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Apramycin 6 and saccharocin 69 are antibiotics active against Gram-positive and Gram-negative bacteria, including strains resistant to other aminoglycoside antibiotics. Structurally, 6 and 69 contain the unusual bicyclic aminooctodialdose and, in addition, 4-aminodeoxy-D-glucose and D-glucose units respectively. The aldehyde 61 was converted by our carbon-elongation method to the acetyl glycal This was submitted to azidonitration using sodium azide and ammonium ceric nitrate to give azidoglycosyl nitrate The C3 position of the dimesylate 64 was selectively chlorinated to form the 3'-chloro compound, which was dechlorinated with tributylstannane to give the 3'-deoxy compound Epimerization of the 6'-hydroxy group, by heating 65 with sodium acetate trihydrate, yielded the cis cyclic carbamate 66 needed for the apramycin skeleton.

Removal of all protecting groups gave aprosamine Thienamycin 7 was discovered in fermentation broths of Streptomyces cattleya and showed exceptional antibacterial potency and spectrum. Removal of the N -sulfonyl group of 73 by Birch reduction produced the corresponding amino acid This was hydrolyzed and then esterified to give the furanose Oxidation of 75 to the lactone 76 was the key step of our strategy, although the lactone could not be obtained under usual oxidation conditions.

The next important operation in the synthesis was to epimerize stereoselectively and simultaneously the configurations at the C2 and C3 positions of This result indicated that the C4 configuration of 76 controlled the stereoselective construction of the C2 and C3 configurations of For our purpose, a Grignard-mediated cyclization of the silylated derivative seemed most promising. This was identical in all respects to the authentic sample. Key steps include our original skeletal rearrangement with ring-contraction, oxidation of the 2-aminofuranose, and stereoselective epimerization to the desired configurations.

Consequently, it was our intention to successfully develop a novel general method of entry into the Z -isomer, even though several methods have already been reported for the production of We devised a novel and concise preparation directed toward the mass production of the Z -methoxyimino compound: This reaction mechanism was reasonably supported by the isolation of the similar intermediate 85 from 3-aminoisoxazole The compound 85 was also converted to 83 through The moderate yield was ascribed to purification difficulties due to their polar nature.

Without isolation of the keto-ester, the methyl ester 83 was quantitatively converted into the desired Z -isomer of 2- methoxyimino acetate. Saponification provided the target product 88 in quantitative yield. This was derived to cefozopran 89 , which was marketed in For almost half a century, tetracycline 8 has been widely recognised as a major antibiotic, due to both its unique structural features as well as antibacterial activities.

The total synthesis of natural — -tetracycline 8 remained an unanswered challenge, despite the remarkable achievements as described above. The starting-point glucosaminide 90 , which was prepared from D-glucosamine, was converted into the selenide Treatment of 91 with borane followed by H 2 O 2 oxidation stereoselectively gave the alcohol by simultaneous formation of a new olefin group, which was benzylated to the olefin This was submitted to Ferrier reaction with HgCl 2 to give the cyclohexanone Therefore, 93 was epimerized at C2 and dehydrated to the isomer The tandem Michael-Dieckmann type reaction of 96 with the isobenzofuranone 97 gave the tetracyclic compound Manipulation of the protective groups of 98 gave the diol 99 , which was adequate to oxidate the right wing.

The primary alcohol of 99 participated in the bromination of Ca olefin to give the desired This transformation realized the concurrent oxidation of primary and secondary alcohols accompanied by introduction of the C12a hydroxyl group. The nitrile was transformed through and the perhydroxide into — -tetracycline 8 , which was identical with natural — -tetracycline in all respects, thus completing the first total synthesis.

Our tetracycline synthesis was the first to be accomplished, some 50 years after its structure had been determined. The tetracyclic UCE6 was isolated from fermentation broth of Actinomycetes strain and possessed strong antitumor ability. Deprotection of afforded racemic UCE6 , which was identical with the natural product. Pyranonaphthoquinone antibiotics — have been shown to possess significant antimicrobial, antifungal and antitumor activities Fig. Structurally, the stereo-alignment of nanaomycin D is included in nanaomycin A and BEB , while that of kalafungin is in medermycin and BEA Carbohydrates have been used widely as chiral sources in stereospecific syntheses of natural products, as mentioned above.

