Handbook of Naturally Occurring Compounds. Volume 1: Acetogenins, Shikimates, and Carbohydrates

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It advanced to Phase I clinical trials against solid tumors but was withdrawn in late [ 87 , 88 , 89 ]. Cryptophycin 37 was selected for clinical trials in the mid s then advanced to phase II trials but was terminated in due to toxicity and lack of efficacy Figure 11 [ 90 ]. Plitidepsin 34 , ET, Spisulosine 36 and Cryptophycin Algae macroalgae, seaweed are represented by at least 30, species worldwide supplying oxygen to the biosphere, food for fish and man, medicine and fertilizers as well as being a prolific source of structurally unique natural products [ 91 ]. The terpenoids are a class of compounds predominantly isolated from marine algae in the —s.

Chemical investigations into terpenoid-type structures have led to the isolation of many classes including brominated, nitrogen and oxygen heterocycles, phenazine derivatives, sterols, amino acids, amines and guanidine derivatives [ 92 ]. With respect to biological activity, green, brown and red algae have been intensively assessed for their antibacterial and antifungal activities [ 93 ].

Polycavernoside-A 38 isolated from the red alga Polycaverosa tsudai was suspected to be the toxic glycoside responsible for seafood poisoning, when, in thirteen people became ill and three died in Japan Figure 12 [ 94 , 95 , 96 ]. The brown alga, Dictyota dichotoma afforded diterpenes, 4-acetoxydictylolactone 39 , dictyolides A 40 , B 41 and nordictyolide 42 which display antitumor activities [ 97 , 98 ]. Another example is crenuladial 43 , isolated from the brown alga Dilophus ligatus which displayed antimicrobial activity against Staphylcoccus aureus , Micrococcus luteus and Aeromonas hydrophyla Figure 12 [ 98 , 99 ].

Red algae, in particular the genus Laurencia Rhodophyta , are unsurpassed as a source of halogenated sesquiterpenes. Chemical investigations into the genus Laurencia for secondary metabolites have been active since the s. The most commonly occurring secondary metabolites are the halogenated sesquiterpenes and diterpenes. Furthermore, this genus is unique in producing C 15 -acetogenins, for example those constituents which possess a terminal enyne such as 44 [ ].

Other examples include the class of compounds known as the chamigrenes, which are halogenated terpenes possessing unique structures such as 45 and 46 Figure There have been many chamigrenes, which have been isolated to date from the genus Laurencia , which grows in many very different geographical areas [ , , , ].

Carbohydrate Chemistry and Metabolism

Productivity in agriculture in the last half century has been as a result of advances in pest control due to synthetic chemical pesticides SCPs [ ]. However, the search for new pesticides has been necessary due to the significant rise in the resistance to current control agents.

As a result, a significant amount of research has focused on the isolation of insecticidal leads from marine algae. This has led to the isolation of over 40 active constituents [ ]. These compounds show insecticidal activity against the Aster leafhopper, Macrosteles fascifrons [ ]. Other examples include laurepinnacin 49 , an acetylenic cyclic ether from the red alga Laurencia pinnata Yamada [ ], and Z -laureatin 50 and related compounds from the red alga L.

These have all shown to display potent insecticidal activity against the mosquito larva, C. Sponges Porifera are sessile organisms, which lack a nervous, digestive and circulatory system and maintain a constant water flow through their bodies to obtain food, oxygen and to remove wastes. They are considered to be the first multicellular animals and have changed very little in approximately million years.

The first notable discovery of biologically active compounds from marine sources can be traced back to the reports of Bergmann on the isolation and identification of C -nucleosides, spongouridine 51 and spongothymidine 52 from the Caribbean sponge, Cryptotheca crypta in the early s Figure 14 [ ]. These compounds were found to possess antiviral activity and the synthesis of structural analogues led to the development of cytosine arabinoside Ara-C as a clinical anticancer agent, together with Ara-A as an antiviral agent 15 years later [ ].

This was an important discovery since previously it was believed that for a nucleoside to possess biological activity, it had to have a deoxyribose or ribose sugar moiety.

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These investigations led to the identification of Ara-C as a potent antileukemic agent [ ]. The class of synthetic derivatives known as the bryologs, such as 53 , are derived from bryostatin 1 54 , an antineoplastic compound isolated from the bryozoan, Bulgula neritina [ 5 , ]. Bryostatin 1 54 has been isolated in sufficient quantities to permit more than 80 clinical trials to date, with 20 being completed at both phase I and phase II levels Figure 15 [ 78 ].

It has displayed positive responses acting as a single agent with effects ranging from complete to partial remission [ 28 ]. From to date there were four Phase I and eight Phase II clinical trials, all combination studies with biologicals or cytotoxins against multiple carcinomas. Halichondrin B 55 has been isolated from several sponges including, Halichondria okadai Japan [ ]; Axinella sp. Halichondrin B 55 has been successfully synthesized [ ] along with several structural analogues including Halichondrin E 56 which has been selected for further development and is currently in phase III clinical trials for the treatment of breast carcinoma Figure 15 [ ].

These programs provided lead compounds for the treatment of cancer, microbial infections, hypercholesteremia and tissue rejection in organ transplantations [ , ]. However, many of the larger pharmaceutical companies decommissioned their NPD programs during the s and early s.

As a result, many of the pharmaceutical companies disbanded or sold their collections of screening extracts [ , ] as it was believed that traditional extract-based screening resulted in the continuous re-discovery of previously isolated compounds and that the structural complexity of natural products required total synthesis and derivatization which is both economically and synthetically problematic. Because of supply problems, the time required to develop a natural product from an extract hit to a pharmaceutical was deemed to be too long; HTS technologies rely on combinatorial chemistry to generate large compound libraries.

