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PubMed1991

How far can one go in the field of structural elucidation of natural products?

Structural elucidation of bioactive compounds has always been and remains a field of interest for organic chemists. Tools have constantly evolved over the past fifty years and the field has become so sophisticated and relies so heavily on instruments and computers that is becoming an area for specialists. Specialization has become such that the natural product chemist now faces X-ray professionals, mass spectrometry specialists, not to speak of NMR experts; all these people use different tools, different quantities of material and it may happen that once our natural product chemists opens the door of one of their laboratories, he is not welcome in the others anymore. The purpose of this paper is to discuss briefly what can be done best with each of the tools. It will be also shown that chemistry may still find a use, especially when problems are very difficult to tackle. Examples will be chosen among terpenes, antibiotics and toxins.

Magnetic Resonance Spectroscopy↗
PubMed1993

Tapping an Amazônian plethora: four medicinal plants of Marajó Island, Pará (Brazil).

This study focused its attention on four medicinal plants (Carapa guianensis, Elephantopus scaber, Piper umbellatum, Stachytarpheta cayenensis) used by Caboclo communities on Marajó, the main island of the Amazon delta. In the field, interviews were conducted with Caboclos and the medicinal usages and preparation procedures of the four plants were recorded. In the laboratory, the plant extracts were subjected to bioassays and their crude chemical composition was established. All four plants showed significant bioactivity and the chemical tests confirmed the presence of bioactive compounds. In addition, the results of both the field and laboratory studies corresponded well with those of a literature search. The ethnopharmacological significance of the four plants is discussed.

Animals↗
PubMed1996

Absence of alkaloids in Psychotria carthagenensis Jacq. (Rubiaceae).

Psychotria viridis and P. carthagenensis are often discussed in relation to the hallucinogenic beverage Ayahuasca, used for religious, medicinal and social purposes. The significance of including Psychotria species in this beverage has been understood on the basis of substantial amounts of tryptamine alkaloids detected on leaves of both P. viridis and P. carthagenensis. Nevertheless, there is a long lasting debate over the identification of which Psychotria species are actually traditionally employed. We here report that a P. carthagenensis leaf ethanol extract was found to be devoid of alkaloids. The extract significantly decreased mice body temperature (350 and 500 mg/kg). Toxicity assessment revealed that the extract induced sedation and slight ptoses (75% of animals treated with 1000 mg/kg). Lethality was not observed within 48 h. The data indicate that P. carthagenensis does have bioactive compound(s), possibly active at the central nervous system, but unlikely to be tryptamine alkaloids as in the case of P. viridis. Therefore, if P. carthagenensis is indeed used by ayahuasqueros, its chemical and pharmacological significance have yet to be elucidated.

Analysis of Variance↗
PubMed1992

Production of the cytostatic agent aeroplysinin by the sponge Verongia aerophoba in in vitro culture.

1. The marine sponge Verongia aerophoba contains two bioactive secondary metabolites from tyrosine, (+)-aeroplysinin-1 [3',5'-dibromo-1',2'-dihydroxy-4'- methoxycyclohexa-3',5'-dien-1'-yl-methyl-cyanide; abbreviated AP] and dibromoverongia-quinol [3',5'-dibromo-1'-hydroxy- 4'-oxocyclohexa-2',5'-dien-1'-yl-acetamide; abbreviated DV], which display strong cytostatic activity. 2. The concentrations causing 50% inhibition of cell growth are 0.47 microM (AP) and 1.21 microM (DV), resp. 3. Depending on depth regions from which the sponges were collected, differences in occurrence of metabolites were observed. 4. AP and DV were found to be present in sponges collected at a depth of 5-10 m, whereas only DV could be detected in material from deeper regions (20-30 m). 5. AP is present only in the surface layers (both the outer and oscular region) of the sponge, while in the centre of the sponge only DV is detected. 6. Cubes from sponges, collected at a depth of 30 m, were cultivated in seawater in vitro and were found to have the capacity (i) to synthesize AP, and (ii) to release this bioactive material into the medium under defined conditions. Under optimal conditions (light and aeration) 100 g of sponge synthesize and release 13.02 mg of AP during a 10-day incubation period. 7. In the dark and without aeration this synthesis was prevented. 8. These data show that also under in vitro conditions sponges retain the capability of producing bioactive compounds and can be induced to produce even substances which they did not secrete in their natural environment.

Acetamides↗
PubMed1991

"Enzymatic" lipid peroxidation: reactions of mammalian lipoxygenases.

