IC50 of natural and synthetic analogs (50 cembranoids) in the bacterial biofilm and quorum sensing inhibition assays.
This chapter presents some significant study cases on octocoral organisms (Eunicea succinea, Eunicea mammosa, Eunicea knighti, Pseudoplexaura flagellosa, Eunicea laciniata, Antillogorgia elisabethae, Muricea austera, Paragorgia sp., Lobophyton sp., Sarcophyton glaucum and Sinularia lochmodes) that have been identified as a source of promising bioactive compounds and whose results have further been used for studies on structure-activity relationship (SAR) as a strategy to increase the value of the activity initially detected. The scientific literature data discussed here were obtained with the SciFinder tool during the period 2000–2016 and from the additional results here presented for the biofilm inhibition activity of compounds and synthetic analogs for the cases related with Eunicea knighti and Pseudoplexaura flagellosa (until now unpublished data of the authors of this chapter).
- marine natural products
- structure-activity relationship
- synthetic and natural analogs
Animals, plants and microorganisms of marine origin are suitable sources for the discovery and development of numerous medicines and industrial products. Among the 36 animal phyla described to date, 34 are represented in the marine environment, with about half being exclusively marine [1, 2]. Such statistics demonstrate the immense potential of marine biodiversity from which only a small percentage has been studied as a source of compounds useful to humans. The next few lines will briefly describe a very short history of marine natural products drug discovery, until today one of the major fields of application of marine natural products (extensive reviews on the subject can be found in Refs. [3, 4, 5, 6, 7, 8]).
Studies began in the early 1950s with the discovery of spongouridine and spongothymidine isolated from the marine sponge
Since then, thanks to tremendous efforts by scientists, to the improvement and easy access to better techniques of collection of organisms (snorkeling, scuba, submersibles, remote operated vehicles (ROVs)), to the discovery of modern techniques of chemical analysis and of biological activity, to the emergence of the “omic” approaches (genomics, proteomics, metabolomics, transcriptomics), to the recent genome mining approaches (exploitation of genome public data) for the discovery of new natural products, and to the use of molecular biology in the field of bioengineering, today approximately 25,000 bioactive marine compounds with novel structure are known, many of them with potential industrial use . Focusing only on the pharmaceutical industry, 8 marine compounds approved by the FDA and/or by the European Medicines Agency (EMEA) are on the market as therapeutic agents, 11 in different clinical phases, 1458 in the preclinical phase (the data on the compounds in the clinical and preclinical phases were taken as reported in recent references [3, 13, 14] and from A.M.S. Mayer’s website in the USA (http://marinepharmacology.midwestern.edu, accessed: 2017-01-30). In addition, there are many other compounds that remain in the laboratories of academic research groups or research centers waiting for the opportunity and adequate funding to enter the commonly so-called marine pharmaceutical pipeline, which allows them to start the path toward their conversion to new drugs.
Furthermore, it is worth mentioning that in parallel with the aforementioned studies, toward the first decade of the present century, numerous researchers turned their attention to look for new sources of bioactives, that is, marine microorganisms (cyanobacteria, marine fungi and other classes of Eubacteria) hoping to find new compounds and new activities, and because it began to be known that many compounds previously isolated from macroorganisms were actually produced by their associated microbes, as described in .