Thus, it is hoped that both enantiomeric chiral synthons in the total synthesis are derived from only one abundant enantiomer of a carbohydrate. On the protected hydroquinone , the isomerization at the C3 position was carried out to obtain the lactone by elimination-recyclization equilibrium under basic conditions.

Using the quinone , the isomerization at C1 and C4 positions was realized to afford the lactone by enolization-protonation equilibrium under acidic conditions. This methodology was widely applied to the construction of pyranonaphthoquinone antibiotics. Treatment of with zinc powder and sodium iodide in reflux aqueous acetonitrile gave the unsaturated alcohol This olefin formation was also developed in our laboratories.

The lactol was submitted to Wittig reaction, which afforded the cis -lactone and the trans -hydroxyl ester The lactone was oxidized to the quinone , which was subsequently de- O -methylated to give nanaomycin D The hydroxyl ester was converted to the quinone , which was subjected to the above-mentioned acidic isomerization to produce kalafungin , the enantiomer of nanaomycin D The first total synthesis of was accomplished by us to help determine the absolute structure. Thus their absolute structures were determined.

A Historical Overview of Natural Products in Drug Discovery

The was lithiated to couple with the l -pyroglutamic acid derivative to obtain the ketone The lactone was suitable for the synthesis of the natural product , while the hydroxyl ester could also be transformed to in high yield by heating with KHCO 3 and crown-6 in DMF. Acidic removal of two Boc groups in was followed by oxidative de- O -methylation to give the quinone This was effectively cyclized to the hexacyclic product through proton-tautomerization.

This was de- O -methylated by BCl 3 to give the re-tautomerized compound , which was identical in all respects with natural BEB. In recent years, much attention has been focused on the synthesis and development of glycosidase inhibitors because of an increasing awareness of the vital role played by carbohydrates in biological processes. Therefore, the chemical and biochemical studies on glycosidase inhibitors may lead to understanding of the molecular basis of intractable diseases such as diabetes mellitus, cancer and AIDS, and may also provide therapeutic approaches to them.

As part of an ongoing program to clarify the mode of action of glycosidase inhibitors, we have synthesized cyclophellitol , nagstatin , pyralomicin 1c , valienamine and validamine , and their analogs which have different configurations and functionalities. These syntheses have featured general methods of entry into the carba-sugars and their nitrogenous analogs. Glycosidase inhibitory activities of cyclophellitol , nagstatin and their analogs.

Intramolecular cycloaddition of the oxime , which was derived from L-glucose , was realized by using NaOCl via the intermediary nitrile oxide to afford the isoxazoline as a single product. The stereospecific reaction was found to be governed by the configuration of the C2 substituent. The isoxazoline opening was achieved by reduction of with Raney Ni-W4 in the presence of AcOH to afford the keto-diol, which was silylated with diethylisopropylsilyl triflate to give the protected ketone The diethylisopropylsilyl DEIPS group was developed in our laboratories and effectively used as an O -protecting group, 52 because this silyl group was found to be readily removed under hydrogenolysis conditions using Pd OH 2.

The mesylate was subjected to hydrogenolysis followed by epoxidation to give cyclophellitol , thereby completing the first total synthesis. The aziridine analog and thiirane analogs were also prepared from and The thiirane analogs having an S atom showed no bioactivity. This lack of selectivity was expected from unspecified chelation of and both products were useful for the synthesis of analogs. De- N -tritylation and the S N 2-type intramolecular cyclization of or were effectively realized in a one-pot by reaction with BnSO 2 Cl in pyridine to give, preferentially, the 5- O -sulfonate which, after treatment with Ac 2 O gave the desired acetate, which was de- O -acetylated to the nitrogenous D-talose analog or D-galactose analog The effective de- N -tritylation seemed to be affected by the pyridinium acetate produced.

The inversion of the hydroxyl group in using HN 3 afforded the azido derivative, which was subjected to hydrogenolysis and N -acetylation, leading to the N -acetyl-D-galactosamine analog , which corresponded to de-branched nagstatin. Similarly, nitrogenous D-glucose , D-mannose and N -acetyl-D-glucosamine analogs were efficiently prepared from an L-xylofuranose derivative. The triazole analogs and were predominantly synthesized from the aforesaid and L-xylofuranose by reaction with lithiated triazole. With regard to bioactive compounds, our interest goes far beyond total synthesis methodologies.

