Natural Products That Changed Society.

Until the end of the 19th century all drugs were natural products or minerals. During the 19th century chemists succeeded in isolating pure natural products such as quinine, morphine, codeine and other compounds with beneficial effects. Pure compounds enabled accurate dosing to achieve serum levels within the pharmacological window and reproducible clinical effects. During the 20th and the 21st century synthetic compounds became the major source of drugs. In spite of the impressive results achieved within the art of synthetic chemistry, natural products or modified natural products still constitute almost half of drugs used for treatment of cancer and diseases like malaria, onchocerciasis and lymphatic filariasis caused by parasites. A turning point in the fight against the devastating burden of malaria was obtained in the 17th century by the discovery that bark from trees belonging to the genus Cinchona could be used for treatment with varying success. However isolation and use of the active principle, quinine, in 1820, afforded a breakthrough in the treatment. In the 20th century the synthetic drug chloroquine severely reduced the burden of malaria. However, resistance made this drug obsolete. Subsequently artemisinin isolated from traditional Chinese medicine turned out to be an efficient antimalarial drug overcoming the problem of chloroquine resistance for a while. The use of synthetic analogues such as chloroquine or semisynthetic drugs such as artemether or artesunate further improved the possibilities for healing malaria. Onchocerciasis (river blindness) made life in large parts of Africa and South America miserable. The discovery of the healing effects of the macrocyclic lactone ivermectin enabled control and partly elimination of the disease by annual mass distribution of the drug. Also in the case of ivermectin improved semisynthetic derivatives have found their way into the clinic. Ivermectin also is an efficient drug for treatment of lymphatic filariasis. The serendipitous discovery of the ability of the spindle toxins to control the growth of fast proliferating cancer cells armed physicians with a new efficient tool for treatment of some cancer diseases. These possibilities have been elaborated through preparation of semisynthetic analogues. Today vincristine and vinblastine and semisynthetic analogues are powerful weapons against cancer diseases.

Large Scale Conversion of Trilobolide into the Payload of Mipsagargin: 8-O-(12-Aminododecanoyl)-8-O-Debutanoylthapsigargin.

In spite of the impressing cytotoxicity of thapsigargin (Tg), this compound cannot be used as a chemotherapeutic drug because of general toxicity, causing unacceptable side effects. Instead, a prodrug targeted towards tumors, mipsagargin, was brought into clinical trials. What substantially reduces the clinical potential is the limited access to Tg and its derivatives and cost-inefficient syntheses with unacceptably low yields. Laser trilobum, which contains a structurally related sesquiterpene lactone, trilobolide (Tb), is successfully cultivated. Here, we report scalable isolation of Tb from L. trilobum and a transformation of Tb to 8-O-(12-aminododecanoyl)-8-O-debutanoylthapsigargin in seven steps. The use of cultivated L. trilobum offers an unlimited source of the active principle in mipsagargin.

A new flavonol glycoside and other flavonoids from the aerial parts of Taverniera aegyptiaca.

Isolation of flavonoids from the aerial parts of Taverniera aegyptiaca Bioss. (Fabaceae) led to identification of one new flavonol glycoside, isorhamnetin-3-O-α-l-rhamnopyranosyl-(1→2)-α-l-arabinopyranoside (1), along with eleven compounds, which previously have not been isolated from this plant quercetin-3-O-α-l-rhamnopyranosyl-(1→2)-[α-l-rhamnopyranosyl-(1→6)-ß-d-galactopyranoside] (2), isorhamnetin-3-O-α-l-arabinopyranoside (3), quercetin-3-O-α-l-rhamnopyranosyl-(1→6)-ß-d-glucopyranoside (4), isorhamnetin-3-O-α-l-rhamnopyranosyl-(1→6)-ß-d-glucopyranoside (7), isorhamnetin 3-O-α-l-rhamnopyranosyl-(1→2)-[α-l-rhamnopyranosyl-(1→6)-ß-d-galactopyranoside] (8), isorhamnetin 3-O-α-l-rhamnopyranosyl-(1→2)-[α-l-rhamnopyranosyl-(1→6)-ß-d-glucopyranoside] (9), kaempferol 3-O-α-l-rhamnopyranosyl-(1→2)-[α-l-rhamnopyranosyl-(1→6)-ß-d-galactopyranoside] (10), isorhamnetin (11), 4,4'-dihydroxy-2'-methoxychalcone (12), formononetin (13) and calycosin (15)] and some compounds already known from this plant [quercetin-3-O-robinobioside (5), isorhamnetin-3-O-robinobioside (6), afrormosin (14) and odoratin (16)].

Can phylogeny predict chemical diversity and potential medicinal activity of plants? A case study of Amaryllidaceae.

