Synthesis of analogs of amathamide A and their preliminary antimicrobial activity

Syntheses of three non-brominated analogs of amathamide A (1), a natural alkaloid isolated from the Tasmanian marine bryozoan Amathia wilsoni, are described. Antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomona aeruginosa, and Candida albicans was tested. Test results for amathamide A (1) showed a weak activity against C. albicans and E. coli. The three non-natural analogs 2-4 proved to be inactive compounds.     

Selective determination of mono- and dihydroxylated analogs of polybrominated diphenyl ethers in marine sponges by liquid-chromatography tandem mass spectrometry

A number of bioactive brominated secondary metabolites, including hydroxylated polybrominated diphenyl ethers, have been isolated from algae, sponges, and bacteria. In the present study, a screening method using liquid-chromatography tandem mass spectrometry was developed for the identification and selective determination of dihydroxy (diOH), hydroxy-methoxy (OH-MeO), and dimethoxy (diMeO) analogs of tetra- to hexa-BDEs in marine biota. In negative atmospheric pressure chemical ionization (APCI) mode, diOH and OH-MeO analogs provided intense [M-H](-) ions, whereas diMeO analogs provided characteristic [M-Br+O](-) and [M-CH(3)](-) ions. This enabled the diOH-, OH-MeO-, and diMeO-PBDEs to be distinguished using selected reaction monitoring transitions in the APCI source. Recoveries of 2'-OH-6-MeO-2,3',4,5'-tetra-BDE in spiked marine samples were 84 ± 5 %, with a limit of quantification at 9.1 ng mL(-1) (signal-to-noise ratio = 10). The developed method was used to analyze two sponge species collected from Palau, Micronesia; the concentration ratio of diOH-tetra-BDE:OH-MeO-tetra-BDE was 10:1 for the Lamellodysidea sp., whereas it was 1:30 for the Callyspongia sp.     

Parallel Synthesis of Novel 3-Substituted 1-Ethyl-6-methylpyrimido[4,5-c]pyridazine-5,7(1H,6H)-dione Analogs

A library of novel 1H-pyrimido[4,5-c]pyridazine-5,7-dione analogs was prepared in a parallel fashion via the cyclization of 6-(1-ethylhydrazinyl)-3-methylpyrimidine-2,4(1H,3H)-dione (4) with α-bromoketones and was then isolated by a two-step purification method with >90% purity. Both the library synthesis and purification method proved suitable for analogs with a high diversity of substitution at the 3-position including various alkyl, aryl, and heteroaryl groups.     

Amdigenol A,a long carbon-backbone polyol compound,produced by the marine dinoflagellate Amphidinium sp

A polyol compound, amdigenol A, was isolated from the dinoflagellate Amphidinium sp. that adhered to the surface of the marine alga Digenea simplex. A structural elucidation was performed by 2D-NMR spectroscopy, degradation with a second generation Hoveyda–Grubbs catalyst and ESI-CID-MS/MS analyses. Amdigenol A consists of a C₉₈-linear carbon backbone including two core structures of amphidinol analogs and is likely formed linearly by two amphidinol analogs.     

Polycavernoside C and C2, the new analogs of the human lethal toxin polycavernoside A, from the red alga, Gracilaria edulis

Two new analogs of the human lethal toxin polycavernoside A, polycavernoside C and C2 (0.1-0.2 mg for each), were isolated from the red alga, Gracilaria edulis. The relative stereostructure of polycavernoside C and the absolute structure of polycavernoside C2 were determined by spectroscopic analysis and synthesis of the model of their aglycon.     

Complete assignments of (1)H and (13)C NMR spectral data of nine surfactin isomers

A new surfactin isomer (1) was isolated from a mangrove bacteria strain 'Bacillus sp'. Its structure was identified, and full assignments of (1)H and (13)C NMR spectral data were achieved for the first time by a combination of mass spectrometry and 1D and 2D NMR experiments including DEPT, (1)H-(1)H COSY, HSQC, HMBC, TOCSY, ROESY, and HSQC-TOCSY. The NMR spectral data of eight known analogs (2-9) are also reported.     

Synthesis and Evaluation of Pancreatic Lipase Inhibitory Effects Halogenated Polyunsaturated Lipids from Marine Natural Products: Methyl Xestospongoate and Analogs

Methyl xestospongoate (MXS), a brominated polyunsaturalted lipid recently isolated from the Chinese marine sponge Xestospongia testudinaria, showed strong in vitro pancreatic lipase (PL) inhibitory activity. Inspired by its promising activity and potential clinical application, a series of shorter or longer‐chain and chlorinated analogs of MXS was prepared and evaluated for PL inhibitory activity. The result of a bioassay indicated that the terminal brominated ones are better than the chlorinated ones on their bioactivity, and 16–20 C‐atoms in the structures of MXS analogs might be optimal for their PL inhibitory activity. The results obtained in the present work are useful for the design of novel pancreatic lipase inhibitors.     

