Total Synthesis and Anti-Inflammatory Bioactivity of (-)-Majusculoic Acid and Its Derivatives.

The first total synthesis of marine natural product, (-)-majusculoic acid (1) and its seven analogs (9-15), was accomplished in three to ten steps with a yield of 3% to 28%. The strategy featured the application of the conformational controlled establishment of the trans-cyclopropane and stereochemical controlled bromo-olefination or olefination by Horner-Wadsworth-Emmons (HWE) reaction. The potential anti-inflammatory activity of the eight compounds (1 and 9-15) was evaluated by determining the nitric oxide (NO) production in the lipopolysaccharide (LPS)-induced mouse macrophages RAW264.7. (-)-Majusculoic acid (1), methyl majusculoate (9), and (1R,2R)-2-((3E,5Z)-6-bromonona-3,5-dien-1-yl)cyclopropane-1-carboxylic acid (12) showed significant effect with inhibition rates of 33.68%, 35.75%, and 43.01%, respectively. Moreover, they did not show cytotoxicity against RAW264.7 cells, indicating that they might be potential anti-inflammatory agents.

Synthesis and anti-tubercular activity of N(2)-arylbenzo[g]isoquinoline-5,10-dione-3-iminium bromides.

Tuberculosis has remained a challenge for medicinal chemists worldwide. In the framework of a collaborative program to identify and evaluate novel antitubercular candidate compounds, the biological properties of benzo[g]isoquinoline-5,10-diones have been found to be very promising. In this paper we have further expanded the library by incorporation of an amidinium moiety into the benzo[g]isoquinoline-5,10-dione scaffold. The presence of this functional group also increased the solubility of the quinones in polar solvents. To this purpose N(2)-arylbenzo[g]isoquinoline-5,10-dione-3-iminium bromides were synthesized in a straightforward way by means of a reaction of anilines with 2-(bromomethyl)-3-(cyanomethyl)-1,4-dimethoxynaphthalene. Following the biological evaluation, N(2)-(4-chlorophenyl)-5,10-dioxobenzo[g]isoquinoline-3(2H)-iminium bromide (MIC = 1.16 µM, CC50 = 28.51 µM, SI = 24.58) was selected as the most promising representative. Apart from the nano-molar anti-mycobacterial activity, the compound was able to target intracellular residing Mycobacterium tuberculosis and the susceptibility of a multi-drug-resistant strain towards the compound was confirmed.

Synthesis and pharmacological evaluation of benzannulated derivatives as potent and selective sigma-1 protein ligands.

The σ1 proteins are considered to be a new class of target structures for several central nervous system disorders, including depression, anxiety, psychosis, and Parkinson's and Alzheimer's diseases. Recently, the involvement of these receptors in neuropathic pain and cancer has also been observed. So far, only a few ligands are in clinical trials. In a continuation of our previous studies on the development of σ1 ligands, a new series of benzannulated heterocycles was designed and synthesised. In vitro competition binding assays showed that many of them possessed high σ1 receptor affinity (Ki = 0.6-10.3 nM), and good σ2/σ1 subtype selectivity, without cytotoxic effects on SY5Y cells (human neuroblastoma cell line).

Novel pyridinium-based tags: synthesis and characterization for highly efficient analysis of thiol-containing peptides by mass spectrometry.

In this study, a novel type of pyridinium-based tags, 1-[3-[(2-iodo-1-oxoethyl)amino]propyl]-4-methylpyridinium bromide (IMP) and 1-[3-[(2-iodo-1-oxoethyl)amino]propyl]-4-propylpyridinium bromide (IPP), were designed, synthesized, and applied to the derivatization of thiol-containing peptides. With model peptides as the sample, the labeling efficiency and the stability of the peptide derivatives were investigated. The results indicate that nearly 100% derivatization yield was achieved with the developed tags and the peptide derivatives were stable at room temperature for at least one week. Furthermore, improved ionization efficiency and increased charge states were achieved via both matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MS) and electrospray ionization (ESI) MS, of which IPP exhibited the more obvious improvement of ionization efficiency. Further analysis of tryptic digests of bovine serum albumin (BSA) and α-transferrin, showed that increased identification efficiency of the thiol-containing peptides was achieved by combination with IMP or IPP derivatization. For example, the identification efficiency of the thiol-containing peptides of α-transferrin increased more than 42% upon combination with the IMP or IPP derivatives. We anticipate the novel tags are promising for highly efficient thiol-containing peptide identification in proteome research, especially for low concentrations.

