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. As in the 2012 and 2016 reviews, 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 FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or synthetic variations using their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from 1946 to 1980, of the 75 small molecules, 40, or 53.3%, are N or ND. In the 1981 to date time frame the equivalent figures for the N* compounds of the 185 small molecules are 62, or 33.5%, though to these can be added the 58 S* and S*/NMs, bringing the figure to 64.9%. In other areas, the influence of natural product structures is quite marked with, as expected from prior information, the anti-infective area being dependent on natural products and their structures, though as can be seen in the review there are still disease areas (shown in Table 2) for which there are no drugs derived from natural products. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are still able to identify only two de novo combinatorial compounds (one of which is a little speculative) approved as drugs in this 39-year time frame, though there is also one drug that was developed using the “fragment-binding methodology” and approved in 2012. We have also added a discussion of candidate drug entities currently in clinical trials as “warheads” and some very interesting preliminary reports on sources of novel antibiotics from Nature due to the absolute requirement for new agents to combat plasmid-borne resistance genes now in the general populace. We continue to draw the attention of readers to the recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the “host from whence it was isolated”; thus we consider that this area of natural product research should be expanded significantly.
Introduction
It is now close to 23 years since the publication of our first review covering drugs from 1984 to 1995 (1) and 17 years since the second that covered the period from 1981 to 2002, (2) 12 years since our third covering the period 1981 to the middle of 2006, (3) seven years since we covered 1981 to 2010, (4) and almost five years since our last full analysis (covering the period 1981 to 2014), which was published in early 2016, (5) of the sources of new and approved drugs for the treatment of human diseases. In this current review, we have covered the almost five years from the first of January 2015 to the 30th of September 2019.
Since the last review, we have also published either together, independently, or with other authors a number of intermediate reports and/or standalone articles on natural products as drug leads or actual drugs. A partial listing includes the following: endophytic and epiphytic microbes as sources of bioactive natural products; (6−8) marine drug candidates; (9) a chemometric analysis of the natural product drugs in the 2016 review versus synthetic drugs; (10) a review of methods of “persuading” microbes to reveal their hidden genetic information; (11) natural product scaffolds of value in drug discovery; (12) a discussion on the value of marine-derived drugs; (13) the influence of nucleosides and adrenergic agents on drug discovery; (14) a discussion on the influence of Brazilian biodiversity on drug discovery covering the pederine-based drug candidates and the sources of ACE inhibitors; (14) the screening of natural product extracts to identify complex 1 bypass factors; (15) a review of currently uncultured microbes as sources of natural products; (16) a chapter on biodiversity and drug discovery (in a Brazilian book); (17) a review on marine-derived warheads for antitumor antibody–drug conjugates; (18) a review on current screening methods to identify natural product-based compounds; (19) a book chapter on microbial involvement in natural product production by organisms from all kingdoms; (20) a requested review on bioactive cyclic molecules and drug design; (21) a short discussion article on synthetic modifications of vancomycin structures to overcome resistance; (22) a chapter on natural products as antitumor compounds; (23) a chapter on pharmacological aspects of marine natural products, but not involving any antitumor agents; (24) a discussion piece covering the “true producers” of natural products from microbial sources; (25) a review discussing the use of both large-scale collections and genomic techniques with marine natural products; (26) a chapter on extremophilic marine fungi; (27) and a recent article on marine-derived agents as warheads in ADCs. (28) All these articles demonstrate that natural product and/or natural product structures continued to play a highly significant role in the drug discovery and development process.
In addition, for the benefit of new readers, we have shown in Table 1 the codes that we have used and modified over the years with the dates of the reviews in which we introduced them.
Table 1. Codes Used in Analyses
code
brief definition/year
B
biological macromolecule, 1997
N
unaltered natural product, 1997
NB
botanical drug (defined mixture), 2012
ND
natural product derivative, 1997
S
synthetic drug, 1997
S*
synthetic drug (NP pharmacophore), 1997
V
vaccine, 2003
/NM
mimic of natural product, 2003
That Nature in one guise or another has continued to influence the design of small molecules is shown by inspection of the information given below, where with the advantage of now almost 39 years of data from 1981 to the end of September 2019, the system has been refined in the following ways. We have eliminated some more duplicative entries that crept into the earlier data sets and continued to revise some source designations as newer information was obtained from diverse sources. In particular, as behooves authors originally from the National Cancer Institute (NCI), in the specific case of cancer treatments, we continued to consult the records of the FDA and added comments from investigators who have informed us of compounds that may have been approved in other countries and that were not captured in our earlier searches. As a slight modification from prior reports, we are presenting the cancer data in two time series: agents approved before the beginning of 1981 with the first “date” now being 1946, thus covering the molecules from 1946 to the end of 1980, then antitumor agents approved from 01JAN1981 to 30SEP2019. This avoids duplication in the relevant tables, and we have added a graphic demonstrating the total “sources” of approved antitumor agents from 1946 in the relevant sections later in the review.