Thus we have elucidated the mechanism of action of various natural products through detailed investigation of their structure-activity relationships exploiting our synthetic organic analysis. The configurations from C8a to C5 of the analogs parallel the alignment from C1 to C5 of the corresponding glycopyranosides.

These findings are similar to those of cyclophellitol and its analogs. Pyralomicin 1c was isolated from a culture broth of Microtetraspora spiralis and found to have novel antitumor properties, including glucosidase-inhibiting activities. Thus, Mitsunobu conditions would be suitable for the glycosylation step, which was first developed in our laboratories.

We had already synthesized during the first total synthesis of pyralomicin 2c, the glucose analog of This methodology had already been developed for synthesis of progesterone receptor ligands, PFs in our laboratories, 65 and applied to the total synthesis of valienamine and validamine The SnCl 4 -promoted aldol condensation of resulted in the formation of the cyclohexenone , which was converted to through the introduction of a hydroxymethyl group.

In the highlands it was traditionally sprinkled on stockings at the start of a journey to prevent inflammation of the feet [ 20 , 21 ] and in Ireland it was used as a cure for bad sores under the chin as well as for burns and cuts [ 14 ]. By comparison, the marine environment has very few reported applications in traditional medicine. The red algae Chondrus crispus and Mastocarpus stellatus were sources of a beverage, which was popular as a folk cure for colds, sore throats, chest infections including tuberculosis.

The alga was also boiled in milk or water and used for kidney trouble and burns [ 22 , 23 ]. Secondary metabolites are generally not essential for the growth, development or reproduction of an organism and are produced either as a result of the organism adapting to its surrounding environment or are produced to act as a possible defense mechanism against predators to assist in the survival of the organism [ 26 , 28 ]. The biosynthesis of secondary metabolites is derived from the fundamental processes of photosynthesis, glycolysis and the Krebs cycle to afford biosynthetic intermediates which, ultimately, results in the formation of secondary metabolites also known as natural products [ 26 ].

It can be seen that although the number of building blocks are limited, the formation of novel secondary metabolites is infinite. The most important building blocks employed in the biosynthesis of secondary metabolites are those derived from the intermediates: Acetyl coenzyme A acetyl-CoA , shikimic acid, mevalonic acid and 1-deoxyxylulosephosphate. They are involved in countless biosynthetic pathways, involving numerous different mechanisms and reactions e.

Modifications in the biosynthetic pathways may be due to natural causes e. It is the unique biosynthesis of these natural products, produced by the countless number of terrestrial and marine organisms, which provides the characteristic chemical structures that possess an array of biological activities.

Traditional medicinal practices have formed the basis of most of the early medicines followed by subsequent clinical, pharmacological and chemical studies [ 5 ]. Probably the most famous and well known example to date would be the synthesis of the anti-inflammatory agent, acetylsalicyclic acid 1 aspirin derived from the natural product, salicin 2 isolated from the bark of the willow tree Salix alba L. Investigation of Papaver somniferum L. It was in the s that crude morphine derived from the plant P. Historically, it is documented that the Sumerians and Ancient Greeks used poppy extracts medicinally, whilst the Arabs described opium to be addictive [ 30 ].

Formal use of the bark to treat malaria was established in the mid s when the British began the worldwide cultivation of the plant [ 30 ]. Pilocarpine 6 found in Pilocarpus jaborandi Rutaceae is an L-histidine-derived alkaloid, which has been used as a clinical drug in the treatment of chronic open-angle glaucoma and acute angle-closure glaucoma for over years.

In , an oral formulation of pilocarpine 6 was approved by the FDA to treat dry mouth xerostomia which is a side effect of radiation therapy for head and neck cancers and also used to stimulate sweat glands to measure the concentrations of sodium and chloride Figure 1 [ 31 ]. In , the oral preparation was approved for the management of Sjogren's syndrome, an autoimmune disease that damages the salivary and lacrimal glands.

Macro and micro fungi have been part of human life for thousands of years. They were used as food mushrooms , in preparation of alcoholic beverages yeasts , medication in traditional medicine and for cultural purposes.

