published papers, what may be considered as “canned biological assays”...

Correction for ‘Antiviral drug discovery: preparing for the next pandemic’ by Catherine S. Adamson et al. , Chem. Soc. Rev. , 2021, 50 , 3647–3655, DOI: 10.1039/D0CS01118E.

Covering: 1981 to 2019Natural products continue to play a major role in drug discovery, with half of new chemical entities based structurally on a natural product. Herein, we report a cheminformatic analysis of the structural and physicochemical properties of natural product-based drugs in comparison to top-selling brand-name synthetic drugs, and a...

The National Cancer Institute's (NCI) Natural Products Repository is one of the largest and most diverse publicly available collections of natural product extracts used for drug discovery research. In this work, a new bispyrroloiminoquinone alkaloid was isolated from a Thai collection of the ascidian Clavelina sp. The structure of the new natural p...

Two bispyrroloiminoquinone alkaloids, wakayin (1) and a new natural product 16‐hydroxy‐17‐oxindole wakayin (2), were isolated from a Thai collection of the ascidian Clavelina sp. Herein, we present the isolation and structural elucidation of the new natural product and compare its NCI‐60 cytotoxic activity to the known analogue wakayin and a series...

This article covers microbially sourced antibiotics and anticancer agents that have either been approved by regulatory agencies (US and EU), are awaiting approval or are generally in Phases I–Phase III (cancer) or Phase I–IV (antibiotics). Also included are discussions of compounds that have been “developed” by synthetic chemists using as their tem...

As of early November 2020, there are 10 approved antibody drug conjugates (ADCs) plus two others that are not usually listed. In addition, there are 70 ADCs at stages from phase I to phase III and 23 that are at the preclinical stage. The warheads of all of these drugs and drug candidates have their origins in natural product structures. The source...

Clinically approved antiviral drugs are currently available for only 10 of the more than 220 viruses known to infect humans. The SARS-CoV-2 outbreak has exposed the critical need for compounds that can be rapidly mobilised for the treatment of re-emerging or emerging viral diseases, while vaccine development is underway. We review the current statu...

The chapter is designed to demonstrate both the past and current roles of natural products as drug entities and leads to new drug candidates. The examples are based upon the original natural product structure, their pharmacophores, and/or chemical isosteres of the parent compound. The compounds used as examples were originally isolated from marine,...

For millennia, medicinal plants have been the source of medicines initially for everyone, but since approximately the middle of the twentieth century, in the West, their use has been decreasing significantly as drugs that though frequently came directly from plants and/or microbes were substituted for direct usage of plant extracts or mixtures. Cur...

The reported numbers of Covid‐19 cases and deaths were compared for 18 countries (14 in Western Europe, plus Australia, Brazil, Israel and the USA) to assess the effect of historic and current national BCG immunizations. In view of the high death rate for Covid‐19 patients over 70 years of age, and given the fact that BCG vaccination is typically g...

The ocean’s organisms continue to deliver a chemical biodiversity that contributes to both the global preclinical and clinical pharmaceutical pipelines. Thus, in November 2019, the clinical marine pharmaceutical pipeline consisted of 9 approved marine‐derived drugs: for Herpes Simplex Virus, vidarabine (Vira‐A®, FDA‐approved 1976); for pain, zicono...

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 (e...

It is frequently assumed, particularly in the last 15 plus years, that “Natural Product Structures” are no longer a source of drugs in the twenty-first century. In fact, this is not at all true. Even today, in the search for novel agents against manifold diseases, natural product structures, some quite old and some quite recent, are behind the comp...

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 origi...

Volume 1 of Chemoinformatics of Natural Products lays down the fundamental concepts of chemical informatics and is exclusively dedicated to the investigation of natural products (NPs) or secondary metabolites (SMs), the main source of lead compounds for drug discovery. Several experts in the field, working in different continents and from diverse b...

The US National Cancer Institute’s Natural Product Repository is one of the world’s largest, most diverse collections of natural products containing over 230,000 unique extracts derived from plant, marine and microbial organisms that have been collected from biodiverse regions throughout the world. Importantly, this national resource is available t...

Seven new butanolides, peltanolides A–G (1–7), and two lignan glucosides, peltasides A (8) and B (9), along with eleven known compounds, 10–20, were isolated from a crude CH3OH/CH2Cl2 (1:1) extract of the fruit of Hernandia nymphaeifolia (Hernandiaceae). The structures of 1–9 were characterized by extensive 1D and 2D NMR spectroscopic and HRMS anal...

