Biotransformation of guttiferones, Symphonia globulifera metabolites, by Bipolaris cactivora, an endophytic fungus isolated from its leaves.

The search for active microorganisms for the biotransformation of guttiferone A (1) and C (6) has been successfully undertaken from a collection of endophytic fungi of Symphonia globulifera. Of the twenty-five isolates obtained from the leaves, three are active and have been identified as Bipolaris cactivora. The products obtained are the result of xanthone cyclisation with the formation of two regioisomers among four possible and corresponding to 1,16-oxy-guttiferone and 3,16-oxy-guttiferone. The biotransformation conditions were studied. Interestingly, both oxy-guttiferones A are present in the plant, and the ratio of 3,16-oxy-guttiferone to 1,16-oxy-guttiferone is 4 : 1, very close to that observed by biotransformation (3.8 : 1). These results are consistent with the involvement of endophytes in their formation pathway from guttiferone A, in planta. Finally, biotransformation made it possible to obtain and describe for the first time oxy-guttiferones C.

A Photoalkylative Fluorogenic Probe of Guttiferone A for Live Cell Imaging and Proteome Labeling in Plasmodium falciparum.

Guttiferone A (GA) 1, a polycyclic polyprenylated acylphloroglucinol (PPAP) isolated from the plant Symphonia globulifera (Clusiaceae), constitutes a novel hit in antimalarial drug discovery. PPAPs do not possess identified biochemical targets in malarial parasites up to now. Towards this aim, we designed and evaluated a natural product-derived photoactivatable probe AZC-GA 5, embedding a photoalkylative fluorogenic motif of the 7-azidocoumarin (AZC) type, devoted to studying the affinity proteins interacting with GA in Plasmodium falciparum. Probe 5 manifested a number of positive functional and biological features, such as (i) inhibitory activity in vitro against P. falciparum blood-stages that was superimposable to that of GA 1, dose-response photoalkylative fluorogenic properties (ii) in model conditions using bovine serum albumin (BSA) as an affinity protein surrogate, (iii) in live P. falciparum-infected erythrocytes, and (iv) in fresh P. falciparum cell lysate. Fluorogenic signals by photoactivated AZC-GA 5 in biological settings were markedly abolished in the presence of excess GA 1 as a competitor, indicating significant pharmacological specificity of the designed molecular probe relative to the native PPAP. These results open the way to identify the detected plasmodial proteins as putative drug targets for the natural product 1 by means of proteomic analysis.

Guttiferone A Aggregates Modulate Silent Information Regulator 1 (SIRT1) Activity.

Natural products guttiferone A, hyperforin, and aristoforin were able to inhibit or increase SIRT1 catalytic activity, depending on protein concentration and presence of detergent. On the basis of NMR data for guttiferone A, we demonstrated that the aggregation state of the natural product played a crucial role for its interaction with the enzyme. These results are useful to interpret future in vitro structure-activity relationship studies on these natural products in the quest of their biological target(s).

Isolation of Guttiferones from Renewable Parts of Symphonia globulifera by Centrifugal Partition Chromatography.

The aim of this study was to investigate the species Symphonia globulifera, a source of polycyclic polyprenylated acyl phloroglucinols such as guttiferone A, which is known to exhibit a variety of biological activities including noticeable antileishmanial properties. Our goal was the identification and the quantification of guttiferone A in different renewable parts of S. globulifera and its preparative isolation. To the best of our knowledge, there is no data concerning its mechanism of action. Consequently, it is particularly interesting to isolate it in gram quantities in order to establish structure activity relationship studies. After performing high-performance liquid chromatography profiles detecting the presence of guttiferone A and proceeding to its quantification, a centrifugal partition chromatography methodology using a two-phase solvent system of cyclohexane/ethyl acetate/methanol/water (20 :  1 :  20 : 1, v/v/v/v) was applied to each extract. In conclusion, a centrifugal partition chromatography system has been developed to ensure a fast, reliable, and scalable way to isolate, with a high level of purity, guttiferone A from five renewable parts of S. globulifera. Moreover, this methodology can be extended to the isolation of other polycyclic polyprenylated acyl phloroglucinols such as guttiferones B, C, and D.

Polycyclic Polyprenylated Xanthones from Symphonia globulifera: Isolation and Biomimetic Electrosynthesis.