The aforementioned shows that marine organisms really are a fascinating source of molecules with unique structures and exploitable biologic activity. The following are some of the compounds of marine origin established in the market as therapeutic agents or used as industrial products [3, 13, 14]: compounds used in cancer treatment such as cytarabine (CytosarU™, Depocyt™) (mentioned above), trabectedina (Yondelis™), complex tetrahydroisoquinoline alkaloid obtained from tunicate
Among marine organisms source of bioactives, octocorals—a sub-class of Anthozoa—are a diverse group of colonial animals with 8 tentacle polyps and 8 internal mesenteries comprising about 3000 species (1.5% of all marine animals) of soft corals, gorgonians (sea fans, sea whips), sea pens and blue corals [15, 16] found throughout the world’s oceans. They have proven to be a prolific source of natural products having new structures, many of them without terrestrial-counterpart with relevant biological activities, which have been arising enormous interest both in the academic world and in the industry in the last 50 years. The first publication on octocorals came out in 1958 . Since then, many studies on metabolites from octocorals have been published in the chemical literature and biological activity and high-quality reviews have appeared on the subject. Among such important contributions, it is worth mentioning the article written by Coll in 1992 , the annual reviews initiated by Faulkner in 1984 until 2002  and continued by Blunt and his New Zealand group since 2003 , as well as the reviews by Rodríguez in 1995 , Berrue and Kerr in 2009 , Berrue et al. in 2011 , Almeida et al. in 2014 , Hu et al. in 2015  and by Lei et al. in 2016 . According to all these published data, the chemical constituents of octocorals are mostly steroids, acetogenins, sesquiterpenes and numerous diterpenes (with at least 40 skeletal classes) and diterpenes glycosides (compounds unique to gorgonians), exhibiting biological activities such as ichthyotoxic, antimicrobial, anticancer or/and cytotoxic, antiviral, antiinflammatory, antiproliferative, feeding stimulation, feeding deterrent, antipredatory, antifouling, antileishmanial, antiplasmodial and antiHIV-1, among others.
All the studies mentioned above clearly show that the natural products from Cnidaria (mostly corals) and from Porifera (mostly sponges) accounting for 56.89% of the total reported marine bioactives  have become a very attractive source of study for scientists, with the added value of being exploited industrially, particularly in pharmacology. However, for a compound discovered in a laboratory to be transformed in an industrial product, it is first necessary to maximize its biological activity and face the big problem of the sustainable supply (as mentioned in the literature : whatever the use given to the compound,
These current problems are critical in the industrial development of natural products and have lead to the development of new alternate ways such as preparation of synthetic or hemisynthetic analogs, among other applications, enhancing the activity and designing pharmacophores of lower complexity that can then be synthesized by faster and easier routes.
For this reason, this chapter aims to show some studies of the scientific literature in the last 15 years, where octocorals emerge as an excellent source of bioactive compounds and how the increase in their activity has been achieved through the use of the structure-activity relationship (SAR) strategy. This method has become a powerful tool for the discovery of new bioactive compounds and to promote the activity by converting bioactive compounds through synthesis into chemical analogs. Furthermore, we will discuss how the preparation of analogs could also be a way of helping the key current problem of material supply in a sustainable manner. Finally, we will present some recent unpublished experimental data from our laboratory where the isolation of terpenoids and some of their natural homologs from octocorals, and their conversion by chemical synthesis into compounds with higher biological activity have been a good strategy to achieve the aforementioned purposes.
2. SAR study cases in octocorals (2000–2016)
The studies highlighted in this item show the results of the literature survey using the SciFinder tool between 2000 and 2016, of some relevant studies reported, describing natural analogs and semi-synthetic derivatives prepared as a strategy to promote biological activity of compounds isolated from octocorals. The analyzed cases are chronologically organized throughout the chapter and each SAR study appears in the chemical literature grouped under subheadings with the name of the corresponding species. Figure 1 presents some of octocoral species discussed here.