Synthesis,Profiling, and Bioactive Conformation of trans‐Cyclopropyl Epothilones

A series of new 3‐deoxy‐C(12),C(13)‐trans‐cyclopropyl‐epothilones have been prepared, bearing benzothiazole, quinoline, thiazol‐5‐ylvinyl, or isoxazol‐3‐ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring‐closure was based on ring‐closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole‐containing 16‐desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring‐closure either by RCM or by macrolactonization. Benzothiazole‐ and quinoline‐based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol‐5‐ylvinyl or an isoxazol‐3‐ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)?C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)?C(11) torsion angle in the tubulin‐bound conformation of 12,13‐trans‐epothilones.     

Cytotoxic 5‐Hydroxyindole Alkaloids from the Marine Sponge Scalarispongia sp.

Three new 5‐hydroxyindole alkaloids ( 1 , 2 , 3 ) along with seven known analogs ( 4 , 5 , 6 , 7 , 8 , 9 , 10 ) were isolated from a Dokdo marine sponge Scalarispongia sp. The elucidation of the structures of the new compounds by spectroscopic analyses indicated that these compounds were an indole glyoxylate ( 1 ), a mono‐indole analog of hyrtinadine A ( 2 ), and a symmetrical bis‐indole with pyridine linker ( 3 ). The comparison of IC₅₀ values for obtained compounds against a human leukemia cell line revealed that the bis‐indole structure is a requirement for cytotoxicity.     

Three New Bisabolane Sesquiterpenes from Ligularia songarica

Three new bisabolane sesquiterpenes, songaricalarins F–H ( 1 – 3 , resp.), and five known analogs, 4 – 8 , were isolated from roots and rhizomes of Ligularia songarica. The structures were elucidated by spectroscopic methods, including 2D‐NMR techniques. The isolated compounds were also evaluated for their cytotoxic activities, against human lung carcinoma (A‐549) and human breast adenocarcinoma (MCF‐7) cell lines, and three compounds were found to show moderate cytotoxicities.     

Total syntheses of thiocoraline and BE-22179 and assessment of their DNA binding and biological properties.

Full details of the total syntheses of thiocoraline (1) and BE-22179 (2), C(2) symmetric bicyclic octadepsipeptides possessing two pendant 3-hydroxyquinoline chromophores, are described in which their relative and absolute stereochemistry were established. Key elements of the approach include the late-stage introduction of the chromophore, symmetrical tetrapeptide coupling, macrocyclization of the 26-membered octadepsipeptide conducted at the single secondary amide site following disulfide formation, and a convergent assemblage of the tetradepsipeptide with introduction of the labile thiol ester linkage in the final coupling reaction under near racemization free conditions. By virtue of the late-stage introduction of the chromophore and despite the challenges this imposes on the synthesis, this approach provides ready access to a range of key chromophore analogues. Thiocoraline and BE-22179 were shown to bind to DNA by high-affinity bisintercalation analogous to echinomycin, but with little or no perceptible sequence selectivity. Both 1 and 2 were found to exhibit exceptional cytotoxic activity (IC(50) = 200 and 400 pM, respectively, L1210 cell line) comparable to echinomycin and one analogue, which bears the luzopeptin chromophore, was also found to be a potent cytotoxic agent.     

Synthesis of substance P analogs and agonistic and antagonistic activities.

Fourteen analogs of substances P (SP), six previously synthesized by a solution method and eight newly synthesized by a solid-phase technique, have been tested for agonistic and antagonistic activities utilizing the isolated guinea pig ileum. The primary objective is to achieve effective inhibitors of SP. These analogs had agonistic activities ranging from negligible to that equivalent to SP. Six of the fourteen analogs had some degree of antagonistic activity [D-Leu8, D-Phe9]-SP is an analog which constitutes a lead to new substitutions, because it had antagonistic activity, but only negligible agonistic activity. One concept for effective antagonistic activity requires negligible or no agonistic activity.     

Three New Cadinene Derivatives from Xenia Puerto‐Galerae

Chromatographic investigation of an acetone extract of the octocoral Xenia puerto‐galerae afforded three new cadinene sesquiterpenes; 8‐epi‐xenitorin A ( 1 ), 10‐epi‐xenitorin C ( 2 ), and 7‐isopropenyl‐4,10‐dimethyl‐2,3,4,5‐tetrahydronaphthalene ( 3 ), in addition to four known cadinene analogs ( 4 , 11–13 ) and six xenicanes ( 5–10 ). The structures were elucidated through spectroscopic analysis, especially 2D NMR. A biogenetic pathway of 1–3 and analogs was proposed.     