Design and synthesis of novel antineoplastic agents inspired from marine bromopyrrole alkaloids.

Azetidin-2-one, a ß -lactam four-membered heterocyclic ring is widely identified for its diverse medicinal properties. Ezetimibe a cholesterol absorption inhibitor and Aztreonam a potent cephalosporinase inhibitor proved the medicinal value of azetidin-2-ones. On the other hand marine bromopyrrole alkaloids are well known for their diverse biological significance. Hence twenty novel conjugates of azetidin-2-ones integrated with 4,5-dibromopyrrole motif were synthesized and screened for antineoplastic activity using MTT assay. Synthesized hybrids displayed good antineoplastic profile particularly towards breast cancer cell line MCF7, where hybrid 5e displayed maximum cytotoxicity (IC50 = 0.5 µM). The selective cytotoxicity displayed by these conjugates towards tested cancer cells with non-toxicity against normal human VERO cells indicated their potential for further antineoplastic drug development.

Versatile routes to marine sponge metabolites through benzylidene rhodanines.

The first total synthesis of the marine natural products Psammaplin C and Tokaradine A is described. Benzylidene rhodanines were utilized as versatile intermediates toward the synthesis of seven brominated marine sponge metabolites through the optimization of protection group strategies. Spermatinamine demonstrated good inhibition of all cancer cell lines tested, in particular the leukemia K562 and colon cancer HT29 cell lines.

Iron-catalyzed cross-coupling of N-heterocyclic chlorides and bromides with arylmagnesium reagents.

A simple, practical iron salt catalyzed procedure allows fast cross-couplings of N-heterocyclic chlorides and bromides with various electron-rich and -poor arylmagnesium reagents. A solvent mixture of THF and tBuOMe is found to be essential for achieving high yields mainly by avoiding homocoupling side reactions.

Synthesis and α-glucosidase inhibitory mechanisms of bis(2,3-dibromo-4,5-dihydroxybenzyl) ether, a potential marine bromophenol α-glucosidase inhibitor.

Bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (BDDE), derived from the marine algae, is a potential α-glucosidase inhibitor for type 2 diabetes treatment. In the present study, a synthetic route was established as a valid approach to obtain BDDE. Fluorescence spectra, circular dichroism spectra and molecular docking methods were employed to elucidate the inhibitory mechanisms of BDDE against α-glucosidase. The results showed that BDDE could be prepared effectively and efficiently with the established synthetic methods. Synthetic BDDE bound with α-glucosidase and induced minor conformational changes of the enzyme. The docking results indicated the interaction between BDDE and α-glucosidase was driven by both hydrophobic forces and hydrogen bonds. The docked BDDE molecule was completely buried in the α-glucosidase binding pocket with part of the molecule reaching the catalytic center and overlapping with the position of glucose, and the rest of the molecule extending towards protein surface. This study provides useful information for the understanding of the BDDE-α-glucosidase interaction and for the development of novel α-glucosidase inhibitors.

Use of isotope differential derivatization for simultaneous determination of thiols and oxidized thiols by liquid chromatography tandem mass spectrometry.

