Natural and Semisynthetic Chalcones as Dual FLT3 and Microtubule Polymerization Inhibitors.

Activating mutations in FLT3 receptor tyrosine kinase are found in a third of acute myeloid leukemia (AML) patients and are associated with disease relapse and a poor prognosis. The majority of these mutations are internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3, which have been validated as a therapeutic target. The clinical success of selective inhibitors targeting oncogenic FLT3, however, has been limited due to the acquisition of drug resistance. Herein the identification of a dual FLT3/microtubule polymerization inhibitor, chalcone 4 (2'-allyloxy-4,4'-dimethoxychalcone), is reported through screening of 15 related chalcones for differential antiproliferative activity in leukemia cell lines dependent on FLT3-ITD (MV-4-11) or BCR-ABL (K562) oncogenes and by subsequent screening for mitotic inducers in the HCT116 cell line. Three natural chalcones (1-3) were found to be differentially more potent toward the MV-4-11 (FLT3-ITD) cell line compared to the K562 (BCR-ABL) cell line. Notably, the new semisynthetic chalcone 4, which is a 2'-O-allyl analogue of the natural chalcone 3, was found to be more potent toward the FLT3-ITD+ cell line and inhibited FLT3 signaling in FLT3-dependent cells. An in vitro kinase assay confirmed that chalcone 4 directly inhibited FLT3. Moreover, chalcone 4 induced mitotic arrest in these cells and inhibited tubulin polymerization in both cellular and biochemical assays. Treatment of MV-4-11 cells with this inhibitor for 24 and 48 h resulted in apoptotic cell death. Finally, chalcone 4 was able to overcome TKD mutation-mediated acquired resistance to FLT3 inhibitors in a MOLM-13 cell line expressing FLT3-ITD with the D835Y mutation. Chalcone 4 is, therefore, a promising lead for the discovery of dual-target FLT3 inhibitors.

Consecutive loss of two benzyl radicals from the [M + Na]+ adduct ions of pyrogallol tribenzyl ether and its derivatives.

The electrospray ionization-collision-induced dissociation mass spectra of nine pyrogallol tribenzyl ethers, 2-10, and a catechol dibenzyl ether, 11, that bear various functional groups or larger structural extensions have been studied with respect to the occurrence of a highly characteristic consecutive loss of two benzyl radicals from the sodiated molecular ions, [M + Na]+. It is shown that this specific fragmentation reaction strongly dominates other fragmentation routes, such as loss of carbon monoxide, formaldehyde and water. In addition, elimination of benzaldehyde occurs as a minor fragmentation channel in most cases. In contrast to these aryl-benzyl ethers, the consecutive two-fold loss of C7H7• is suppressed in the [M + Na]+ ions of dibenzyl ethers derived from multiply benzylated gallocatechin and catechin, where the elimination of benzyl alcohol prevails the primary fragmentation almost completely. The secondary fragmentation of the [M + Na]+ ions, which also comprises the two-fold loss of C7H7•, as well as a remarkable primary fragmentation of a flavene-based congener leading to particularly stable sodium-free chromylium product ions is also presented. † Deceased.

Inhibitory and Activating Effects of Some Flavonoid Derivatives on Human Pyruvate Kinase Isoenzyme M2.

Pyruvate kinase isoenzyme M2 (PKM2) is expressed excessively in many different cancer types and it plays an important role in the control of glucose metabolism. Thus, it is evaluated as an important target in the development of medication for cancer. The flavonoids comprise a large group of natural products with variable phenolic structures and occur mainly in plants. They are of great interest due to their biological properties. In this study, the effects of various flavonoid derivatives on the PKM2 enzyme activity were analyzed in vitro. The flavonoid derivatives 1 and 2 showed inhibition effect with IC50 values of <60 µM. IC50 values of compounds 3-8 were calculated as 134, 415, 145, 163, 295 µM, and 3.5 mM, respectively. The molecules 9-12 showed an activation effect with values of AC50 of less than 90 µM. The IC50 values of the derivatives 13-17 were calculated as 115, 150, 200, 221, and 275 µM, respectively. The results show that catechin derivatives can be probably used as lead compounds for the design of PKM2 enzyme activators and inhibitors.

Microsphaerol and seimatorone: two new compounds isolated from the endophytic fungi, Microsphaeropsis sp. and Seimatosporium sp.