Eunicea succinea and Eunicea mammosa
Octocorals of the
In 2000, Puerto Rican scientists  synthesized a series of unusual analogs of natural cembranolides
As there is not much published information about the antiviral activity of dolabellanes isolated from soft corals, in 2014 Colombian and Brazilian researchers studied the dolabellanes diterpenoids 13-keto-1(R),11(S)-dolabella-3(E),7(E),12(18)-triene (
Eunicea knighti and Pseudoplexaura flagellosa
In this section, we show our recent published results on quorum sensing inhibition (QSI) and our until now unpublished biofilm inhibition data, related as antipathogenic activity of natural compounds isolated from
Quorum sensing (QS) is defined as a phenomenon related to the gene expression of bacteria in function of the density of their population, allowing the synchronization of phenotypes through bacterial communication. Recently, quorum sensing has been recognized as one of the main factors that regulates phenotypes such as bioluminescence, transfer of tumor-inducing plasmids (Ti plasmids), antibiotic production, swarming motility, biofilm maturation (assembled bacterial communities that coordinate themselves for the expression of different phenotypes that change over time and with the environment) and the production of virulence factors . Many bacteria do not express virulence factors until the population density is high enough to overwhelm host defense and establish infection. Compounds with QS inhibitory activity are capable of preventing bacterial communication and suppress some virulence factors. These compounds have been termed as antipathogenic drugs . Furthermore, some QS inhibitor makes biofilms susceptible to antimicrobial treatments and can reduce mortality and virulence in experimental models of infection. Thus, compounds with QSI and biofilm inhibition activity can be considered as leads to antipathogenic drugs .
In the last 10 years, many researchers have focused their studies on marine metabolites, mainly from octocorals , that exhibit antipathogenic activity, which involve, as mentioned, QSI and biofilm inhibition activity. As previously described by Tello and colleagues in 2009, 2011 and 2012 [32, 33, 34], octocorals
|Assay||Biofilm Inhibition IC50 (ppm)a||Quorum sensing Inhibitionb (μg/disk)c|
Based on the results of QS inhibition (QSI) and biofilm inhibition, on their high amounts in the gorgonians and on the diverse reactive functional groups present in their structures (e.g. epoxide groups in the C-7 and C-8, hydroxy groups in the C-2 and C-18, reactive double bonds between the C-3/C-4 and C-11/C-12, and keto or hydroxy reactive groups in C-3, C-6 and C-11) six of the natural compounds were selected as lead compounds to improve their QSI activity and to establish their biofilm inhibition activity via preparation of synthetic analogs using regioselective, straightforward and reproducible reactions such as epoxide ring opening, oxidations, treatment with iodine, photochemicals, methylation and acetylation, and synthesis of cyclic hemiketals . In total, we had in hand 50 cembranoids (natural and synthetic) which were assayed for their QSI and biofilm inhibition activities. The results displayed in Table 1 estimate the correlation between QS and biofilm inhibition, demonstrating the potential antipathogenic effect of the 50 cembranoids evaluated, as discussed below.
The results demonstrated that half of the synthetic tested cembranoid analogs showed QSI activity without toxicity against the biosensor bacteria, results worth being highlighted, mainly because 16 active synthetic analogs were obtained from 5 non-active natural compounds (in QSI bioassay). The synthetic compounds with the best QSI activity were
The biofilm inhibition results showed that half of the synthetic analogs inhibited the formation of biofilm in the three bacterial strains used at concentrations lower than 100.0 ppm. It was found that several compounds that did not exhibit QSI did not show inhibition of biofilm formation either in the three biosensor strains evaluated, for example, compounds
In particular, 9 synthetic analogs inhibited
It is worth highlighting that the comparison of the results of the bacterial biofilm inhibition with the results found in the literature showed that the synthetic cembranoids analogs present an excellent activity and low toxicity compared to other natural products reported, for example, oroidin had an IC50 of 0.26 ppm against
Some considerations about the structure-activity relationship of the compounds evaluated in this bioassay must be taken into account, for example, the presence of an electronegative group on C-7 (in most of the compounds “oxygen”) is highly relevant for the activity, since the most active compounds presented this functionality. Also, the formation of a double bond with
In summary, six natural compounds were selected as lead compounds (
Antillogorgia elisabethae (Syn. Pseudopterogorgia elisabethae )
We have had a special interest in pseudopterosins G, and P-U, 3-
Their antiinflammatory activity was evaluated by us using
The results of the cytotoxicity of the natural homologous compounds PsG, PsP, PsQ, PsS, PsT, PsU, 3-O-acetyl-PsU,
Regarding the antimicrobial activity for the natural homologous
Additionally, it is important to mention that in our experiments published in Ref. , we assayed pseudopterosins and
Finally, it is worth mentioning the many studies carried out using the chemical synthesis (total synthesis and semi-synthesis) in order to increase the activity and to solve at least partly the problem of the sustainable supply of pseudopterosins. Those studies were conducted by Broka in 1988, Corey in 1989, 1990, 1998 and 2000, McCombie in 1990 and 1991, Buszek in 1995, Schmalz in 1997, Kociensk in 2001, and Harroweven in 2004 (complete information on this topic can be found cited and widely commented in Ref. ). Unfortunately, the mentioned syntheses have not yet been used, perhaps due to the complexity or/and non-economically ways of the synthetic routes applied. However, those efforts have provided information on improvement of their biological activity, pharmacophore and mechanism of action. Moreover, it is worth noting that semi-synthetic alkoxy or phenoxy substitution such as ether and acetate derivatives of pseudopterosins are under patent protection .