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Currently with the advances in microbiology, their uses have extended to enzymes, biological control, antibiotics and other pharmacologically active products [ 32 ]. Undoubtedly one of the most famous natural product discoveries derived from a fungus microorganism is that of penicillin 7 from the fungus, Penicillium notatum discovered by Fleming in [ 33 ]. A countercurrent extractive separation technique which produced 7 in high yields was required for the in vivo experimentation that ultimately saved countless lives and won Chain and Florey together with Fleming the Nobel prize in Physiology and Medicine Figure 2 [ 34 ].

This discovery led to the re-isolation and clinical studies by Chain, Florey and co-workers in the early s and commercialization of synthetic penicillins, which ultimately revolutionized drug discovery research [ 35 , 36 , 37 , 38 ]. Penicillin 7 , Norcardicin 8 , Imipenem 9 and Aztreonam After publication of the first clinical data on penicillin G 7 between — there was a worldwide endeavor to discover new antibiotics from microorganisms and bioactive natural products [ 39 , 40 ]. Macro fungi such as polypores are a large group of wood-rotting fungi of the phylum Basidiomycota basidomycetes and Ascomycota, which are a major source of pharmacologically active substances.

There are about 25, species of basidiomycetes, of which about are members of the Aphyllophorales [ 42 ]. Many compounds have displayed antiviral, cytotoxic, antineoplastic, cardiovascular, anti-inflammatory, immune-stimulating and anticancer activities [ 42 , 43 ]. Fungi are more commonly microorganisms, some of which can spend at least part of their life cycle inside plant tissues without causing any visible sign of infection or disease [ 44 , 45 ]. They have been found to inhabit trees, grasses, algae and herbaceous plants and live in the intercellular spaces of plant stems, petioles, roots and leaves without affecting the host organism [ 46 ].

Collectively these fungi are known as endophytes. Novel bioactive secondary metabolites derived from fungal sources have yielded some of the most important natural products for the pharmaceutical industry [ 3 ]. In , Edmund Kornfeld first isolated vancomycin 11 a glycopeptide antibiotic produced in cultures of Amycolatopsis orientalis which is active against a wide range of gram-positive organisms such as Staphylococci and Streptococci and against gram-negative bacteria, mycobacteria and fungi and was approved by the FDA in Figure 3.

It is used for the treatment of severe infection and against susceptible organisms in patients hypersensitive to penicillin 7 [ 5 ]. The macrolide erythromycin 12 from Saccharopolyspora erythraea is an antibacterial drug, which contains a membered macrocycle composed entirely of propionate units Figure 3.

Erythromycin 12 has broad spectrum activities against gram-positive cocci and bacilli and is used for mild to moderate, upper and lower respiratory tract infections [ 5 , 26 ]. Single cell viruses represent the smallest existing life forms causing cold, influenza, ebola and SARS. Presently, there seems to be a limited number of antiviral natural products or synthetically derived analogues from fungi [ 47 ]. Betulinic acid 13 , a triterpenoid obtained from the bark of Betula pubescens was originally identified as a weak inhibitor of HIV replication [ 48 , 49 ].

Betulinic acid can inhibit topoisomerase I and is being evaluated in Phase I trials as a cancer chemo-preventive agent Figure 4 [ 50 ]. Doxorubicin 17 is used to treat acute leukaemia, soft tissue and bone sarcomas, lung cancer, thyroid cancer and both Hodgkins and non-Hodgkins lymphomas Figure 5 [ 5 , 26 ].

Amrubicin hydrochloride 16 , Doxorubicin 17 and Torreyanic acid Plants have been well documented for their medicinal uses for thousands of years. They have evolved and adapted over millions of years to withstand bacteria, insects, fungi and weather to produce unique, structurally diverse secondary metabolites. Their ethnopharmacological properties have been used as a primary source of medicines for early drug discovery [ 55 , 56 ].

The knowledge associated with traditional medicine complementary or alternative herbal products has promoted further investigations of medicinal plants as potential medicines and has led to the isolation of many natural products that have become well known pharmaceuticals. The bark from about three mature year old trees is required to provide 1 gram of 19 given that a course of treatment may need 2 grams of the drug. Current demand for 19 is in the region of — kg per annum i.

Baccatin III 20 present in much higher quantities and readily available from the needles of T. Combretastatin A-4 phosphate 23 a stilbene derivative from the South African Bush Willow, Combretum caffrum acts as an anti-angiogenic agent causing vascular shutdowns in tumors necrosis and is currently in Phase II clinical trials Figure 7 [ 66 , 67 ]. Over 60, extracts of plants and marine organisms were tested against lymphoblastic cells infected with HIV The most important result of these tests is the class of compounds known as the calanolides.