A new polychlorinated triphenyl diether named microsphaerol (1), has been isolated from the endophtic fungus Microsphaeropsis sp. An intensive phytochemical investigation of the endophytic fungus Seimatosporium sp., led to the isolation of a new naphthalene derivative named seimatorone (2) and eight known compounds, i.e., 1-(2,6-dihydroxyphenyl)-3-hydroxybutan-1-one (3), 1-(2,6-dihydroxyphenyl)butan-1-one (4), 1-(2-hydroxy-6-methoxyphenyl)butan-1-one (5), 5-hydroxy-2-methyl-4H-chromen-4-one (6), 2,3-dihydro-5-hydroxy-2-methyl-4H-chromen-4-one (7), 8-methoxynaphthalen-1-ol (8), nodulisporins A and B (9 and 10, resp.), and daldinol (11). The structures of 1 and 2 were elucidated by detailed spectroscopic analysis including (1) H- and (13) C-NMR, COSY, HMQC, HMBC, and HR-EI-MS, while the structures of the known compounds were deduced from comparison of their spectral data with those in the literature. Preliminary studies revealed that microsphaerol (1) showed good antibacterial activities against B. Megaterium and E. coli, and good antilagal and antifungal activities against C. fusca, M. violaceum, respectively. On the other hand, seimatorone (2) exhibited moderate antibacterial, antialgal, and antifungal activities.

Microdiplanol and microdiplane: a new m-anisaldehyde and a new 24-methylcholestanol derivative from the endophytic fungus Microdiplodia sp.

Phytochemical investigation of the endophytic fungus Microdiplodia sp. afforded a new m-anisaldehyde derivative named microdiplanol (1) and a new 24-methylcholestanol derivative named microdiplane (2). Their structures were confirmed by a comprehensive analysis of 1D and 2D NMR and mass spectrometric data.

Seimisochromenes A and B: two new dihydroisochromenes from the endophytic fungus, Seimatosporium sp.

Two new dihydroisochromenes, named seimisochromenes A and B (1 and 2), were isolated from an endophytic fungus, Seimatosporium sp. The structures of seimisochromenes A and B have been determined from 1D ((1)H and (13)C NMR spectra) and 2D (COSY, HMQC, HMBC, and NOESY) NMR experiments.

Antimicrobial constituents from three endophytic fungi.

OBJECTIVE: To evaluate the antimicrobial potential of extracts of the endophytic fungi Plectophomella sp., Physalospora sp., and Crataegus monogyna (C. monogyna) and study the tentative identification of their active constituents. METHODS: Crude extracts and isolated compounds were screened for antimicrobial activity using the agar well diffusion method. Four compounds were purified from three endophytic fungi using column chromatography and their structures have been assigned based on their (1)H and (13)C nuclear magnetic resonance spectra. RESULTS: Plectophomella sp., Physalospora sp., and C. monogyna extracts showed promising antifungal, antibacterial and herbicidal properties. (-)-Mycorrhizin A was isolated from Plectophomella sp. while cytochalasins E and K were isolated from Physalospora sp. Similarly radicinin was purified from the endophytic fungus C. monogyna. The ethyl acetate extract of Plectophomella sp. showed significant antifungal activity towards Ustilago violacea (U. violacea) and Eurotium repens (E. repens) and significant antibacterial activity against Bacillus megaterium. Interestingly, the ethyl acetate extracts of Physalospora sp. and C. monogyna showed strong herbicidal and antifungal activities towards Chlorella fusca, U. violacea, E. repens, Mycotypha microspora (M. microspora), Fusarium oxysporum, Escherichia coli, and Bacillus megaterium. (-)-Mycorrhizin A showed significant antifungal activity towards U. violacea and E. repens. Cytochalasins E and K showed strong antifungal activity against E. repens and M. microspora especially towards fungal Mycotypha microspora. Similarly cytochalasins E and K showed good herbicidal activity towards Chlorella fusca. Radicinin showed strong antifungal activity against E. repens and M. microspora. CONCLUSIONS: Antimicrobial activities demonstrated by the extracts of the endophytic fungi Plectophomella sp., Physalospora sp., and C. monogyna and four isolated compounds clearly demonstrate that these fungi extracts and active compounds present a great potential use in the food, cosmetic and pharmaceutical industries.

Coniothyren: a new phenoxyphenyl ether from the endophytic fungus, Coniothyrium sp.

Phytochemical investigation of the endophytic fungus Coniothyrium sp. resulted in the isolation of a new phenoxyphenyl ether, named coniothyren (1), and two known compounds, coniol (2) and (+)-epoxydon (3). The structure of the new compound was elucidated by detailed spectroscopic analysis, namely, (1)H NMR, (13)C NMR, COSY, HMQC, HMBC, and HR-EI-MS. Preliminary studies demonstrated that (+)-epoxydon (3) displayed good antibacterial and antialgal activities toward Bacillus megaterium and Chlorella fusca, respectively.