Nevertheless advances in technology and sensitive instrumentation for the rapid identification of novel bioactive natural products and structure elucidation continues to improve the natural product discovery process [ ]. From the s onwards it was thought that combinatorial chemistry would be the future source of numerous novel carbon skeletons and drug leads or new chemical entities NCEs. This has clearly not been the case as there has only been one combinatorial NCE approved by the U. Combinatorial chemistry has indeed revolutionized the development of novel active chemical leads resulting in the synthesis of structural analogues [ ].

At the time, combinatorial libraries consisted of hundreds to thousands of new compounds, but during the late s synthetic chemists realized that these libraries lacked the complexity of the intricate natural products synthesized by nature [ ]. The concept of diversity-oriented synthesis DOS was adopted in which synthetic chemists would synthesize compounds that resembled natural products mimics or that are based on natural product topologies. These compounds are currently being tested in a large number and variety of biological screens in order to determine their role s as leads to novel drug entities [ ].

A drug discovery program endeavors to search for a novel bioactive natural product s , which possess es some form of potent biological activity. Nevertheless, the isolation of known and undesirable natural products with no chemical or pharmacological interest is inevitable. The process of identifying known compounds responsible for the activity of an extract prior to bioassay-guided isolation is referred to as dereplication [ 28 , 29 ].

At present there are many advanced methodologies and protocols that distinguish novel entities from known natural compounds at an early stage of a drug discovery program or in a natural product isolation strategy [ 29 ]. It is important to realize that the isolation of novel natural products was far more frequent during the s and is steadily declining, although natural sources e. As such, the time, effort and cost to find new chemical entities must be considered as their discovery has become far more infrequent [ ]. Therefore, it is exceedingly important to recognize previously known compounds early on, not only for saving time and money, but to allocate resources to more profitable extracts.

It is evident that natural product programs require more patience and perseverance for the identification of adequate lead compounds than programs strictly based on synthetic chemicals.

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This is also dependent on availability of bioassay-guided fractionation, in -house screening, accessibility to higher field NMR and mass spectrometers, all of which are necessary to efficiently run such a program. Lead compounds arising from natural product discovery programs are structurally unique due to their co-evolution with target sites in biological systems.

However, the speed at which lead compounds can be generated and progressively advanced is slower than corresponding synthetic drug discovery approaches [ ]. Dereplication strategies generally involve a combination of bioassay, separation science, spectroscopic methods, and database searching and can be regarded as chemical or biological screening processes. There are many commercially available databases, which can assist in the dereplication process and will often reduce the time taken for structure elucidation of known compounds.

1. Introduction

Access to scientific databases such as the ones mentioned, is a fundamental and crucial step in a well-governed natural product program. Thorough and extensive literature searches are necessary when the following questions need to be addressed:. Have there been any previous literature reports on the target organism terrestrial or marine? What kind of compound classes has been isolated from the species and if not from the species, then the genus or family?

Is there incomplete or poor NMR spectroscopic data for previously uncharacterized natural products? Are there any new biological activities for known compounds that have been overlooked? It is fundamentally important to address these questions early as one of the most common issues that occurs is the time consuming process of isolating, purifying and determining the structure of a suspected novel compound and realizing that it has already been reported in the literature.

Natural product extracts often contain a large number of constituents including those, which are challenging to separate. In cases where the absolute configuration cannot be determined, synthesis or single-crystal X-ray analysis is utilized. As classical separation techniques are tedious and time consuming, the direct hyphenation of an efficient separation technique with powerful spectroscopic techniques can assist in the dereplication process [ ].

Such hyphenated systems though not in widespread use include HPLC-FTIR, which is useful for the detection of functional groups in major constituents of mixtures. HPLC-FTIR has been used by their designers but has not found wide application due to limitations in compatibility; that is, obtaining optimal separation together with sufficient detection [ ]. After the pump stops, the spectrometer acquires the scout scan to determine the location of solvent peaks and then acquires the solvent suppressed spectrum.

After completion, a signal is sent to the solvent pump to flush the old sample from the NMR flow-cell [ ]. HPLC-NMR-MS is an advanced spectrometric hyphenated technique which is used in the dereplication of natural product extracts typically plant extracts [ ]. The extraction is normally the first step for both marine and terrestrial organisms. The choice of the extraction solvent followed by solvent partitioning or by trituration can result in many problems including the formation of artifacts.

Further, homogenization and lyophilization with organic solvents can affect the nature and relative amounts of extracted secondary metabolites present.

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Capillary NMR allows for the use of non-deuterated solvents in the off-line HPLC separation providing a broader range of solvents to be used and low costs. A number of recent publications have been reported in utilizing this approach [ , , , ].

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Systems biology is an emerging field encompassing tools in the post-genomics revolution such as transcriptomics, proteomics, glycomics and fluxomics with the ambition to characterize all gene and cell products including mRNA, proteins, glycan structures and metabolites in the most comprehensive manner.

The objectives of metabolomics are to construct unbiased observations with highly reproducible analytical tools followed by data analysis to locate correlations between all available data. In the emerging field of metabolomics a single analytical technique capable of profiling all low molecular weight metabolites of a given organism does not exist. This emerging field combines analytical chemistry, biochemistry and sophisticated informatics allowing the analysis of thousands of small molecules metabolites in any biological system.

Mass spectrometry hyphenated with gas chromatography GC , liquid chromatography LC or capillary electrophoresis CE and nuclear magnetic resonance NMR spectroscopy are the leading analytical platforms. Both primary and secondary metabolites in tissues and biofluids are extracted utilizing unbiased crude extraction procedures aiming to efficiently extract all or most metabolites in their natural form prior to analysis in the solvents used.