Natural products: an evolving role in future drug discovery.

Throughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology. Within the sphere of cancer, a number of important new commercialised drugs have been obtained from natural sources, by structural modification of natural compounds, or by the synthesis of new compounds, designed following a natural compound as model. The search for improved cytotoxic agents continues to be an important line in the discovery of modern anticancer drugs. The huge structural diversity of natural compounds and their bioactivity potential have meant that several products isolated from plants, marine flora and microorganisms can serve as “lead” compounds for improvement of their therapeutic potential by molecular modification. Additionally, semisynthesis processes of new compounds, obtained by molecular modification of the functional groups of lead compounds, are able to generate structural analogues with greater pharmacological activity and with fewer side effects. These processes, complemented with high-throughput screening protocols, combinatorial chemistry, computational chemistry and bioinformatics are able to afford compounds that are far more efficient than those currently used in clinical practice. Combinatorial biosynthesis is also applied for the modification of natural microbial products. Likewise, advances in genomics and the advent of biotechnology have improved both the discovery and production of new natural compounds.

Natural products as leads to anticancer drugs.

https://pubs.rsc.org/en/Content/ArticlePDF/2016/NP/C6NP00021E

Recent advances in research on lignans and neolignans

This paper describes the substances of plant and marine origin that have anticancer properties. The chemical structure of the molecules of these substances, their properties, mechanisms of action, their structure–activity relationships, along with their anticancer properties and their potential as chemotherapeutic drugs are discussed in this paper. This paper presents natural substances from plants, animals, and their aquatic environments. These substances include the vinca alkaloids, mistletoe plant extracts, podophyllotoxin derivatives, taxanes, camptothecin, combretastatin, and others including geniposide, colchicine, artesunate, homoharringtonine, salvicine, ellipticine, roscovitine, maytanasin, tapsigargin, and bruceantin. Compounds (psammaplin, didemnin, dolastin, ecteinascidin, and halichondrin) isolated from the marine plants and animals such as microalgae, cyanobacteria, heterotrophic bacteria, invertebrates (e.g., sponges, tunicates, and soft corals) as well as certain other substances that have been tested on cells and experimental animals and used in human chemotherapy.

https://www.mdpi.com/1422-0067/19/11/3533/pdf

Anticancer Activity of Natural Compounds from Plant and Marine Environment

Many important bioactive compounds have been discovered from natural sources using bioactivity-directed fractionation and isolation (BDFl) [Balunas MJ, Kinghorn AD (2005) Drug discovery from medicinal plants. Life Sci 78:431–441]. Continuing discovery has also been facilitated by the recent development of new bioassay methods. These bioactive compounds are mostly plant secondary metabolites, and many naturally occurring pure compounds have become medicines, dietary supplements, and other useful commercial products. Active lead compounds can also be further modified to enhance the biological profiles and developed as clinical trial candidates. In this review, the authors will summarize research on many different useful compounds isolated or developed from plants with emphasis placed on those recently discovered by the authors’ laboratories as antitumor and anti-HIV clinical trial candidates.

Plant-derived natural product research aimed at new drug discovery.

Podophyllotoxin is a naturally occurring lignan with important antineoplastic and antiviral properties and supported by detailed understanding of their mechanism of action, and facilitated by chemical manipulations that have amplified their bioactivity, the podophyllotoxin analogues have advanced to the forefront of several areas of therapeutic and developmental chemotherapy. Additive and synergistic laboratory interactions with other cytotoxic drugs have been exploited to allow development of podophyllotoxin-based multidrug regimens, which are showing important activity in several malignancies, and many of its related analogues will complement conventional pharmaceuticals in treatment, prevention and diaganosis of disease, while at the same time adding value to agriculture. Additive and synergistic laboratory interactions with other cytotoxic drugs have been exploited to allow development of etoposide-based multidrug regimens, which are showing important activity in several malignancies. Extensive structural modifications of podophyllotoxin have been performed in order to obtain more potent and less toxic antitumour agents, which resulted in the widespread clinical introduction of two semisynthetic glucoconjugate analogues of etoposide and teniposide and newer agents with promising preclinical activity are in various stages of clinical assessment. As knowledge of molecular and biochemical mechanisms of action and resistance continues to expand, newer and better podophyllotoxin-based strategies for treatment of malignant disease are likely to evolve. This review provides a detailed discussion of research advances in the synthetic and medicinal chemistry of podophyllotoxin, and addresses the short history and pharmacological action of these compounds and further outlines the preclinical development and clinical trials of drugs in the pipeline and marketing approval. Finally, a systemic evaluation of novel and important analogues of podophyllotoxin and their contribution to the current structure-activity profile are considered. It is hoped that this review will be able to address the contributions of podophyllotoxin-related research to overall drug discovery and development and the role that this field will play in future.

Xuan Tian

Papers

Podophyllotoxin: Current Perspectives