In particular the isolation of calanolide A 24 and calanolide B 25 from the Calonphyllum species, along with prostratin 26 from Homalanthus nutans , have now progressed into clinical and preclinical development Figure 8 [ 68 , 69 , 70 ]. Calanolide A 24 was licensed and evaluated to Phase II clinical trials by Sarawak Medichem Pharmaceuticals, however there has been no subsequent announcement for further drug development.

Calanolide A 24 , Calanolide B 25 and Prostratin Arteether 27 , introduced in , as Artemotil is derived from artemisinin 28 introduced in as Artemisin which was first isolated from the plant Artemisia annua and are both approved antimalarial drugs Figure 9 [ 47 ]. The plant was originally used in traditional Chinese medicine as a remedy for chills and fevers. Other derivatives of artemisinin 28 are in various stages of clinical development as antimalarial drugs in Europe [ 3 , 26 ].

To date, a synthetic trioxolane modeled on the 28 pharmacophore, is being assessed in combination with piperaquine a synthetic bisquinoline antimalarial drug in an effort to treat malaria Figure 9 [ 71 ]. Grandisines A 29 and B 30 are two indole alkaloids which were isolated from the leaves of the Australian rainforest tree, Elaeocarpus grandis Figure Grandisine A 29 contains a unique tetracyclic skeleton, while Grandisine B 30 possesses an unusual combination of isoquinuclidinone and indolizidine ring systems. Apomorphine 32 is a derivative of morphine 31 isolated from the poppy P.

Tubocaurarine 33 isolated from the climbing plant, Chondrodendron tomentosum Menispermaceae is one of the active constituents used as a muscle relaxant in surgical operations, reducing the need for deep anesthesia. The limited availability of tubocurarine 33 has led to the development of a series of synthetic analogues which are now preferred over the natural product Figure 10 [ 26 ]. Grandisine A 29 , Grandisine B 30 , morphine 31 , apomorphine 32 and tubocaurarine Though plants have proven to be a novel source for bioactive natural products the marine environment has a clear track record in also offering novel structural entities.

It was left as a deep secret. It seemed ridiculous to me that the ocean — with such a vast habitat — had escaped anyone's notice. But there are good reasons. Exploration of the marine environment and organisms algae, sponges, ascidians, tunicates and bryozoans became possible due to modern snorkeling, the introduction of SCUBA s , to the use of manned submersibles s and more recently the use of remotely operated vehicles ROVs s. These progressive advancements in the past 40 years of exploration of the marine environment have resulted in the isolation of thousands of structurally unique bioactive marine natural products.

To date, the global marine pharmaceutical pipeline consists of three Food and Drug Administration FDA approved drugs, one EU registered drug, 13 natural products or derivatives thereof in different phases of the clinical pipeline and a large number of marine chemicals in the pre-clinical pipeline [ 78 ].

Stereoselective Synthesis (Part K)

Plitidepsin 34 is effective in treating various cancers, including melanoma, small cell and non-small cell lung, bladder as well as non-Hodgkin lymphoma and acute lymphoblastic leukemia and is currently in Phase II clinical trials Figure 11 [ 78 , 81 ]. The quantities of ET 35 required for advanced pre-clinical and clinical studies was achieved by adopting very large-scale aquaculture of E.

Spisulosine 36 , isolated from the marine clam Spisula polynyma , exhibited substantial selective activity against tumor cells compared to normal cells [ 86 ]. 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 [ , , , ].

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.

Total synthesis and development of bioactive natural products

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. 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.

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.

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:. 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 [ ].


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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 [ , , , ]. 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. Since metabolite extracts are extremely complex, given the huge chemical diversity of metabolites they represent, there is no one single analytical platform and methodology, which is capable of analyzing all metabolites simultaneously.

Multiple separation chemistries have to be employed to achieve the greatest comprehensiveness in the analysis [ ]. Due to the improvement in sensitivity, resolution and advances in instrumentation hundreds of compounds can be simultaneously analyzed with subsequent refined informatics tools developed to extract information from the resulting data, filtering algorithms to remove background noise, detection and integration of peaks throughout large data sets and normalization and transformation of resulting data matrices prior to any statistical analysis can now be achieved [ ].