Structure and C-13 signal assignments of new methylsterols from nervilia purpurea by two-dimensional NMR spectroscopy

The structures of cyclonervilasterol (1a) and its analogs (2a, 3a, and 4a), isolated from Nervilia purpurea, were confirmed by application-of 2-D NMR spectroscopy including INADEQUATE and also their ¹³C NMR signals were assigned.     

Ruptenes: A Family of Terpene Analogs Give Insight into Cyclisation Mechanisms by Cascade Disruption

The terpenoid substrate analogs (7R)-6,7-dihydrogeranylgeranyl diphosphate (6,7-dihydro-GGPP) and (7R)-6,7-dihydrogeranylfarnesyl diphosphate (6,7-dihydro-GFPP) were synthesised from (S)-citronellol and enzymatically converted with nine diterpene and two sesterterpene synthases, respectively. In two cases the substrate analogs were converted into diterpenes in cyclisation reactions corresponding to those observed for the native substrate GGPP, while the cyclisation cascade was disrupted or redirected in the other nine cases, leading to products that were named ruptenes. Several of the isolated ruptenes represent deprotonation products of cationic intermediates that are analogs of the intermediates proposed along the cyclisation cascades for the native substrates GGPP or GFPP, thus giving insights into the complex reaction mechanisms of terpene synthase mediated biosynthesis.     

Semisynthesis of Some 7-Deoxypaclitaxel Analogs from Taxine B

Taxine B (3), isolated from the dried needles of Taxus baccata, was converted into six novel 7-deoxypaclitaxel analogs, 20, 21a,b, and 23-25, that have structural changes at C1, C2, and C4. A method for the introduction of the benzoyl function at C2, via a benzylidene acetal at C1-C2, will be revealed. All compounds showed very little or no measurable cytotoxic activity against some well-characterized human tumor cell lines, probably due to the nonacylated hydroxyl group at C4.     

Alkaloids from the Twigs and Leaves of Daphniphyllum macropodum

Three new alkaloids, macrodumines A–C ( 1 – 3 , resp.), along with ten known analogs, were isolated from the twigs and leaves of Daphniphyllum macropodum. Their structures were elucidated on the basis of spectroscopic methods. The 11‐OH configuration of the known alkaloid hydroxydaphgraciline ( 4 ) was assigned as α for the first time by comparing the NMR data with those of macrodumine C ( 3 ).     

Room Temperature Phosphorescence from Tryptophan and Halogenated Tryptophan Analogs in Amorphous Sucrose

Abstract. Tryptophan phosphorescence lifetime and quantum yield are sensitive to the local environment. The phosphorescence from tryptophan analogs, however, has not been studied. We report here data on the room temperature phosphorescence of tryptophan, 4-, 5- and 6-fluoro-DL-tryptophan (4-F-trp, 5-F-trp and 6-F-trp) and 5-bromo-DL-tryptophan (5-Br-trp) embedded in glassy powders of freeze-dried sucrose. In aqueous solution, the absorption of the analogs was either blue-shifted (4-F-trp), red-shifted (5-F-trp and 5-Br-trp) or not shifted (6-F-trp) with respect to tryptophan. The phosphorescence emission spectra of all analogs were red-shifted compared to trp (442 nm) with maxima at 446 nm (5-F-trp), 451 mn (6-F-trp), 452 nm (5-Br-trp) and 469 nm (4-F-trp). The 5-F-trp and 6-F-trp analogs had emission intensities similar to tryptophan (relative quantum yields of 0.68 and 0.91, respectively, compared to tryptophan), while the intensities of the 4-F and 5-Br analogs were lower (relative quantum yields of 0.039 and 0.022, respectively). All analogs exhibited complex decay behavior requiring several exponentials for an adequate fit; the average lifetimes were all lower than that of trp (1039 ms). The average lifetimes of the fluorinated analogs (5-F, 721 ms; 6-F, 482 ms and 4-F, 35 ms) scaled approximately with the relative quantum yields while that of 5-Br (0.53 ms) was significantly lower. Analysis of the individual lifetimes suggested that the fluorinated analogs differ in their sensitivity to environmental interactions, with 5-F- and 6-F-trp quenched 1.5-2-fold and 4-F-trp about 23-fold more efficiently than tryptophan. The red-shifted 5-F-trypto-phan analog, which has been incorporated into proteins, may provide an alternative phosphorescence probe for selective phosphorescence detection of a specific protein in a complex mixture.