Two regioisomeric polycyclic xanthones, 3,16-oxyguttiferone A (2) and 1,16-oxyguttiferone A (3), which are polyprenylated acylphloroglucinol-derived analogues, were isolated from the seeds of Symphonia globulifera, together with their presumed o-dihydroxybenzoyl precursor, guttiferone A (1). Anodic oxidation of 1 into the corresponding o-quinone species proved to be an efficient biomimetic method to generate xanthones 2 and 3 in high overall yield and to confirm their structures. Both compounds displayed cytotoxicity against the HCT 116 colon carcinoma cell line with IC50 values of 8 and 3 µM, respectively.

Symphonia globulifera, a widespread source of complex metabolites with potent biological activities.

Symphonia globulifera has been widely used in traditional medicine and has therefore been subjected to several phytochemical studies in the American and African continents. Interestingly, some disparities have been observed concerning its metabolic profile. Several phytochemical studies of S. globulifera have led to the identification of more than 40 compounds, including several polycyclic polyprenylated acylphloroglucinols. Biological evaluations have pointed out the promising biological activities of these secondary metabolites, mostly as antiparasitic or antimicrobial, confirming the traditional use of this plant. The purpose of this review is to describe the natural occurrence, botanical aspects, ethnomedicinal use, structure, and biogenesis, as well as biological activities of compounds isolated from this species according to their provenance.

Comparative LC-MS-based metabolite profiling of the ancient tropical rainforest tree Symphonia globulifera.

In the last few years, several phytochemical studies have been undertaken on the tropical tree Symphonia globulifera leading to the isolation and characterisation of several compounds exhibiting antiparasitic activities against Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani. The comparative LC-MS based metabolite profiling study conducted on the tree led to the identification of compounds originating from specific tissues. The results showed that renewable organs/tissues can be used as the starting material for the production of polycyclic poly-prenylated-acylphloroglucinols, therefore reducing impacts on biodiversity. This study also underlined the lack of knowledge on the secondary metabolites produced by S. globulifera since only a small number of the total detected features were putatively identified using the database of known compounds for the species.

Synthesis of novel guttiferone A derivatives: in-vitro evaluation toward Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani.

The catechol pharmacomodulation of the natural product guttiferone A, isolated from the Symphonia globulifera tree, led to the semisynthesis of a collection of twenty derivatives. The ester and ether derivatives of guttiferone A were evaluated for their anti-plasmodial, trypanocidal and anti-leishmanial activities. Some compounds described below have shown potent antiparasitic activity against Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani in a range from 1 to 5 µM. The evaluation of guttiferone A derivatives against VERO cells highlighted catechol modulations as an interesting tool to decrease the toxicity and keep the activity of this natural compound. The current study revealed new molecules as promising new antiparasitic drug candidates.

Yeast-mediated xanthone synthesis through oxidative intramolecular cyclization.

Benzoylphloroglucinol derivatives are natural products showing diverse biological activities that could be modulated by structural modifications. For this purpose, we studied the biotransformation of guttiferone A and of maclurin using a combinatorial approach for screening active microorganism strains. We found a novel and unexpected yeast-catalyzed oxidation that has selectively given a new oxy-guttiferone A and norathyriol.

A new sphingolipid and furanocoumarins with antimicrobial activity from Ficus exasperata.

From the methanol extract of the stem bark of Ficus exasperata, a new sphingolipid named Ficusamide, (2S,3S,4R,11E)-2-[(2',3'-dihydroxyhexacosanoylamino)]-11-octadecene-1,3,4-triol (1), along with three known furanocoumarins, (S)-(-) oxypeucedanin hydrate (2), (R)-(+) oxypeucedanin hydrate (3), bergapten (5-methoxypsoralen) and six other known compounds, were isolated. Their structures were characterized basing on spectroscopic methods and chemical evidence. Compounds (1-3) were analyzed for their antimicrobial activity. Ficusamide (1) showed wick activity (minimal inhibitory concentration (MIC)=312.5 µg/mL) against Escherichia coli, while the furanocoumarins (2) and (3) showed significant activity (MIC=9.76 µg/mL) against Bacillus cereus, Candida albicans and Microsporum audouinii.

Cytotoxic prenylated acetophenone dimers from Acronychia pedunculata.

Three new acetophenone dimers or Acronychia-type acetophenones, acropyrone (1), acropyranol A (2), and acropyranol B (3), were isolated from the trunk bark of Acronychia pedunculata and structurally characterized, together with four known acetophenone dimers, acrovestone (4), acrovestenol (5), acrofolione A (6), and acrofolione B (7), the acetophenone monomer acronyline (8), and four furoquinoline alkaloids. The chemical structures of the new isolated compounds were elucidated unambiguously by spectroscopic data analysis. The cytotoxic activities of the isolated acetophenone dimers were evaluated against the DU145 prostate and A2058 melanoma human cancer cell lines as well as the NHDF normal cell line. Acrovestone (4) and acrovestenol (5) exhibited substantial cytotoxicity, with IC(50) values of 0.38 and 2.8 µM against A2058 melanoma cells as well as 0.93 and 2.7 µM against DU145 prostate cancer cells, respectively.