The greatest bottleneck in metabolomics is the ability to identify the detected signals with respect to their chemical nature. Many of these unknown structures i. Fingerprinting, footprinting, profiling or target analyses are common terms used in this field.

Metabolite profiling techniques require that signals can be assigned to a specific metabolite whether it is of a known or novel nature. The term target analysis aims to determine and quantify a specific metabolite of interest [ ]. There are few reports in the scientific literature, which discuss the unison of classical natural product chemistry approaches with metabolomics to identify novel bioactive natural products. These have generally focused on the study of plants [ ]. The identification of bioactive natural products from plants remains a multifaceted task because of their high chemical diversity and complexity.

By measuring the metabolome of different extracts or fractions of a plant and combining these data with its corresponding biological activity, signals related to the compounds related to the displayed activity can potentially be determined. PCA of the analytical data explained that the five Panax herbs could be separated into five different groups of phytochemicals [ ]. The results and methodology demonstrated this method to be reliable for the rapid analysis of a group of metabolites present in natural products extracts [ ]. In the case of NMR of crude extracts, patterns can be visualized and interpreted which is generally combined with multivariate data analysis.

This can be carried out in a comparative manner distinguishing differences between relatively similar extracts or it can be linked with a specific generally in vitro biological activity. Ultimately this enables the construction of a complex database of the metabolome [ , , ]. An NMR based metabolomics approach has recently been utilized in the study of Galphimia glauca , a Mexican plant which has been used in traditional medicine for the treatment of central nervous disorders [ ]. Six collections from the Mexican area demonstrated sedative and anxiolytic activities, with only two collections of G.

The PLS-DA loadings plot demonstrated a signal strongly correlated with sedative and anxiolytic activities was found to be galphimine 63 Figure A targeted HPLC metabolomic approach was also conducted which provided evidence that the two collections possessing strong sedative and anxiolytic activities contained high amounts of galphimine while both other less active samples did not [ ]. Zhi and co-workers analyzed the effect of different antibiotics with different modes of action on various microbes [ ].

The results concluded that dihydrocucurbitacin FO-acetate 64 , a major constituent of the Chinese plant Hemsleya pengxianensis , showed antimicrobial activity [ ]. The metabolome of a Staphylococcus aureus culture treated with a plant extract, 64 and several known antibiotics were compared. PCA analysis revealed that 64 was the component responsible for the main antimicrobial activity on S.

NMR based metabolomics has many applications in plant science and can be used in functional genomics to differentiate plants from different origin, or after different treatments [ ]. Kim and co-workers describe the advantage of a NMR metabolomic analysis and the possibility of identifying metabolites by comparing NMR data with references or by structure elucidation using 2D-NMR [ ]. Deyrupa and co-workers also demonstrated the use of 2D-NMR spectroscopy to screen a library of biorationally selected insect metabolite samples for partial structures.

This investigation enabled the detection of novel compounds in complex metabolite mixtures without prior fractionation or isolation. This led to the discovery and isolation of two families of tricyclic pyrones in Delphastus catalinae , a tiny ladybird beetle that is employed commercially as a biological pest control agent [ ]. In summary, we propose that a combination of metabolomics technologies with natural product discovery processes will be beneficial on multiple levels.

Firstly, by increasing the number of identifications in our metabolomics data we may provide novel structures to be tested for bioactivity for any disease under investigation. Multi-parallel analysis using metabolomics technologies will also enhance and increase throughput of chemical characterization processes of many different species from natural resources.

Secondly, as mentioned above, natural product chemists have collected a lifetime of compound libraries of active and also inactive pure compounds which can now be analyzed to construct mass spectral and NMR spectral libraries and therefore improve biological interpretations of metabolomics data.

Total synthesis and development of bioactive natural products

The advancements in analytical instrumentation and sophisticated hyphenation of separation techniques with high sensitive detectors have allowed for greater detection of small molecule compounds measurable in biological systems i. National Center for Biotechnology Information , U. Journal List Metabolites v. Published online Apr This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license http: This article has been cited by other articles in PMC.

Abstract Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Natural Products in History Natural products secondary metabolites have been the most successful source of potential drug leads [ 1 , 2 , 3 , 4 , 5 ].