Cryptosporioptide: a bioactive polyketide produced by an endophytic fungus Cryptosporiopsis sp.

An antibiotic polyketide, Cryptosporioptide (1) was isolated from the culture extract of the endophytic fungus Cryptosporiopsis sp. The structure of Cryptosporioptide has been established with the help of 1D ((1)H, (13)C), 2D NMR (HSQC, HMBC, COSY, NOESY) techniques and mass spectrometry (FABMS, HRFABMS). The absolute configuration was established by means of electronic circular dichroism (ECD). Cryptosporioptide exhibited both lipoxygenase inhibitory and anti-Bacillus megaterium activities.

Advances in the total synthesis of biologically important callipeltosides: a review.

An overview of synthetic efforts toward callipeltosides A-C, macrolide natural products, from 1998 to present is provided. The emphasis of this review is the various ring-constructing and stereoforming strategies employed in these synthetic routes.

Kenganthranol F, a new anthranol from Psorospermum aurantiacum.

A new anthranol, kenganthranol F, was isolated from the ethyl acetate extracts of the seeds and the whole plant of the Cameroonian plant Psorospermum aurantiacum (Hypericaceae), together with fifteen known compounds viz., ferruginin B, vismin, vismion D, haronginanthrone, kenganthraquinone, kenganthranol B and kenganthranol E isolated from the fruits and 3-geranyloxyemodinanthrone, 2-geranylemodin, bianthrone A1, vismione D, 1,8-dihydroxy-3-geranyloxy-6-methylanthraquinone, vismione M, vismiaquinone, vismiaquinone C being isolated from the whole plant. The structure of the new isomer of kenganthranol F was determined to be 1,8,10-trihydroxy-3,4-[2,2-dimethyldihydropyrano]-6-methyl-2,5-bis-(3,3-dimethylallyl)-anthrone.

Structural and stereochemical studies of hydroxyanthraquinone derivatives from the endophytic fungus Coniothyrium sp.

Four known hydroxyanthraquinones (1-4) together with four new derivatives having a tetralone moiety, namely coniothyrinones A-D (5-8), were isolated from the culture of Coniothyrium sp., an endophytic fungus isolated from Salsola oppostifolia from Gomera in the Canary Islands. The structures of the new compounds were elucidated by detailed spectroscopic analysis and comparison with reported data. The absolute configurations of coniothyrinones A (5), B (6), and D (8) were determined by TDDFT calculations of CD spectra, allowing the determination of the absolute configuration of coniothyrinone C (7) as well. Coniothyrinones A (5), B (6), and D (8) could be used as ECD reference compounds in the determination of absolute configuration for related tetralone derivatives. This is the first report of anthraquinones and derivatives from an isolate of the genus Coniothyrium sp. These compounds showed inhibitory effects against the fungus Microbotryum violaceum, the alga Chlorella fusca, and the bacteria Escherichia coli and Bacillus megaterium.

Antitubercular activity of the semi-polar extractives of Uvaria rufa.

OBJECTIVE: To investigate the inhibitory activity of the chloroform extract, petroleum ether and chloroform sub-extracts, lead-acetate treated chloroform extract, fractions and secondary metabolites of Uvaria rufa (U. rufa) against Mycobacterium tuberculosis (M. tuberculosis) H(37)Rv. METHODS: The antituberculosis susceptibility assay was carried out using the colorimetric Microplate Alamar blue assay (MABA). In addition, the cytotoxicity of the most active fraction was evaluated using the VERO cell toxicity assay. RESULTS: The in vitro inhibitory activity against M. tuberculosis H(37)Rv increased as purification progressed to fractionation (MIC up to 23 µg/mL). The chloroform extract and its sub-extracts showed moderate toxicity while the most active fraction from chloroform sub-extract exhibited no cytotoxicity against VERO cells. Meanwhile, the lead acetate-treated crude chloroform extract and its fractions showed complete inhibitions (100%) with MIC values up to 8 µg/mL. Phytochemical screening of the most active fraction showed, in general, the presence of terpenoids, steroids and phenolic compounds. Evaluation of the antimycobacterial activity of known secondary metabolites isolated showed no promising inhibitory activity against the test organism. CONCLUSIONS: The present results demonstrate the potential of U. rufa as a phytomedicinal source of compounds that may exhibit promising antituberculosis activity. In addition, elimination of polar pigments revealed enhanced inhibition against M. tuberculosis H(37)Rv. While several compounds known for this plant did not show antimycobacterial activity, the obtained results are considered sufficient reason for further study to isolate the metabolites from U. rufa responsible for the antitubercular activity.