A trend mentioned in our 2003 review, (2) namely, the shift away from large combinatorial libraries, has continued today, with the emphasis continuing to be on small focused (100 to ∼3000 plus) collections that contain much of the “structural aspects” of natural products. In previous reviews we described the various names given to these newer processes including “diversity-oriented syntheses”. As mentioned in our last (2016) review, (5) we still prefer to simply refer to such compounds as “more natural product-like” in terms of their combinations of heteroatoms and significant numbers of chiral centers within a single molecule as described in 2005 by Reayi and Arya. (29) Another term could be “natural product mimics” if they happen to be direct competitive inhibitors of the natural substrate, which was the origin of our subset listed as ?/NM. Although we have mentioned it before, Lipinski’s fifth rule effectively states that the first four rules do not apply to natural products nor to any molecule that is recognized by an active transport system when considering “druggable chemical entities”. We will reference those papers in this review that demonstrate this, as even today, many years later, synthetic chemists still do not (or will not?) take this into account. (30−32) We also suggest that, even though it is now seven plus years old, the paper by Koehn in 2012 be “mandated reading for chemists” interested in NP-based drug design. In that article, the list in their Table 1 shows the 26 drugs approved between 1981 and 2011, based on 18 natural product structures, that do not obey the “Rule of 5” and its strictures. (33) Following on from the Koehn article, in 2017, a group at AbbVie published an excellent and relatively short perspective in the Journal of Medicinal Chemistry showing the 12 FDA-approved drugs that are orally active and were approved from 2014 to 2016. Six of these drugs were for the treatment of HCV, four were antitumor agents, one was for the treatment of nausea from chemotherapy, and one was for cardiovascular treatment, with molecular weights ranging from 531 to 894 and cLogP values from −0.9 to 10.4. The paper is also worth reading for its discussion of the large number of AbbeVie compounds that are orally active and violate more than one of the Lipinski rules. The paper was online in late 2017 and formally published in 2018. (34) An earlier paper in 2014 by the Khilberg group also demonstrated that bioactive compounds can significantly violate the Lipinski rules and demonstrate oral bioactivity. (35)
Current examples of the use of small focused libraries (with “small” meaning less than 5000 compounds in a related library) are given in four recent papers. These range from the results of a 96-member quinone-based click chemistry library against Cdc25 phosphatases, demonstrating a potent and selective agent that was active against the vinca alkaloid-resistant cell line KB-vin; (36) the use of a peptide array synthesis based upon a microfluidic printing system from which 625 tetrapeptides were screened against the α4β1 integrin system identifying Arg-Ala and Ala-Asp constructs that did not bind to Jurket cells, thus demonstrating both the technique and discovery of potential structures with the desired activities; (37) and the use of the Waldmann BIOS system to discover a simplified structure derived from an indole alkaloid-like skeleton that inhibited the crm-1/NPM1 locus (structures 1, 2). (38) Then, very recently an extension of methodologies has demonstrated how compound libraries from (some) privileged structures can lead to compounds that would have been marked by the PAINS filters first established in the 2010 time frame and discussed in conjunction with the IMPs compounds in our 2016 review; these newly identified compounds now have utility as probes even though they would be marked by the PAINS filters. (39) Thus, one needs to be careful in rejecting compounds via automated processes. The IMPs and PAINS compounds referred to above were further discussed in a comprehensive though short paper in PLOS Pathogens in 2018 by Plemper and Cox, where they pointed out the large number of papers in the scientific literature that had given totally false impressions of the “value” of most of these compounds as viable leads to new drug entities, mainly from initial high-throughput screens. (40) This article contains interesting statistics on publications covering resveratrol and curcumin as false leads, thus demonstrating the value of the two review articles warning of the problems.
Even though combinatorial chemistry has now been used in one way or another as a discovery source for over 90% of the time covered by this review, to date, we still can find only three approved new chemical entities (NCEs) reported in the public domain: the antitumor compound known as sorafenib (Nexavar, 3) from Bayer, originally approved by the FDA in 2005 for treatment of renal cell carcinoma; ataluren (Translarna; 4), (41) which was approved in the EU in 2014; and, third (though not in chronological sequence), vemurafenib (5), approved by the FDA in 2011, which could be described as using a variation on “combichem”. This was the first (anticancer) drug constructed by use of fragment screening and model fitting,
To date we cannot find other examples, but as emphasized by the current authors, and a significant number of other authors in prior reviews on this topic, the developmental capability of combinatorial chemistry as a means for structural optimization, once an active skeleton has been identified, is without par. Two recent reviews, one in 2017 (42) and the other in 2018, (43) aptly demonstrate what can be achieved using bioactive compound collections and identifying their targets usually via phenotypic screening. However, as found in our 2016 review, which covered up to the end of 2014, although the numbers of approved drugs from worldwide sources (not simply the U.S. FDA, an error frequently made by authors when referencing our reviews) have moved upward, with figures ranging from 48 (for January through September of 2019) to 75 in 2018, a significant number fell into the “B” and “V” categories in those four and three-quarter years. The numbers in the “B” category would have been substantially higher, but we deliberately did not count any approvals of “biosimilars”, defined as a biological agent that was effectively identical to an earlier approved drug entity, in any country during this time frame, nor as done previously, did we count any approval aside from the first one irrespective of country/disease.