Lipoxygenase is a dioxygenase which incorporates one molecule of oxygen at a certain position of unsaturated fatty acids such as arachidonic and linolenic acids. The enzymatic oxygenation of unsaturated fatty acids is stereospecific concomitant with a stereoselective abstraction of hydrogen atom. Fatty acid cyclooxygenase is an atypical lipoxygenase incorporating two molecules of oxygen, and initiates the biosynthesis of prostaglandins and thromboxanes. Arachidonate 5-lipoxygenase is responsible for the leukotriene synthesis. No such bioactive compound has been found as a metabolite of the 12- and 15-lipoxygenase pathways, and their physiological roles are still unclarified. These enzymes have been purified, and their molecular and catalytic properties have been investigated. Their cDNA clones have been isolated, and their nucleotide sequences have been determined deducing the primary structures of the enzymes.

Animals↗
PubMed1995

Effect of orotic acid on TGF-beta 1-induced growth inhibition of L1210 leukemic cells.

UNLABELLED: Transforming growth factor-beta 1 (TGF-beta 1) exerted growth-inhibitory effect on L1210 leukemic cell line, manifested by the decrease in viable and increase in dead cells. The cell death evoked by TGF-beta 1 was both necrotic and apoptotic, quantified by the trypan blue exclusion method and apoptotic index, respectively. The induction of programmed cell death by TGF-beta 1 was confirmed by gel electrophoresis of DNA, where the characteristic 'DNA ladder' resulting from the internucleosomal DNA cleavage was visualized. The enhancement of cell mortality by TGF-beta 1 was associated with the inhibition of ornithine decarboxylase (ODC) expression (measured by the reverse transcriptase-polymerase chain reaction method) and impaired activity of this key enzyme in polyamine synthesis. Orotic acid (OA)--a known tumor promoter--stimulated proliferation of L1210 leukemic cells and diminished the necrotic effect of TGF-beta 1, but it did not change the extent of apoptosis evoked by TGF-beta 1. OA increased the expression of ODC and diminished depressional influence of TGF-beta 1 on transcription and activity of ODC in leukemic cells. IN CONCLUSION: OA is a bioactive compound stimulating the growth of leukemic cells and diminishing the growth-inhibitory effect of TGF-beta 1. ODC gene is probably one of the targets for both OA and TGF-beta 1 influences in L1210 leukemic cells.

Animals↗
PubMed1994

Conformation of a water-soluble derivative of taxol in water by 2D-NMR spectroscopy.

BACKGROUND: Taxol is a natural product produced by the Pacific yew, Taxus brevifolia, that has emerged as a prominent chemotherapeutic agent for the treatment of solid tumors. It binds to microtubules, stabilizing them and arresting cells in mitosis. Taxol has been produced synthetically and a wealth of structure-activity data has recently emerged. To data, however, no single conformational model exists for the interpretation of these data. Studies of taxol and its analogs in organic solvents showed two distinct conformations, one in which the 3'-benzamido group and the 2-benzoyl group are in close proximity, and another in which the 2-benzoyl group is instead close to the 3'-phenyl group. We decided to use a derivative of taxol that has improved water-solubility to determine the structure of taxol in water. RESULTS: We have synthesized and characterized a stable water-soluble derivative of taxol that binds to microtubules and has a cytotoxicity profile very similar to that of taxol. 1D and 2D 1H NMR experiments with this bioactive compound in D2O indicate the presence of one conformer with a well-defined structure. In this structure, the 2-benzoyl group is clustered with the 3'-phenyl group. CONCLUSION: The determination of the conformation of taxol in water may allow quantitative three-dimensional interpretation of the structure-activity data obtained for taxol, and hence enable the design of novel taxol mimics.

Magnetic Resonance Spectroscopy↗
PubMed1995

Peptides.

If we include beta-lactam antibiotics on the grounds that they have the same biosynthetic origin, peptides remain commercially the most important group of pharmaceuticals. However, our increasing knowledge of the genetic and enzymic background to biosynthesis, and of the regulation of metabolite production, will eventually bring a more unified approach to bioactive compounds. Mixing of structural types will become important, and we will be able to use our knowledge of biosynthetic genes and their regulatory networks. We will also benefit from an appreciation of the modular organization of catalytic functions, substrate transfer mechanisms and signalling between interacting enzymes. Since all of this is, in fact, the basis for enzymic synthesis of complex natural products in vivo, the exploitation of living cells requires mastery of a formidable network of cellular controls and compartments. For the present we are able to see fascinating connections emerging between genes in a variety of reaction sequences, not only in biosynthetic but also in degradative pathways. Peptide synthetases show surprising similarities to acylcoenzyme A synthetases, which are key enzymes in forming polyketides as well as in generating the CoA-derivatives that serve as substrates in degradative pathways. 4'-Phosphopantetheine, the functional half of CoA, plays a key role as the intrinsic transfer cofactor in various multienzyme systems. The comparatively small catalogue of reactions modifying natural products, notably epimerization, methylation, hydroxylation, decarboxylation (of peptides) and reduction/dehydration (of polyketides) can be found within or amongst biosynthetic proteins, generally as modules and organized in a specified order. The biochemist is coming close to the synthetic chemist's recipes, and may soon be recruiting proteins to carry them out.

Amino Acid Sequence↗
PubMed2006

A versatile method of identifying specific binding proteins on affinity resins.

The isolation of both specific and nonspecific binding proteins on affinity matrices bearing bioactive compounds hinders the identification of drug cellular targets. Although solid-phase elution and competition methods conventionally are used to distinguish between specific and nonspecific receptor-ligand interactions, these approaches often are severely restricted by low ligand solubility and/or slow kinetic dissociation. This article describes an alternative and versatile method, termed serial affinity chromatography, to identify ligand receptors using affinity resins.

Affinity Labels↗
PubMed2006

Rosemary (Rosmarinus officinalis) diterpenes affect lipid polymorphism and fluidity in phospholipid membranes.

Rosemary (Rosmarinus officinalis) extracts are widely used in the food, nutraceutical and cosmetic areas. Their major bioactive components have shown antioxidant, antimicrobial, anti-inflammatory, antitumorigenic and chemopreventive activities. In this work, the bioactive compounds deriving from rosemary leaves (carnosol, CAR; carnosic acid, CA; rosmadial, RAL; genkwanin, GW; rosmarinic acid, RA) were isolated and their effects on the phase behaviour of model membranes were studied by several complementary biophysical techniques. All diterpenes studied, and specifically CAR, decreased the hydrophobic interactions between acyl chains, as well as broadened and shifted the phospholipid transition to lower temperatures into dimyristoylphosphatidylcholine (DMPC) membranes. In addition, all diterpenes and genkwanin increased the lipid order of fluid DMPC membranes, exhibiting CAR and RAL the strongest membrane-rigidifying effect. The diterpenoids, especially CA and RAL, promoted the formation of hexagonal-H(II) phases at low temperatures in dielaidoylphosphatidylethanolamine (DEPE) membranes which exhibited a smaller tube-to-tube distance compared to pure phospholipid. These diterpenes were also able of promoting isotropic structures in DEPE membranes which consisted of non-periodically ordered lipid structures as demonstrated by X-ray diffraction. In contrast, minor effects were observed by rosmarinic acid. In conclusion, diterpenes and genkwanin from rosemary show membrane-rigidifying effects which may contribute to their antioxidant capacity through hindering diffusion of free radicals.

Diterpenes↗
PubMed2005

Recent progress in ocular drug delivery for posterior segment disease: emphasis on transscleral iontophoresis.

Age-related macular degeneration, diabetic retinopathy, posterior uveitis, and retinitis due to glaucoma are leading causes of vision loss in the United States and other developed countries. Because these diseases are located in the posterior segment of the eye, topical application of ophthalmic medicines is of limited benefit, since topically applied drugs rarely reach therapeutic levels in the affected posterior tissues such as the choroid and retina. Intravitreal injections can deliver drugs to the posterior segment without the side effects associated with systemic administration. However, the repeated and long-term injections often needed may cause complications, such as vitreous hemorrhage, retinal detachment, or endophthalmitis. Recent advances in ocular drug delivery methods and the development of novel biopharmaceutical agents could lead to new regimens for the treatment of disease of the posterior retina, choroids, and macula. This review will summarize recent literature concerning ocular drug delivery of bioactive compounds to the posterior segment of the eye with emphasis on transscleral iontophoresis.

Animals↗
PubMed2005

Interaction between hesperetin and human serum albumin revealed by spectroscopic methods.