BACKGROUND: During evolution, plants and other organisms have developed a diversity of chemical defences, leading to the evolution of various groups of specialized metabolites selected for their endogenous biological function. A correlation between phylogeny and biosynthetic pathways could offer a predictive approach enabling more efficient selection of plants for the development of traditional medicine and lead discovery. However, this relationship has rarely been rigorously tested and the potential predictive power is consequently unknown. RESULTS: We produced a phylogenetic hypothesis for the medicinally important plant subfamily Amaryllidoideae (Amaryllidaceae) based on parsimony and Bayesian analysis of nuclear, plastid, and mitochondrial DNA sequences of over 100 species. We tested if alkaloid diversity and activity in bioassays related to the central nervous system are significantly correlated with phylogeny and found evidence for a significant phylogenetic signal in these traits, although the effect is not strong. CONCLUSIONS: Several genera are non-monophyletic emphasizing the importance of using phylogeny for interpretation of character distribution. Alkaloid diversity and in vitro inhibition of acetylcholinesterase (AChE) and binding to the serotonin reuptake transporter (SERT) are significantly correlated with phylogeny. This has implications for the use of phylogenies to interpret chemical evolution and biosynthetic pathways, to select candidate taxa for lead discovery, and to make recommendations for policies regarding traditional use and conservation priorities.

6-O-methylkrigeine, a new amaryllidaceae alkaloid from Nerine huttoniae Schönland.

A novel Amaryllidaceae alkaloid, 6-O-methylkrigeine, has been isolated from Nerine huttoniae and the configuration was elucidated by 1-D and 2-D (1)H-NMR, (13)C-NMR, HRMS and optical rotation.

Isolation of immunomodulatory triterpene acids from a standardized rose hip powder (Rosa canina L.).

A previously published systematic review and a metaanalysis have concluded that the consumption of standardized rose hip powder (Rosa canina L.) can reduce pain in osteoarthritis patients. Synovial inflammation has been suggested to play an important role in the pathogenesis of osteoarthritis and mainly to involve infiltration of the synovial membrane by macrophages. Therefore, the immunomodulatory effect of standardized rose hip powder of Rosa canina L. was investigated and active principles isolated using the Mono Mac 6 cell line as a model for human macrophages. Treatment of Mono Mac 6 cells with the residue of a crude dichloromethane extract of rose hip powder significantly and concentration dependently inhibited the lipopolysaccharide induced interleukin-6 release. Through bioassay-guided fractionation the immunomodulatory effect of the dichloromethane extract was correlated to a mixture of three triterpene acids; oleanolic acid, betulinic acid and ursolic acid (IC(50) 21 ± 6 µm). Further studies revealed that only oleanolic acid and ursolic acid, but not betulinic acid, could inhibit the lipopolysaccharide induced interleukin-6 release from Mono Mac 6 cells when tested separately. Combination of either oleanolic acid or ursolic acid with betulinic acid enhanced the immunomodulatory effect of the two triterpene acids.

Ancistrotanzanine C and related 5,1'- and 7,3'-coupled naphthylisoquinoline alkaloids from Ancistrocladus tanzaniensis.

Three new naphthylisoquinoline alkaloids, the 7,3'-coupled ancistrotanzanine C (6), the 5,1'-coupled O-methylancistrocladinine (7), and the likewise 5,1'-coupled O,N-dimethylancistrocladine (8, previously known only as a partial-synthetic compound), have been isolated from the highland liana Ancistrocladus tanzaniensis, along with the two known 7,3'-coupled naphthylisoquinoline alkaloids ancistrocladidine (4) and ancistrotectorine (5). All of the compounds are S-configured at C-3 and bear an oxygen at C-6, and thus belong to the so-called Ancistrocladaceae type, similar to 1-3 previously isolated from this newly discovered plant species. The structural elucidation was achieved by chemical, spectroscopic, and chiroptical methods. The biological activities of the alkaloids against the pathogens causing malaria tropica, leishmaniasis, Chagas' disease, and African sleeping sickness were evaluated.

An antiplasmodial lignan from Euterpe precatoria.

As a part of a study on new antiplasmodial natural products, a new 8-5' linked lignan dehydrodiconiferyl dibenzoate (2) and p-hydroxybenzoic acid (1) were isolated from the roots of the palm Euterpe precatoria. In contrast to compound 1, compound 2 showed a moderate antiplasmodial activity.

Antiplasmodial compounds from Cochlospermum tinctorium.

Fractionation of an ethanol extract of roots of Cochlospermum tinctorium afforded five compounds: 3-O-E-p-coumaroylalphitolic acid (1), cochloxanthin (2), dihydrocochloxanthin (3), alphitolic acid (4), and 1-hydroxytetradecan-3-one (5). This is the first example of a 1-hydroxyalkan-3-one obtained from plant material after gentle workup. The antiplasmodial activities of the compounds were determined, and the IC(50) value of 3-O-E-p-coumaroylalphitolic acid was 2.3 microM.

In vitro antimycobacterial and antilegionella activity of licochalcone A from Chinese licorice roots.

Licochalcone A, extracted and purified from Chinese licorice roots, showed in vitro inhibitory effect on human pathogenic Mycobacteria species and Legionella species. M. tuberculosis, M. bovis and BCG were inhibited by < 20 mg/l licochalcone A, whereas all non- M. tuberculosis complex species were resistant to > 20 mg/l Legionella pneumophila (serogroups 1 - 7) and L. bozemanii, L. dumoffii, L. feelei, L. longbeacheae and L. wadsworthii were inhibited by licochalcone A 1 - 4 mg/l, whereas L. gormanii and L. micdadei were inhibited by licochalcone A 500 - 1000 mg/l. These data indicate that licochalcone A might be of interest as a new class of antibacterial drug in the treatment of severe lung-infections.