Villarinol, a new alkenoyloxyalkenol derivative from the endemic Philippine Rubiaceae species Villaria odorata.

Villarinol (1), a new alkenoyloxy alkenol metabolite, has been isolated from the dichloromethane extract of Villaria odorata, an endemic Rubiaceae Philippine plant, along with the known compounds stigmasterol and 4-hydroxybenzaldehyde. The structure of 1 was elucidated on the basis of spectroscopic and spectrometric studies. The extracts of V. odorata exhibited moderate inhibition against Mycobacterium tuberculosis H37Rv, based on the colorimetric microplate alamar blue assay.

Photoactivated [3+2] addition of 6,7-seco-angustilobine B to fullerene [C60].

A synthesis of a new alkaloid-fullerene conjugate (1) is reported. The reaction was carried out by photoinduced [3+2] cycloaddition of the Alstonia indole alkaloid, 6,7-seco-angustilobine B (2), to fullerene[C60] (3) under aerobic conditions. The major monoaddition photoadduct (1) was characterized unambiguously by UV, IR, MALDI-TOFMS and NMR experiments. A mechanism highlighted by sequential photoinduced electron transfer andradical recombination pathways is also proposed. No significant enhancement in inhibition against M. tuberculosis H37Rv was observed for 1 compared with its parent compounds 2 and 3.

New quinoline-5,8-dione and hydroxynaphthoquinone derivatives inhibit a chloroquine resistant Plasmodium falciparum strain.

We report on the design, synthesis, and in vitro evaluation of new quinoline-5,8-dione and hydroxynaphthoquinone derivatives. The synthesized compounds were evaluated for in vitro antimalarial activity against Plasmodium falciparum. Of the 15 compounds, 7a-c, 8a, 9b, 11, and 15 were effective in growth inhibition with IC(50) values of below 5 µM.

Bioactive briarane diterpenoids from the South China Sea gorgonian Dichotella gemmacea.

Six new briarane diterpenoids, gemmacolides T-Y (1-6), were isolated together with three known analogs, juncenolide J (7), praelolide (8), and junceellolide C (9), from the South China Sea gorgonian Dichotella gemmacea. The structures of the new compounds were elucidated by detailed spectroscopic analysis and comparison with reported data. The absolute configuration was suggested based on biosynthetic considerations. In an in vitro bioassay, compounds 3 and 6 showed potent growth inhibition towards tumor cell lines of A549 and MG63, being stronger than the positive control of adriamycin. These compounds also exhibited weak antimicrobial activity against the bacterium Escherichia coli and the fungi Microbotryum violaceum and Septoria tritici.

Two new antimicrobial metabolites from the endophytic fungus, Seimatosporium sp.

Two new acaranoic acids, named seimatoporic acid A and B (1, and 2), together with six known compounds, R-(-)-mellein (3), cis-4-hydroxymellein (4), trans-4-hydroxymellein (5), 4R-hydroxy-5-methylmellein (6), (-)-5-hydroxymethylmellein (7), and ergosterol (8) were isolated from an endophytic fungus, Seimatosporium sp, by a bioassay-guided procedure. The structures of the new compounds have been assigned from analysis of the 1H and 13C NMR spectra, DEPT, and by 2D COSY, HMQC, HMBC and NOESY experiments. A mixture of compounds 1 and 2 showed strong antifungal activity against Botrytis cinerea, Septoria tritici, and Pyricularia oryzae.

Eucleanal: a new napthalene derivative from Euclea divinorum.

A new naphthalene derivative, named eucleanal (1), was isolated from Euclea divinorum Hiern., and its structure elucidated by detailed spectroscopic (1H, 13C NMR, COSY, HMQC, HMBC) and HREIMS analysis.

Pyrenocines J-M: four new pyrenocines from the endophytic fungus, Phomopsis sp.

Four new pyrenocines, named pyrenocines J-M (1-4), were isolated from an endophytic fungus, Phomopsis sp, by a bioassay-guided method. The structures of the new compound have been assigned from ¹H and ¹³C NMR spectra, DEPT, and by 2D COSY, HMQC, and HMBC experiments. Preliminary studied showed that compounds 1, 2 and 4 showed good antifungal, antibacterial, and algicidal properties, while compound 3 had good antibacterial and algicidal properties.