Here we report a new isotopic pair of derivatization reagents, ω-bromoacetonylquinolinium bromide (BQB) and d(7)-ω-bromoacetonylquinolinium bromide (d(7)-BQB). BQB and d(7)-BQB both rapidly and selectively reacted with thiols in acidic medium within 3min with the aid of a microwave. Reduced thiols and total thiols in urine were labeled with BQB and d(7)-BQB, respectively. The BQB- and d(7)-BQB-labeled urine samples were then mixed and separated on a HILIC (hydrophilic interaction chromatography) column followed by electrospray ionization tandem mass spectrometry (ESI-MS/MS) detection. The new strategy, which we have named isotope differential derivatization, allows us to simultaneously determine thiols and oxidized thiols in a single run. Compared with positive mode ESI detection of unlabeled thiols, the positive mode ESI-MS signal intensities of BQB-labeled thiols were found to increase by 10-, 20-, and 40-fold for cysteine (Cys), homocysteine (HCys), and glutathione (GSH), respectively (unlabeled N-acetylcysteine (Nac) is difficult to detect by ESI-MS in positive mode due to its low ionization efficiency). The detection limits calculated at a signal-to-noise ratio of 3 were found to be 8.02, 1.56, 0.833, and 3.27nmol/L for Cys, HCys, Nac, and GSH, respectively. Recoveries of thiols and disulfides from spiked urine samples were between 80% and 105%. The method was successfully used to determine thiols and oxidized thiols in urine samples of 25 healthy volunteers.

Efficient preparation of [11C]CH3Br for the labeling of [11C]CH3-containing tracers in positron emission tomography clinical practice.

BACKGROUND AND AIM: [C]methyl iodide ([C]CH3I) is the most extensively used methylation agent for the preparation of a majority of C-labeled positron emission tomography (PET) radiotracers, which is commonly produced by the wet method and the gas-phase method. On account of the complexity of the gas-phase method, a simple automated synthesis of [C]methyl bromide ([C]CH3Br) as an analog of [C]CH3I is derived by the wet method in this study. Radiosynthesis of L-[S-methyl-C]methionine (MET), L-[S-methyl-C]cysteine (MCYS), [N-methyl-C]choline (CH), [C]methyl triflate ([C]CH3OSO2CF3), and [C]-2-ß-carbomethoxy-3-ß-(4-fluorophenyl)-tropane (CFT) by methylation reaction with [C]CH3Br, and PET imaging of patients are also described. METHODS: The preparation of [C]CH3Br by a one-pot wet method involved the following steps: reduction of [C]carbon dioxide with lithium aluminium hydride (LiAlH4) solution, treatment with hydrobromic acid, and distillation of [C]CH3Br under continuous nitrogen flow. [C]methylation of L-homocysteine thiolactone hydrochloride, L-cysteine, 2-dimethylaminoethanol, silver triflate, and nor-ß-CFT as precursors with [C]CH3Br and purification with Sep-Pak cartridges gave MET, MCYS, CH, [C]CH3OSO2CF3, and CFT, respectively. In addition, PET imaging of brain cancer and Parkinson's disease was carried out. RESULTS: The uncorrected radiochemical yield of [C]CH3Br was (37.8±2.5%) based on [C]carbon dioxide within a total synthesis time of 10 min and the radiochemical purity of [C]CH3Br was greater than 95%. The uncorrected yields of MET, MCYS, CH, [C]CH3OSO2CF3, and CFT were 70.1±0.5%, 70.2±2.3%, 60.3±1.8%, 95.1±2.2%, and 60.1±1.5% (from [C]CH3OSO2CF3) within a total synthesis time of 2, 2, 5, 1, and 8 min, respectively. The radiochemical purity of MET, MCYS, CH, [C]CH3OSO2CF3, and CFT was more than 95%. Good PET images in the patients are obtained. CONCLUSION: Automated synthesis of [C]CH3Br can be done by the wet method on the commercial [C]CH3I synthesizer. [C]CH3Br can be used for a [C]methylation reaction to produce C-labeled tracers for clinical PET imaging.

An efficient H2O2-based oxidative bromination of alkenes, alkynes, and aromatics by a divanadium-substituted phosphotungstate.

A divanadium-substituted phosphotungstate TBA(4)[γ-HPV(2)W(10)O(40)] (TBA = tetra-n-butylammonium) could act as an effective homogeneous catalyst for the H(2)O(2)-based oxidative bromination.