The isolation of 12 secondary metabolites, including seven new acetophenone monomers, from the 50% CH3OH/CH2Cl2 extract (N089419-L/6) of Acronychia trifoliolata was reported previously. In the present work, three new prenylated acetophenone dimers (1-3) and five known dimers (4-8) were isolated, and their structures were elucidated by using various...

With the discovery of penicillin in 1929 and the subsequent work that led to the later industrial production of this compound, it can be said that the “Golden Age of Antibiotics” began. This chapter will discuss, though not in detail, but with relevant current and past references, the early work on cyclic peptides, the semisynthesis of beta‐lactams...

A CH3OH-CH2Cl2 (1:1) extract (N025439) of the leaves and twigs of Cryptocarya laevigata furnished eight new compounds, 1-8. Based on extensive 1D and 2D NMR spectroscopic data examination, the new δ-lactone derivatives 1-6 are monoterpene-polyketide hybrids containing a unique spiro[3.5]nonenyl moiety. Their trivial names, cryptolaevilactones G-L,...

Botanical-based natural products are an important resource for medicinal drug discovery and continue to provide diverse pharmacophores with therapeutic potential against cancer and other human diseases. A prototype Traditional Chinese Medicine (TCM) plant extract library has been established at the US National Cancer Institute, which contains both...

The marine world is the largest underexplored ecosystem for bioactive compounds due to its inaccessibility beyond the intertidal, hindering the isolation of new chemical entities. There is reason to explore marine environments, as seven marine natural products have been approved by either the FDA or the EMA, five of which are derived from mutualist...

Introduction: The aim of this perspective is to discuss the current and potential situation concerning the loss of biodiversity and its current and potential effects upon the search for novel bioactive agents from natural sources, be they from marine, microbial or terrestrial environments. Areas covered: Herein, the author covers terrestrial plant...

Currently a few compounds isolated from marine sources have become drugs, mainly directed towards cancer and pain. Compounds from marine sources have exquisite potencies against eukaryotic cells, as they act as protective agents against attack by predators in the marine environment. Their toxicities act as a “double-edged sword” as they are often t...

Covering: 1957 to 2017 Algae constitute a heterogeneous group of eukaryotic photosynthetic organisms, mainly found in the marine environment. Algae produce numerous metabolites that help them cope with the harsh conditions of the marine environment. Because of their structural diversity and uniqueness, these molecules have recently gained a lot of...

The ocean's organisms continue to deliver a chemical biodiversity that contributes to both the global preclinical and clinical pharmaceutical pipelines. Thus, in November 2018, the clinical marine pharmaceutical pipeline consisted of seven marine‐derived drugs approved by the United States Food and Drug Administration (FDA) : for cancer, cytarabine...

TCM-based medications have been used for millennia in China and have always been "different" from current Western-based medicines in that they frequently are still mixtures of predominately plant products. From the early 20th Century, there has been a move to identify both the actual compounds in these mixes, and then over the past approximately 50...

Two new cassaine-type diterpenoids, namely erythrofordins D (1) and E (2), sourced from a Cameroon collection of Erythrophleum suaveolens were isolated and assessed for anti-tumor activity. In the NCI-60 cancer cell assay, erythrofordins D (1) and E (2) were found to be cytotoxic in the low micro molar ranges with a mean GI50 value of 2.45 and 0.71...

It is frequently assumed, particularly in the last 15 plus years, that “Natural Product Structures” are no longer a source of drugs in the twenty-first century. In fact, this is not at all true. Even today, in the search for novel agents against manifold diseases, natural product structures, some quite old and some quite recent, are behind the comp...

Sir Derek Barton’s seminal work on steroid conformational analysis opened up a new era of enquiry into how the preferred conformation of any molecule could have profound effects on its physical–chemical properties and activities. Conformation-based effects on molecular activity and reactivity continue to manifest, with one key area of investigation...

The initial sources of marine-derived compounds that on a small scale exhibited interesting biological activities, were often confined to collection levels ranging from <100 grams to a kilogram. Then if significant interest was shown, collections on a larger scale were made of the nominal source organism. Due to many reasons, including but not limi...

The pharmaceutical potential of the enormousbiodiversity of organisms present in the world's oceans continues to be the focus of intense global preclinical and clinical research. In October 2016 there were six marine‐derived drugs approved by the FDA : for cancer, cytarabine (Cytosar‐U®, Depocyt®, FDA‐approved 1969), eribulin mesylate (Halaven®, FD...

For millenia, plants have been a major source of medications against human and animal diseases. In the case of anticancer agents, a significant number of current agents can trace their source back to nominally plant secondary metabolites, with examples being taxol, vinca alkaloids, camptothecin (CPT), and their modified derivatives. However, it is...