Hesperetin (5,7,3'-trihydroxyl-4'-methoxyl-flavanone) is an important bioactive compound in Chinese traditional medicine and has multiple biological and pharmacological activities. The interaction of hesperetin with human serum albumin (HSA) has been investigated by UV absorption, fluorescence and Fourier transformed infrared spectrometry. Fluorescence results showed that one molecule of protein combined with one molecule of drug at the molar ratio of drug to HSA ranging from 0.3 to 7 and the binding affinity (K(A)) was 8.11x10(4) M(-1). The primary binding site was most likely located on subdomain IIA. The binding ability of the drug to protein decreased from pH 6.4 to 8.4 in the drug to protein molar ratio of 1. Combining the curve-fitting results of infrared amide I band in D2O and H2O phosphate buffers, the alterations of protein secondary structure after drug complexation were estimated. With increasing the drug concentration, the percentage of protein alpha-helix structure decreased gradually. The reduction of protein alpha-helix structure reached about 7-9% after the protein interacted with hesperetin in D2O and H2O buffer solution at pH 7.4 when the drug to protein molar ratio was 10. This indicated a partial unfolding of HSA in the presence of the drug. From the results of UV absorption, fluorescence and Fourier transformed infrared spectrometry, the binding mode was discussed. The main mechanism of protein fluorescence quenching was a static quenching process and the hydroxyl groups of the drug in its neutral part played an important role in the binding process.

Hesperidin↗
PubMed2006

Cell-based chemical genetic screen identifies damnacanthal as an inhibitor of HIV-1 Vpr induced cell death.

Viral protein R (Vpr), one of the human immunodeficiency virus type 1 (HIV-1) accessory proteins, contributes to multiple cytopathic effects, G2 cell cycle arrest and apoptosis. The mechanisms of Vpr have been intensely studied because it is believed that they underlie HIV-1 pathogenesis. We here report a cell-based small molecule screen on Vpr induced cell death in the context of HIV-1 infection. From the screen of 504 bioactive compounds, we identified damnacanthal (Dam), a component of noni [corrected] as an inhibitor of Vpr induced cell death. Our studies illustrate a novel efficient platform for drug discovery and development in anti-HIV therapy which should also be applicable to other viruses.

Anthraquinones↗
PubMed2006

Acylation with diangeloyl groups at C21-22 positions in triterpenoid saponins is essential for cytotoxicity towards tumor cells.

Saponins are natural surfactants, found in many plants. Certain saponins are bioactive compounds with anticancer, antivirus and hemolytic activities. The mechanism is unknown. A saponin with antitumor activity was identified in Xanthoceras sorbifolia Bunge (Sapindaceae) and purified. This saponin is a triterpenoid saponin with a trisaccharide chain attached at C3 of the aglycone and two angeloyl groups acylated at C21 and C22. It inhibits the growth of tumor cells with IC50=2 microg/ml in OVCAR3 cells. To study the structure-activity relationship, the diangeloyl group or the carbohydrates of Xanifolia-Y were removed and tested for activity. It was found that removal of both angeloyl groups in C21 and C22 positions completely abolished its activity (IC50>120 microg/ml). However, when carbohydrates were remove, its activity was reduced but was not abolished (IC50=10 microg/ml). These results suggest that a presence of diangeloyl group in the triterpene structure play an essential role for activity. By comparison, compounds with a similar structure as Xanifolia-Y but have only one angeloyl group at C22: Xanifolia-X (IC50=6 microg/ml) or at C21: beta-escin (IC50=10 microg/ml), have less activity. Results suggest that diangeloyl group in both C21 and C22 positions are important contributing activity. Similar results were observed in hemolytic activity. It is concluded that acylation with angeloyl group at C21 and C22 positions of triterpenoid saponin is essential for its activity.

Acylation↗
PubMed2005

A conductive ormosil encapsulated with ferrocene conjugate and multiwall carbon nanotubes for biosensing application.

Highly non-toxic and conductive ormosil composite film was prepared using (3-aminopropyl)triethoxysilane and 2-(3,4-epoxycyclohexyl)-ethyltrimethoxysilane by doping with ferrocenemonocarboxylic acid-bovine serum albumin (FMC-BSA) conjugate and multiwall carbon nanotubes (MWNTs). With glucose oxidase (GOD) as a model enzyme this film could be used to design an amperometric biosensor for glucose determination. The entrapped FMC-BSA conjugate performed excellent redox electrochemistry and the immobilized GOD was highly stable. Under optimal conditions this biosensor was able to detect glucose with a detection limit of 20 microm (S/N=3) in the linear range of 0.05-20.0 mm in flow system, which was wider than the batch amperometric mode, with an analysis time of 25 s for each sample. The value of K(M)(app) was 6.6 mm. The proximity of these three components FMC-BSA, MWNTs and GOD enhanced the electron transfer between the film and electrode. This film could be used efficiently for the entrapment of other redox bioactive compounds and biosensing/bioelectrochemical applications.