Antimicrobial activity of the methanolic extract and compounds from the stem bark of Drypetes tessmanniana.

OBJECTIVE: To evaluate the antimicrobial activity of the methanol extract from the stem bark of Drypetes tessmanniana, fractions (DTB1-5) as well as compounds [friedelin (2), 3,7-dioxofriedelane (3), 3,15-dioxofriedelane (4), 3beta- O-(E)-3,5-dihydroxycinnamoyl-11-oxo-olean-12-ene (6), and 3beta,6alpha-dihydroxylup-20(29)-ene (7). METHODS: Agar disc diffusion was used to determine the sensitivity of the above samples, whilst the microdilution method was used for the determination of the minimal inhibitory concentration (MIC) and the minimal microbicidal concentrations (MMC). RESULTS: The diffusion test showed that the crude extract was able to prevent the growth of all tested organisms. All other samples showed selective activity. The inhibitory effect of the fraction DTB2 was noted on 63.7%, that of DTB1 and DBT3 on 54.6%, whilst DTB4 and DTB5 were active on 9.1% of the 11 tested organisms. The tested compounds prevented the growth of 81.8% of the tested microbial species for compounds 3 and 4, 36.7% for compound 6, and 18.2% for compound 7. The results of the MIC determinations indicated perceptible values for DTB and compound 4 on 81.8% of the tested organisms. For other samples, MICs were detected on 0-63.7%. The lowest MIC value (78.12 microg/mL) for the crude extract and fractions (DTB2) was observed on M. audouinii. The corresponding value for isolated compounds (156.25 microg/mL) was noted with compounds 3 on S. faecalis and 4 on M. audouinii audouinii. The results of the MMC determination suggested that the microbicidal effect of most of the tested samples on the studied microorganisms could be expected. CONCLUSION: The methanol extract from the stem bark of Drypetes. tessmanniana (Euphorbiaceae) as well as some of the isolated compounds might be potential sources of new antimicrobial drugs.

Synthesis and cytotoxic activity of psorospermin and acronycine analogues in the 3-propyloxy-acridin-9(10H)-one and -benzo[b]acridin-125H-one series.

In order to explore the structure-activity relationships in the acronycine and psorospermin series, simplified analogues of the highly cytotoxic (+/-)-(2R*,1'R*)-5-methoxy-11-methyl-2-(2-methyloxiran-2-yl)-1,2-dihydro-11H-furo[2,3-c]acridin-6-one and (+/-)-(2R*,1'R*)-5-methoxy-13-methyl-2-(2-methyloxiran-2-yl)-1,2-dihydro-13H-benzo[b]furo[3,2-h]-acridin-6-one lacking the fused furan ring, including 3-allyloxy-1-methoxy-10-methyl-acridin-9(10H)-one, 3-allyloxy-1-methoxy-5-methyl-benzo[b]acridin-12(5H)-one, the corresponding epoxides, and related dihydrodiol esters and diesters were prepared. Only the simplified oxirane compounds displayed significant antiproliferative activity compared to the parent compounds. The oxirane alkylating unit appears indispensible to observe significant antiproliferative activity in both series, but the presence of the angularly fused furan ring does not appear as a crucial structural requirement to observe significant cytotoxic activity.

Antitumor psoropermum xanthones and sarcomelicope acridones: privileged structures implied in DNA alkylation.

Fused isopropylfuran and dimethylpyran units are privileged structures present in numerous bioactive natural products exemplified, in the field of anticancer drugs, by the furanoxanthone psorospermin and the pyranoacridone acronycine. Psorospermin binds to the N-7 position of the guanine units in the presence of topoisomerase II. In contrast, acronycine derivatives such as cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine alkylate the 2-amino group of DNA guanine residues in the minor groove. Hybrid compounds associating the acridone or benzo[b]acridone chromophore of acronycine derivatives and the epoxyfuran alkylating unit present in psorospermin also display very potent antiproliferative activities, alkylating DNA guanine units at position N-7 in the major groove, as natural xanthones belonging to the psorospermin series.

Oxidative burst inhibitory and cytotoxic indoloquinazoline and furoquinoline alkaloids from Oricia suaveolens.