Alangium longiflorum is currently in extinction crisis, which will likely severely hamper further phytochemical investigation of this plant species from new collections. A crude extract of leaves of A. longiflorum (N33539), collected for the U.S. National Cancer Institute in 1989, showed potent cancer cell line antiproliferative activity. A phytoch...

The US National Cancer Institute’s (NCI) Natural Product Repository is one of the world’s largest, most diverse collections of natural products containing over 230,000 unique extracts derived from plant, marine and microbial organisms that have been collected from biodiverse regions throughout the world. Importantly, this national resource is avail...

Six novel lactone derivatives, cryptolaevilactones A–F (1–6), were isolated from Cryptocarya laevigata. Their unique spiro[3.5]nonane moiety by hetero [2 + 2] cyclization with monoterpene and polyketide was found for the first time in nature. Structural elucidation using various nuclear magnetic resonance (NMR) techniques revealed that 1–3 and 4–6...

The ocean's organisms continue to deliver a chemical biodiversity that contributes to both the global preclinical and clinical pharmaceutical pipelines. Thus, in November 2017, the clinical marine pharmaceutical pipeline consisted of six marine‐derived drugs approved by the United States Food and Drug Administration (FDA) : for cancer, cytarabine (...

Although vancomycin has been in clinical use since the late 1950s, resistance due to alteration in the target microbe’s peptidoglycan can vary significantly, reducing its activity. Total synthesis of derivatives has now led to a molecule with very significant activity against resistant strains.

Natural products from marine invertebrates and microbes from terrestrial (and marine) sources together with higher plants have been an important source of many clinically useful anticancer agents. Over 60% of the current anticancer drugs have their origin in one way or another from natural sources. Some important examples include the vinca alkaloid...

The isolation studies of a crude MeOH/CH2Cl2 (1:1) extract (N005829) of the bark of Laetia corymbulosa yielded 15 new clerodane diterpenes, designated corymbulosins I–W (1–15), as well as four known diterpenes, 16–19. The structures of 1–15 were characterized on the basis of extensive 1D and 2D NMR and HRMS analyses. The absolute configurations of...

Since 2007, the US National Cancer Institute (NCI) Office of Cancer Complementary and Alternative Medicine (OCCAM), together with the Cancer Institute of the China Academy of Chinese Medical Sciences (CICACMS), institutes at China Academy of Sciences and Chinese Academy of Medical Sciences, have engaged in collaborations on Chinese medicine (CM) an...

With the advent of very rapid and cheap genome analyses and the linkage of these plus microbial metabolomics to potential compound structures came the realization that there was an immense sea of novel agents to be mined and tested. In addition, it is now recognized that there is significant microbial involvement in many natural products isolated f...

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 perm...

A bioactive CH3OH-CH2Cl2 (1:1) extract of the bark of Laetia corymbulosa provided five new clerodane diterpenes with an isozuelanin skeleton, designated as corymbulosins D-H (1-5), as well as the known corymbulosins B (6) and C (7), for which the relative configurations were not previously determined. The structures of 1-5 were characterized on the...

Twelve benzylisoquinoline alkaloids, including pavine and phenanthroindolizidine types, were isolated from a MeOH/CH2Cl2 extract of Cryptocarya laevigata (stem bark) through bioactivity-guided fractionation for antitumor effects. Selected compounds were evaluated for antiproliferative activity against five human tumor cell lines, including a multid...

In this short review, I am discussing the relatively recent awareness of the role of symbionts in plant, marine-invertebrates and fungal areas. It is now quite obvious that in marine-invertebrates, a majority of compounds found are from either as yet unculturable or poorly culturable microbes, and techniques involving “state of the art” genomic ana...

Seven new [acronyculatins I-O (1-7)] and four known acetophenone monomers were isolated from a CH3OH/CH2Cl2 (1:1) extract (N089419) of Acronychia trifoliolata provided by the U.S. National Cancer Institute (NCI, Frederick, MD, USA). Their structures were characterized by using various NMR and HRMS techniques. Among the known compounds, the structur...

Deficiency of mitochondrial complex I is encountered in both rare and common diseases, but we have limited therapeutic options to treat this lesion to the oxidative phosphorylation system (OXPHOS). Idebenone and menadione are redox-active molecules capable of rescuing OXPHOS activity by engaging complex I-independent pathways of entry, often referr...

