Search

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 too toxic for direct use in humans and thus have to be chemically modified. By linking suitably modified compounds to monoclonal antibodies directed against specific epitopes in mammalian cancer cells, they can be delivered to a specific cell type in humans. This review updates and extends an article published in early 2017, demonstrating how by careful chemical modifications, highly toxic compounds, frequently peptidic in nature, can be utilized as antitumor drug candidates. The antibody-drug- conjugates (ADCs) discussed are those that are currently in clinical trials listed in the NIH Clinical Trials Registry as, "currently active, recruiting or in some cases, recently completed". There are also some ADCs discussed that are at the advanced preclinical stage, that in some cases, are repurposing current drug entities, and the review finishes with a short discussion of the aplyronines as potential candidate warheads as a result of scalable synthetic processes.

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 now becoming apparent that these and other plant-derived materials, plus similar agents from marine sources may well have a microbe in their background. In this short Opinion, evidence for such claims are presented for some of the agents currently in use or in preclinical and clinical trials against cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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 available to the research community for the screening of extracts and the isolation of bioactive natural products. However, despite the success of natural products in drug discovery, compatibility issues that make extracts challenging for liquid handling systems, extended timelines that complicate natural product-based drug discovery efforts and the presence of pan-assay interfering compounds have reduced enthusiasm for the high-throughput screening (HTS) of crude natural product extract libraries in targeted assay systems. To address these limitations, the NCI Program for Natural Product Discovery (NPNPD), a newly launched, national program to advance natural product discovery technologies and facilitate the discovery of structurally defined, validated lead molecules ready for translation will create a prefractionated library from over 125,000 natural product extracts with the aim of producing a publicly-accessible, HTS-amenable library of >1,000,000 fractions. This library, representing perhaps the largest accumulation of natural-product based fractions in the world, will be made available free of charge in 384-well plates for screening against all disease states in an effort to reinvigorate natural product-based drug discovery.

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. The application of new techniques and methodology developed through the impressive progress made in multidisciplinary, natural product-related research in recent years should aid substantially in expediting the discovery and development process. This review briefly outlines some of these developments as applied to a number of selected natural product examples, which may also include advances in chemical synthesis of derivatives with extended biological activities.

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. We have included brief discussions of the approved agents, where they are in trials to extend their initial approved activity (a common practice once an agent is approved), and have also included an extensive discussion of the use of auristatin derivatives as warheads, plus an area that has rarely been covered, the use of marine-derived agents to ameliorate the pain from cancers in humans, and to act as an adjuvant in immunological therapies.

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.

The influence of natural products upon drug discovery in general has been quite impressive; one only has to look at the number of clinically active drugs that are in use in cancer therapy to see how many either are natural products or have a natural pro-duct pharmacophore. What is now becoming quite apparent is that materials from natural sources are excellent probes (indicators) for cellular targets that when modulated, may well have a deleterious effect upon the cycling of a tumor cell through the conventional cell cycle. If the particular target is not expressed in normal cell cycling, then a directed "perturbation" of the tumor cell's cycle may well lead to a novel method of treatment for specific tumor types. In this review we have not attempted to be exhaustive but have given a current overview of how natural products from marine, microbial and plant sources have permitted in-depth analyses of various parts of the cell cycle under varying conditions with the ultimate aims of attempting to "control or perturb" the cycling of tumor cells in a fashion that permits their ultimate removal via cellular death, with a minimum of trauma to the host.

This year's American Society of Clinical Oncology International Symposium devoted 2 hours to a lively discussion of various aspects of anticancer drug discovery and development throughout the world. The scientific program started with an overview of efforts directed toward promoting international collaboration in natural product-derived anticancer drug discovery. This was followed by a discussion on the importance of interethnic differences and pharmacogenetics in anticancer drug development. Thereafter, this part of the program was completed by a description of the activities of the newly created Singapore-Hong Kong-Australia Drug Development Consortium and an overview of the contribution of Japan to anticancer drug development. The logistics and regulatory aspects of clinical trials with new anticancer agents in different parts of the world were then presented, with an emphasis on Europe, North America, and Japan. The program was completed with a panel discussion of the efforts to harmonize the exchange of clinical data originating from one region of the globe with other territories, with input from official representatives of the United States Food and Drug Administration and the Medical Devices Evaluation Center of Japan.

Nature has been a source of medicinal treatments for thousands of years, and plant-based systems continue to play an essential role in the primary health care of 80% of the world's population. Nature has provided many of the effective anticancer agents in current use, such as the microbially derived drugs, dactinomycin, bleomycin, and doxorubicin, and the plant-derived drugs vinblastine, irinotecan, topotecan, etoposide, and paclitaxel. The search for novel antitumor agents from natural sources continues with botanists, marine biologists, and microbiologists teaming up with chemists, pharmacologists, toxicologists, and clinicians in the investigation of coral reefs, rainforests, and deep subsurface thermal vents for novel bioactive compounds. The wealth of anticancer drugs of natural origin and critical aspects of the ongoing discovery and development process are discussed.