Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019.

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.

Plant Endophytes and Epiphytes: Burgeoning Sources of Known and "Unknown" Cytotoxic and Antibiotic Agents?

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 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.

Current Status of Marine-Derived Compounds as Warheads in Anti-Tumor Drug Candidates.

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.

Antineoplastic Agents. 585. Isolation of Bridelia ferruginea Anticancer Podophyllotoxins and Synthesis of 4-Aza-podophyllotoxin Structural Modifications.

Cytotoxic constituents of the terrestrial plant Bridelia ferruginea were isolated using bioactivity-guided fractionation, which revealed the presence of the previously known deoxypodophyllotoxin (1), isopicrodeoxypodophyllotoxin (2), β-peltatin (3), β-peltatin-5-O-β-D-glucopyranoside (3a), and the indole neoechinulin (4). As an extension of previous podophyllotoxin research, SAR studies were undertaken focused on 4-aza-podophyllotoxin structural modifications. A number of such derivatives were synthesized following modifications to the A and E rings.

Drugs and Drug Candidates from Marine Sources: An Assessment of the Current "State of Play".

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 successes, but also to show that in a number of disease areas, there are structures originally isolated from marine invertebrates and free-living microbes that have potential, but will need to be "adopted" by pharmaceutical houses in order to maximize their potential.

Natural Products as Sources of New Drugs from 1981 to 2014.

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 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, 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 U.

Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents.

Throughout history, natural products have played a dominant role in the treatment of human ailments. For example, the legendary discovery of penicillin transformed global existence. Presently, natural products comprise a large portion of current-day pharmaceutical agents, most notably in the area of cancer therapy.

Endophytic and epiphytic microbes as "sources" of bioactive agents.

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 product of a microbe in, on or around the macroorganism.

New horizons for old drugs and drug leads.

There is mounting urgency to find new drugs for the treatment of serious infectious diseases and cancer that are rapidly developing resistance to previously effective drugs. One approach to addressing this need is through drug repurposing, which refers to the discovery of new useful activities for "old" clinically used drugs through screening them against relevant disease targets. A large number of potential drug that, for various reasons, have failed to advance to clinical and commercial use can be added to the candidates available for such purposes.

Marine-sourced anti-cancer and cancer pain control agents in clinical and late preclinical development.

The marine habitat has produced a significant number of very potent marine-derived agents that have the potential to inhibit the growth of human tumor cells in vitro and, in a number of cases, in both in vivo murine models and in humans. Although many agents have entered clinical trials in cancer, to date, only Cytarabine, Yondelis® (ET743), Eribulin (a synthetic derivative based on the structure of halichondrin B), and the dolastatin 10 derivative, monomethylauristatin E (MMAE or vedotin) as a warhead, have been approved for use in humans (Adcetris®). In this review, we show the compounds derived from marine sources that are currently in clinical trials against cancer.

Natural products: a continuing source of novel drug leads.

Background: Nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. Following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. Combinatorial chemistry (late 1980s), shifted the focus of drug discovery efforts from Nature to the laboratory bench.

The impact of the United Nations Convention on Biological Diversity on natural products research.

The discovery and development of novel, biologically active agents from natural sources, whether they be drugs, agrochemicals or other bioactive entities, involve a high level of interdisciplinary as well as international collaboration. Such collaboration, particularly at the international level, requires the careful negotiation of collaborative agreements protecting the rights of all parties, with special attention being paid to the rights of host (source) country governments, communities and scientific organizations. While many biodiversity-rich source countries currently might not have the necessary resources for in-country drug discovery and advanced development, they provide valuable opportunities for collaboration in this endeavor with research organizations from more high-income nations.

Natural products as sources of new drugs over the 30 years from 1981 to 2010.

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.

Antitumor Agents. 282. 2'-(R)-O-acetylglaucarubinone, a quassinoid from Odyendyea gabonensis as a potential anti-breast and anti-ovarian cancer agent.

A new quassinoid, designated 2'-(R)-O-acetylglaucarubinone (1), and seven known quassinoids (2-8) were isolated, using bioactivity-guided separation, from the bark of Odyendyea gabonensis (Pierre) Engler [syn. Quassia gabonensis Pierre]. The structure of 1 was determined by spectroscopic analysis and by semisynthesis from glaucarubolone.

Therapeutic agents from the sea: biodiversity, chemo-evolutionary insight and advances to the end of Darwin's 200th year.

Drugs from the sea? Darwin may not have considered this concept when he was thinking about mechanisms that drove diversification of life on earth. In recognition of his 200th year, and celebration of the publication in 1859 of his "On the origin of species", we review the global status of marine biodiscovery in medicinal fields, with a focus on the South Pacific. Furthermore, in the Darwinian spirit, we touch on putative evolutionary drivers and the chemical ecology of the successful leads.

Microbial antitumor drugs: natural products of microbial origin as anticancer agents.

This review discusses the role of microbial secondary metabolites produced by organisms from all three domains of life (the Archaea, Prokarya and Eukarya) as sources of pure natural products or derivatives of natural products, and as leads for novel synthetic compounds that may have the potential to ameliorate cancer. Drugs for which a microbe has either been identified as the producer of the active component or has been associated with its production based on circumstantial evidence are discussed. In addition, the impact of the increase in available genomic information and manipulation is discussed, along with some relevant examples, leading to the realization that the potential of microbes as sources of new leads/agents or as biological probes is large.

Natural product scaffolds as leads to drugs.

Numerous 'scaffolds' that have been identified in natural product structures have led to very significant numbers of approved drugs and drug candidates for a multiplicity of diseases over the years. In this mini-review, we discuss the base scaffolds (chemical skeletons) that we feel have produced very significant numbers of agents as drugs or drug leads and, in a number of cases, compounds that can be used as chemical synthons or that present activities in biological areas that were not obvious from their earlier history.