Sequencing data for the Ndufa9 knockout cell line. (TIF)

Seahorse experiment for menadione, 2-methoxy-1,4-naphthoquinone and 2-methoxy-3-methyl-1,4,-naphthoquinone. This experiment was performed three times and a single representative experiment is shown. (TIF)

Primary data for a screen of ~40,000 natural product extracts using our luminescence-based complex I bypass assay. For extracts that were retested, only the first trial is included. Please see S2 Table for full data for retested extracts. (XLSX)

This file contains analytical data on the lapachone family of metabolites, including 1H NMR, 13C NMR, and HRESIMS spectra for lapachol (4), dehydro-?-lapachone (5), ?-lapachone (6), and dehydroiso-?-lapachone (7). Also included is the chiral HPLC chromatogram for dehydroiso-?-lapachone (7). (PDF)

This file contains analytical data on the chimaphilin family of metabolites, including 1H NMR, 13C NMR, and HRESIMS spectra for chimaphilin (1), 3-hydroxy-chimaphilin (2), and 3-chloro-chimaphilin (3). (PDF)

This table contains the data for the extract plates that were retested in the presence or absence of 125 nM antimycin. The data from the original testing day (?Trial 1?) is included for reference alongside the data from retesting (?Trial 2?). (XLSX)

This relatively short review demonstrates the very important role of the structures of the natural products adrenaline and relatives, in the design and subsequent approval of β-agonists and antagonists, and of modified nucleosides as anticancer, and in particular, antiviral agents against herpes (HSV), human immunodeficiency virus (HIV) and hepatit...

In October 2015 there were six FDA‐approved marine‐derived drugs: for cancer, cytarabine (Cytosar‐U®, Depocyt®, FDA‐approved 1969), eribulin mesylate (Halaven®, FDA‐approved 2010), trabectedin (Yondelis®, FDA‐ orphan drug approval 2005) being EU‐registered, and brentuximab vedotin (Adcetris®, FDA‐approved 2011); for pain, ziconotide (Prialt®, FDA‐a...

The potential of the marine environment to produce candidate compounds (structures) as leads to, or even direct drugs from, has been actively discussed for the last 50 or so years. Over this time frame, several compounds have led to drugs, usually in the area of cancer (due to funding sources). This review is designed to show where there have been...

This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from...

The utility of privileged natural product structures as “starting points” for medicinal chemistry syntheses is demonstrated using as models the arabinose-containing nucleosides that has led to the massive armamentarium of antiviral and antitumor agents now in use as human drugs. This example is then followed by discussions of alkaloids of varying s...

This relatively short review will cover the history of some potential drug entities whose beginnings were from Brazilian flora and fauna that led to scientific findings many years later that could not even have been thought of at the time of their initial discovery. The first two are the discoveries of the effects of peptidic toxins from the highly...

Note: This chapter reflects the opinions of the authors, not necessarily those of the US Government

The development of natural product-derived drugs has some unique problems associated with the process, which can be best described as the "problem of supply". In this short review, four examples are given demonstrating how the "supply problem" was overcome using as examples the development of Picato® from a plant, Kyprolis® modified from a microbia...

Covering: up to 2015Over the centuries, microbial secondary metabolites have played a central role in the treatment of human diseases and have revolutionised the pharmaceutical industry. With the increasing number of sequenced microbial genomes revealing a plethora of novel biosynthetic genes, natural product drug discovery is entering an exciting...

TP53 is the most frequently mutated gene in human cancer, and small-molecule reactivation of mutant p53 function represents an important anticancer strategy. A cell-based, high-throughput small-molecule screen identified chetomin (CTM) as a mutant p53 R175H reactivator. CTM enabled p53 to transactivate target genes, restored MDM2 negative regulatio...

Despite the recent decline of natural product discovery programs in the pharmaceutical industry, approximately half of all new drug approvals still trace their structural origins to a natural product. Herein, we use principal component analysis to compare the structural and physicochemical features of drugs from natural product-based versus complet...

Over the last 15 or so years, there have been multiple reports that "plant-derived" molecules such as paclitaxel, camptothecin, vinca alkaloids, hypericin etc., have been purified from fermented microbes (usually fungal isolates) that were endophytes of the "producing plant". We will discuss these and other reports of the production of molecules as...

Beginning with the report by Stierle and Strobel in 1993 on taxol(R) production by an endophytic fungus (Stierle et al., 1993), it is possible that a number of the agents now used as leads to treatments of diseases in man, are not produced by the plant or invertebrate host from which they were first isolated and identified. They are probably the pr...

Microorganisms continue to serve as valuable sources of natural product therapeutics for the treatment of disease, evidenced by roughly 50 % of approved small molecule antitumor drugs being either directly from or inspired by microbes. The continuous number of drugs derived from these agents that are approved each year remains unmatched by compound...

With the development of the self-contained underwater breathing apparatus (SCUBA) and other recently developed marine collecting techniques, numerous bioactive secondary metabolites have been isolated and characterized from eubacteria, archaea, and fungi. These microorganisms have adopted strategies to grow in marine environments, which, for the pu...