Rational design of fluorescent bioimaging probes by controlling the aggregation behavior of squaraines: a special effect of ionic liquid pendants.

We herein present an effective strategy to create water-soluble fluorescent bioimaging dyes by introducing the imidazolium-based ionic liquid (IL) pendants into a fluorescent skeleton. A new type of water-soluble imidazolium-anchored squaraine dye was synthesized accordingly. The relationship between the aggregate of squaraines and their fluorescent cell imaging application was elucidated in detail. Firstly, the aggregation behavior of squaraines in water solutions could be suppressed by varying the alkyl chain attached to the imidazolium unit. Secondly, the capability of cellular uptake and staining of dyes was also dramatically enhanced upon increasing the length of the paraffinic chain. These squaraine dyes displayed an excellent photostability that could permit real-time fluorescence bioimaging experiments to be monitored over a long time period with constant sample irradiation. Additionally, we designed for the first time an Fe(II)-ion probe on the basis of an attack of the hydroxyl radical to the four-membered ring of squaraine. The results demonstrated that the imidazolium-anchored squaraines could perform "naked-eye" detection of the Fe(2+) ion over a wide range of other interfering metals in aqueous media. More surprisingly, this process showed a fluorescence "turn-off" and "-on" response through the regeneration of squaraines in cells.

Identification of a boron-containing intermediate in the boron tribromide mediated aryl propargyl ether cleavage reaction.

An alternate reaction mechanism for the boron tribromide mediated deprotection of aryl propargyl ethers based on the isolation of a key boron-containing byproduct is proposed. On the basis of the new mechanistic insight, we discovered that HBBr(2) x SMe(2) can also be used for cleaving aryl propargyl ethers.

Identification of glutathione conjugates of 1-bromopentane and its hepatotoxicity in female BALB/c mice.

Halogenated organic compounds, such as 1-bromopentane (1-BPT), are used as cleaning agents, synthesis agents, or extraction solvents in the workplace. In the present study, glutathione (GSH) conjugation and hepatotoxicity induced by 1-BPT were investigated in female BALB/c mice. S-Bromopentyl GSH, S-bromopentyl cysteine, and mono-hydroxypentyl mercapturic acid were identified in liver by liquid chromatography-electrospray ionization tandem mass spectrometry. Oral treatment of mice with 1-BPT at 1500 mg/kg produced maximum GSH conjugates at 6 h after treatment. For hepatotoxicity tests, the animals were treated orally with 1-BPT at 375, 750, or 1500 mg/kg in corn oil once for a dose response study or at 1500 mg/kg for 6, 12, 24, or 48 h for a time course study. 1-BPT dose-dependently increased serum activity of ALT and AST and decreased hepatic GSH levels, peaking at 6 and 12 h after treatment. 1-BPT (750 and 1500 mg/kg) also significantly increased the hepatic content of malondialdehyde. Thus, 1-BPT could cause hepatotoxicity and depletion of GSH content by forming GSH conjugates, presenting a toxicity mechanism and potential biomarkers for low molecular weight haloalkanes.

Total synthesis and biological evaluation of the marine bromopyrrole alkaloid dispyrin: elucidation of discrete molecular targets with therapeutic potential.

The first total synthesis of dispyrin, a recently reported bromopyrrole alkaloid from Agelas dispar with an unprecedented bromopyrrole tyramine motif, was achieved in three steps on a gram scale (68.4% overall). No biological activity was reported for dispyrin, so we evaluated synthetic dispyrin against>200 discrete molecular targets in radioligand binding and functional assays. Unlike most marine natural products, dispyrin (1) possesses no antibacterial or anticancer activity, but was found to be a potent ligand and antagonist of several therapeutically relevant GPCRs, the alpha1D and alpha2A adrenergic receptors and the H2 and H3 histamine receptors.

Total synthesis of ageladine A, an angiogenesis inhibitor from the marine sponge Agelas nakamurai.

[reaction: see text] A 12-step total synthesis of the tricyclic heteroaromatic marine metabolite ageladine A has been achieved using a 6pi-azaelectrocyclization and a Suzuki-Miyaura coupling of N-Boc-pyrrole-2-boronic acid with a chloropyridine as key steps.

Bioactive rearranged and halogenated semisynthetic derivatives of the marine natural product sarcophine.

Cembranoids are natural diterpenes with 14-membered macrocyclic rings. The simplest natural cembranoid, (+)-cembrene, was isolated from pine oleoresin. Sarcophytols A and B are known cembranoids that inhibit tumor promotion. Sarcophine is a related cembranoid isolated from the Red Sea soft coral Sarcophyton glaucum. Sarcophine and its bioconversion products and semisynthetic derivatives are reported to possess cancer chemopreventive activity. Oxymercuration-demercuration of sarcophine using Hg(OAc)2 and NaBH4 afforded four new rearranged and hydroxylated products. Bromination of sarcophine with N-bromosuccinimide (NBS) furnished two new brominated and rearranged products. Reaction with iodine gave the known iso-sarcophinone and (+)-sarcophytoxin B. Structure elucidation was based on a combination of transition state modeling, molecular dynamics, mechanistic considerations, and 2D NMR data. The antiproliferative activity of the new products is also reported.

Cross-couplings of unactivated secondary alkyl halides: room-temperature nickel-catalyzed Negishi reactions of alkyl bromides and iodides.

The development of a nickel- or palladium-catalyzed method for cross-coupling unactivated secondary alkyl halides has been a long-standing challenge in synthetic chemistry. This communication describes a simple catalyst system-Ni(cod)2/s-Bu-Pybox-that achieves room-temperature Negishi reactions of an array of functionalized primary and secondary alkyl bromides and iodides.

Cytotoxic alpha-bromoacrylic derivatives of low molecular weight.

In vitro and in vivo activities of a small series of alpha-bromoacrylic derivatives of low molecular weight (MW) are described and compared with those of alpha-bromoacrylic derivatives of distamycin-like frames. Low MW compounds, when lacking of a strong basic moiety, are potent cytotoxics, while analogues bearing a strong basic moiety are not. This suggests the existence of an active transport mechanism for distamycin-derived cytotoxics characterized by strong basic amidino or guanidino moieties. Low MW compounds are inactive in vivo, possibly because of the metabolic lability of alpha-bromoacrylic moiety. The same moiety is however present in a series of potent anticancer distamycin-like minor groove binders, for example, PNU-166196 (brostallicin), a fact that underlines the features of the latter.

Syntheses and bioactivities of substituted 9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrones. Unusual reactivities with amines.

A number of substituted 9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrones have been synthesized and their anticancer and antimalarial activities evaluated. A one-pot synthesis of 2,5,8-trimethoxy-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4-dione (4) was achieved by heating a mixture of 1,4-dimethoxyanthracene, methoxyhydroquinone, silver oxide, and zinc iodide in toluene. Regioselective bromination of 4 and 2-methoxy-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrone (7) with N-bromosuccinimide provided 2-bromo-3,5,8-trimethoxy-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4-dione and 2-bromo-3-methoxy-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrone (1), respectively. The reactions of 1 with aliphatic primary amines and secondary amines, respectively, produced different products, a result most likely attributed to the different basicities (or nucleophilicities) and steric effects of the two kinds of amines. The structure of the displacement product, 2-bromo-3-[2-(tert-butoxycarbonyl)ethylamino]-9,10-dihydro-9,10-[1,2]benzenoanthracene-1,4,5,8-tetrone, from the reaction of 1 with tert-butyl 3-aminopropanoate was unequivocally determined by a single-crystal X-ray analysis. IC(50) values of triptycene bisquinones for the inhibition of L1210 leukemia cell viability are in the 0.11-0.27 microM range and for the inhibition of Plasmodium falciparum 3D7 are in the 4.7-8.0 microM range.