Biosensing Techniques↗
PubMed2005

Inhibition of COX-1 and COX-2 activity by plasma of human volunteers after ingestion of French maritime pine bark extract (Pycnogenol).

There is evidence from several studies that supplementation with French maritime pine bark extract (Pycnogenol) improves inflammatory symptoms in vivo. However, the molecular pharmacological basis for the observed effects has not been fully uncovered yet. Direct inhibitory effects of plant extracts or components upon cyclooxygenase (COX) activity have been repeatedly reported, but the question remained whether sufficiently high in vivo concentrations of bioactive compounds could be achieved in humans. The purpose of the present study was to determine a possible inhibition of the enzymatic activity of COX-1 and COX-2 by serum samples of human volunteers after intake of French maritime pine bark extract. This methodology considered that the serum samples would contain any bioavailable active principle. Therefore, we obtained blood samples before and after 5 days administration of 200 mg Pycnogenol to five healthy humans. The plasma moderately inhibited both COX-1 and COX-2 activities ex vivo. In a second approach, 10 volunteers received a single dose of 300 mg Pycnogenol. Only 30 min after ingestion of the pine bark extract the serum samples induced a statistically significant increase in the inhibition of both COX-1 (P < 0.02) and COX-2 (P < 0.002). This suggests a strikingly rapid bioavailability of bioeffective compounds after oral intake of the extract. Thus, we provide evidence that Pycnogenol exerts effects by inhibition of eicosanoid generating enzymes which is consistent with reported clinical anti-inflammatory and platelet inhibitory effects in vivo. The next challenge is to identify the active principle(s) that are rapidly bioavailable in human plasma.

Administration, Oral↗
PubMed2006

Design and development of liposomes incorporating a bioactive labdane-type diterpene. In vitro growth inhibiting and cytotoxic activity against human cancer cell lines.

The isolation and identification of bioactive compounds from natural sources has given insights in the discovery of new drugs against several diseases. Labdane-type diterpenes isolated from nature, have been investigated in the past for their pharmaceutical activities. Labd-7,13-dien-15-ol (1), a major lipophilic constituent of the resin 'ladano' was found to exhibit cytotoxic and cytostatic activity against cell lines derived from solid tumors with a profound activity on small lung cancer cells, DMS114. The present study, based on liposomal technology, aimed to develop a suitable carrier of compound 1 to overcome its water insolubility that inhibits further in vivo administration. Liposomes have been proved adequate drug carriers which enhance the solubility of water insoluble drugs and reduce possible side effects. Dipalmitoyl phosphatidylcholine (DPPC), egg phosphatidylcholine (EPC) and dipalmitoyl phosphatidylglycerol (DPPG) were used to prepare liposomes incorporating compound 1 at various molar ratios. Their physicochemical characteristics were determined and liposomes composed of EPC:DPPG 9:0.1 (molar ratio) was chosen as the most suitable carrier concerning their physical characteristics, stability, incorporation efficiency as well as the ability to retain the capture of compound 1 in the presence of RPMI-1640 medium. The activity of the liposomal formulation of compound 1 against human cancer cell lines was compared to that of its free form. The results showed that EPC:DPPG:1 9:0.1:5 (molar ratio) liposomal formulation maintained the pharmacological activity of 1, improved its water solubility and was justified as suitable formulation for in vivo administration of compound 1.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2005

Synthesis and vasodilatory activity of new N-acylhydrazone derivatives, designed as LASSBio-294 analogues.

Conventional therapy to treat hypertension often involves arterial vasodilation. Decrease of blood pressure by vasodilators is normally associated with adverse effects because of their low vascular selectivity. This is of interest to develop new molecules with potential for clinical use and fewer side effects. Recently, a new bioactive compound of the N-acylhydrazone class, LASSBio-294, was shown to produce a cardioinotropic effect and vasodilation. In this report, new derivatives of LASSBio-294 were designed and tested on the contractile response of vascular smooth muscle from Wistar rats. Phenylephrine-induced contracture in the aorta was inhibited by the derivatives LASSBio-785 and LASSBio-788. The concentrations necessary to cause 50% reduction of the maximal vascular response (IC50) were 10.2 +/- 0.5 and 67.9 +/- 6.5 microM. Vasodilation induced by both derivatives is likely to be mediated by a direct effect on smooth muscle because it was not dependent on the integrity of vascular endothelium. LASSBio-785 was seven times more potent than the reference compound LASSBio-294 (IC50 = 74 microM) in producing an endothelium-independent vasodilator effect.

Animals↗