Unraveling Plant Natural Chemical Diversity for Drug Discovery Purposes

Abstract

The screening and testing of extracts against a variety of pharmacological targets in order to benefit from the immense natural chemical diversity is a concern in many laboratories worldwide. And several successes have been recorded in finding new actives in natural products, some of which have become new drugs or new sources of inspiration for drugs. But in view of the vast amount of research on the subject, it is surprising that not more drug candidates were found. In our view, it is fundamental to reflect upon the approaches of such drug discovery programs and the technical processes that are used, along with their inherent difficulties and biases. Based on an extensive survey of recent publications, we discuss the origin and the variety of natural chemical diversity as well as the strategies to having the potential to embrace this diversity. It seemed to us that some of the difficulties of the area could be related with the technical approaches that are used, so the present review begins with synthetizing some of the more used discovery strategies, exemplifying some key points, in order to address some of their limitations. It appears that one of the challenges of natural product-based drug discovery programs should be an easier access to renewable sources of plant-derived products. Maximizing the use of the data together with the exploration of chemical diversity while working on reasonable supply of natural product-based entities could be a way to answer this challenge. We suggested alternative ways to access and explore part of this chemical diversity with in vitro cultures. We also reinforced how important it was organizing and making available this worldwide knowledge in an "inventory" of natural products and their sources. And finally, we focused on strategies based on synthetic biology and syntheses that allow reaching industrial scale supply. Approaches based on the opportunities lying in untapped natural plant chemical diversity are also considered.

Anticancer Activities and Mechanism of Action of Nagilactones, a Group of Terpenoid Lactones Isolated from Podocarpus Species

“…The compounds are usually obtained by extraction from different parts of the plants, but total enantio-selective syntheses have been developed as well, notably for the bioactive compounds such as Nag-F [62][63][64]. The availability of synthetic products is important to provide an easier access to these complex natural products and the supply of large quantities necessary to permit extended pharmacology and toxicology studies, and later to reach industrial scale supply [65]. Nagilactones are endowed with antifungal, anti-inflammatory, anti-atherosclerosis and anticancer activities, as reviewed here.…”

Tick Salivary Compounds for Targeted Immunomodulatory Therapy

“…Current therapies for immune-related illnesses usually have side-effects or suboptimal efficacy (7,8), leading to efforts to identify alternative therapies that might naturally inhibit and/or modulate specific immune system targets without significant off-target effects (9), including bioactive molecules derived from natural sources (10). Compounds with therapeutic potential have traditionally been extracted from plants (phytotherapy) (11), but other sources have included scorpion and snake venom (12,13) and arthropods (14). However, substances extracted from natural sources and applied in practice remain limited, and their clinical utility is hampered by the risk of contamination with impurities (15).…”

Natural Compounds: A Dynamic Field of Applications

“…The compounds produced by nature exhibit a great diversity of chemical structures as a result of the long, selective and evolutive process of species [1], and they constitute the active principles of natural products which have always contributed, a lot, to improve human living conditions [2]. As natural products have widespread uses in traditional medicine [3][4][5], and a wide range of biological effects demonstrated scientifically, they possess high scientific and industrial value [6][7][8][9].…”

“…Despite very significant advances in medicine, many diseases such as cancer, infections, diabetes and cardiovascular diseases remain without affordable, effective and safe therapy. Due to this, the most frequently explored area with relevant results is the development of new drugs from natural sources [7,8,[10][11][12][13][14], with natural product-based new drugs being 51% of small molecules approved and launched in the market between 1981 and 2014 [15].…”

“…Natural compounds are privileged structures because of their structural diversity and multiple biological activities. They are undoubtedly the ideal compounds for the rational design of new drugs and the development of new chemical entities with therapeutic potential [8,14]. Thus, research on natural compounds is necessary and very welcome.…”