At this point, we want to mention the recent studies reported in  where simplified synthetic analogs of pseudopterosins
Given the antiplasmodial activity displayed by natural tyramine derivatives
The octocoral genus
In addition the authors obtained by simple and fast synthesis in the laboratory, the three natural products
Furthermore, to obtain different synthetic analogs, the authors used XCH2CH2NHCOCH3 (X = O or NH) instead of sulfur derivate and prepared analogs with different oxidation patterns at the A-ring. In this way, more than 20 steroids were prepared. These analogs were assayed for their cytotoxic activity against HT-29, A-549 and MDA-MB-231 cell lines. Analog
The six synthetic cembranoids were also evaluated against the same cell lines and the results showed that the derivative O-methyl decaryiol
An interesting example related to the topic of this chapter is the one published by Tanaka et al. in 2013 . This study mentions lectin SLL-2 isolated from octocoral
As we have shown throughout this chapter, there is no doubt that chemical synthesis plays an important role in the bioprospection of chemical compounds isolated from octocorals, either in the production of the bioactive natural product (supply a natural product), facilitating the further ways of its development as a drug and its subsequent commercialization or in the obtaining of a series of analogs that undoubtedly reveal important features on the interaction of the bioactive molecule and its target, allowing the chemists of marine natural products to change at convenience the activity and toxicity initially detected in the isolated compounds and sometimes even to reach the establishment of the pharmacophore. However, it is also a fact that this strategy has important limitations to consider, among them that the chemical reactions used must be efficient, with the fewest possible steps, economical viable option, easy to perform and to supply products with significant values of biological activity and without by-side toxicity.
The studies using the strategy analyzed in this chapter, suggest in most cases that the natural compounds can be potential scaffolds for the design of potent bioactive leads against different biological targets. In addition, the results indicate that a subtle structural change on the lead compounds can dramatically affect the activity and the selectivity of the structure against the different activities evaluated. The above corroborate that the assessment of the synthetic analogs of this chapter appear to be attractive targets for the development of new anticancer, antiinflammatory, antiviral, antimicrobial, antileishmanial, antiplasmodial and antipathogenic agents. However, this strategy should be accompanied by in silico studies that allow to establish the mechanisms of interaction between the proteins involved in the different biological activities mentioned above with the substrates (natural and synthetic analogs), Thus, the work will be carried out in a more effective way, translating into shorter times and in an adequate investment of resources used in this strategy.
It is important to highlight in this section that for the case of the octocorals
The authors would like to thank Universidad Nacional de Colombia and Universidad de La Sabana for the financial support provided for this project. Also thanks to Prof. Dr. Mónica Puyana (MP), Prof. Dr. Sven Zea (SZ), PI. Dr. Marcelino Gutierrez (MG), AD. Dr. Lucie Pautet (LP) and PI. Dr. Rogelio Fernandez (RF) for the photos of the octocorals.
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