Two new ß-indoloquinazoline alkaloids, orisuaveoline A (1) and orisuaveoline B (2), two new furoquinoline alkaloids, quinosuaveoline A (5) and quinosuaveoline B (6), and 12 known compounds were isolated from Oricia suaveolens. The structures of the new compounds were deduced by spectroscopic studies. The absolute configuration of nkolbisine (4) was also determined. Compounds 2, 3, 6-8, 10, and 14 were evaluated for oxidative burst inhibitory activity in a chemoluminescence assay and for cytotoxicity against A549 lung carcinoma cells.

Synthesis, cytotoxic activity, and mechanism of action of furo[2,3-c]acridin-6-one and benzo[b]furo[3,2-h]acridin-6-one analogues of psorospermin and acronycine.

Compounds possessing the epoxyfuran system present in the natural cytotoxic dihydrofuroxanthone psorospermin (4) fused onto the acridone or benzo[b]acridone chromophores present in the antitumor acronycine (1) and S23906-1 (3) were prepared. The basic furoacridone and benzofuroacridone cores bearing an isopropenyl substituent at a convenient position were synthesized by condensation of 1,3-dihydroxyacridone (7) or 1,3-dihydroxybenz[b]acridin-12(5H)-one (9) with (E)-1,4-dibromo-2-methylbut-2-ene. In both series, the (2R*,1'S*) epoxides, with the same relative configuration as psorospermin, were the most active compounds, exhibiting cytotoxic properties with IC50 values in the 10-100 nM range. As in the acronycine and psorospermin series, the new compounds act through alkylation of the DNA guanine units. However, a strong difference was noted in the DNA alkylation site between the benzopyranoacridone S23906-1, which alkylates DNA guanine units at position N-2 in the minor groove, and the new 13H-benzo[b]furo[3,2-h]acridin-6-one derived epoxide 21, which alkylates DNA guanine units at position N-7 in the major groove.

New triterpenoids from the stem barks of Drypetes tessmanniana.

The MeOH extract of the stem barks of Drypetes tessmanniana (Euphorbiaceae) afforded two new triterpene derivatives characterized as 3beta-O-(E)-3,5-dihydroxycinnamoyl-11-oxo-olean-12-ene and 3beta,6alpha-dihydroxylup-20(29)-ene together with seven known compounds. Their structures were established on the basis of spectral analysis.

alpha-Glucosidase inhibitory constituents from stem bark of Terminalia superba (Combretaceae).

The CH(2)Cl(2)/CH(3)OH (1/1) extract of the dried stem bark of Terminalia superba afforded two compounds, (7S,8R,7'R,8'S)-4'-hydroxy-4-methoxy-7,7'-epoxylignan and meso-(rel 7S,8R,7'R,8'S)-4,4'-dimethoxy-7,7'-epoxylignan along with 11 known compounds. The structures of the compounds were established by analysing the spectroscopic data and also comparing it with the data of previously known analogues. All the isolated compounds were evaluated for their glycosidase inhibition activities. Gallic acid and methyl gallate showed significant alpha-glucosidase inhibition activity.

Synthesis, antitumor activity, and mechanism of action of benzo[a]pyrano[3,2-h]acridin-7-one analogues of acronycine.

Twenty-two derivatives belonging to the cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[a]pyrano[3,2-h]acridin-7-one series were synthesized in nine steps starting from 3,5-dimethoxyacetanilide (5) and 2-methoxy-1-naphthalenecarboxylic acid (7). Most of them exhibited submicromolar cytotoxicity when tested against murine leukemia (L1210) and human epidermoid carcinoma (KB-3-1) cell lines. The cytotoxic activity correlated strongly with the ability of the compounds to form covalent adducts with purified DNA. Among the most active compounds, 25, with IC50 values of 0.7 and 0.15 microM against L1210 and KB-3-1, respectively, was selected for evaluation in vivo against Colon 38 adenocarcinoma implanted in mice. This compound was active at 3 mg/kg i.v. (day 12 and 24) with 3/7 tumor free mice by day 80.

Alpha-glucosidase inhibitory and antioxidant acridone alkaloids from the stem bark of Oriciopsis glaberrima ENGL. (Rutaceae).

The CH2Cl2/MeOH extract of the stem bark of Oriciopsis glaberrima ENGL. afforded four new acridone alkaloids namely oriciacridone C, D, E and F along with six known compounds: atalaphyllidine, oleanolic acid, butulinic acid, beta-sitosterol, stigmasterol, glucoside of stigmasterol and one synthetically known acridone: 1,3,5-trihydroxy-4-prenylacridone. The structures were established on the basis of MS, 1D and 2D NMR experiments. The acridones 1, 4 and 5 showed potent activity against alpha-glucosidase, while the acridones 1-5 showed moderate free radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH).