Photoactivatable Liposomes for Blue to Deep Red Light-Activated Surface Drug Release: Application to Controlled Delivery of the Antitumoral Drug Melphalan.

Liposome-based nanoparticles able to release, via a photolytic reaction, a payload anchored at the surface of the phospholipid bilayer were prepared. The liposome formulation strategy uses an original drug-conjugated blue light-sensitive photoactivatable coumarinyl linker. This is based on an efficient blue light-sensitive photolabile protecting group modified by a lipid anchor, which enables its incorporation into liposomes, leading to blue to green light-sensitive nanoparticles. In addition, the formulated liposomes were doped with triplet-triplet annihilation upconverting organic chromophores (red to blue light) in order to prepare red light sensitive liposomes able to release a payload, by upconversion-assisted photolysis. Those light-activatable liposomes were used to demonstrate that direct blue or green light photolysis or red light TTA-UC-assisted drug photolysis can effectively photorelease a drug payload (Melphalan) and kill tumor cells in vitro after photoactivation.

Red Light-Responsive Upconverting Nanoparticles for Quantitative and Controlled Release of a Coumarin-Based Prodrug.

Photolytic reactions allow the optical control of the liberation of biological effectors by photolabile protecting groups. The development of versatile technologies enabling the use of deep-red or NIR light excitation still represents a challenging issue, in particular for light-induced drug release (e.g., light-induced prodrug activation). Here, light-sensitive biocompatible lipid nanocapsules able to liberate an antitumoral drug through photolysis are presented. It is demonstrated that original photon upconverting nanoparticles (LNC-UCs) chemically conjugated to a coumarin-based photocleavable linker can quantitatively and efficiently release a drug by upconversion luminescence-assisted photolysis using a deep-red excitation wavelength. In addition, it is also able to demonstrate that such nanoparticles are stable in the dark, without any drug leakage in the absence of light. These findings open new avenues to specifically liberate diverse drugs using deep-red or NIR excitations for future therapeutic applications in nanomedicine.

α-Tertiary Propargylamine Synthesis via KA2-Type Coupling Reactions under Solvent-Free CuI-Zeolite Catalysis.

The potential of copper(I)-zeolite catalysis was evaluated in the three-component KA2-coupling mediated synthesis of α-tertiary propargylamines. Our archetypal copper(I)-doped zeolite CuI-USY proved to be efficient under ligand- and solvent-free conditions at 80 °C. Usable up to four times, this catalytic material enables the coupling of diverse ketones, alkynes, and amines with a broad functional group tolerance. A decarboxylative and a desilylative version, respectively, involving an alkynoic acid and trimethylsilylacetylene as alkyne surrogates, was also set up to bypass selectivity issues and/or to access α-tertiary propargylamines that are unattainable under standard KA2 conditions. Interestingly, the KA2-type coupling reactions were successfully linked to other CuI-catalyzed reactions, thus resulting in sequential one-pot processes under full CuI-USY catalysis.

Two-Photon Sensitive Coumarinyl Photoremovable Protecting Groups with Rigid Electron-Rich Cycles Obtained by Domino Reactions Initiated by a 5-exo-Dig Cyclocarbopalladation.

We herein report the design, synthesis, and photophysical characterization of extended and rigid coumarinyl derivatives showing large two-photon sensitivities (δaΦu ≤ 125 GM) at 740 and 800 nm. To efficiently synthesize these complex photoremovable protecting groups (PPGs), we used step-economic domino reactions. Moreover, those new coumarinyl PPGs display unique bathochromic shifts (≤100 nm) of the uncaging subproducts as a result of the formation of a more conjugated fulvene moiety.

A Coumarin-Based Analogue of Thiacetazone as Dual Covalent Inhibitor and Potential Fluorescent Label of HadA in Mycobacterium tuberculosis.

A novel coumarin-based molecule, designed as a fluorescent surrogate of a thiacetazone-derived antitubercular agent, was quickly and easily synthesized from readily available starting materials. This small molecule, coined Coum-TAC, exhibited a combination of appropriate physicochemical and biological properties, including resistance toward hydrolysis and excellent antitubercular efficiency similar to that of well-known thiacetazone derivatives, as well as efficient covalent labeling of HadA, a relevant therapeutic target to combat Mycobacterium tuberculosis. More remarkably, Coum-TAC was successfully implemented as an imaging probe that is capable of labeling Mycobacterium tuberculosis in a selective manner, with an enrichment at the level of the poles, thus giving for the first time relevant insights about the polar localization of HadA in the mycobacteria.

Anti-Herpes Simplex Virus Type 1 Activity of Specially Selected Groups of Tannins.

Anti-herpes simplex virus (HSV-1) activity of 9 ellagitannins, including 6 natural compounds (castalin, vescalin, acutissimin A, epiacutissimins A and B, mongolicain) and 3 vescalagin synthetic derivatives (VgSBuSH, VgSOctSH, VgOMe), and 13 gallotannin-type compounds [Gal-01A, Gal-01B, Gal-02A, Gal-02B, Gal-03M, Gal-04A, Gal-04B, Gal-05M, Gal-07, Gal-08, Gal-09, Gal-11M (tannic acid), as well as Gal-12 (gallic acid), Gal-13 and Gal-14 (ellagic acid)] were examined in MDBK monolayer cell culture. Their antiviral activity was determined by the cytopathic effect (CPE) inhibition test and their cytotoxicity was evaluated through the neutral red uptake assay. In general, the series of ellagitannins showed a significantly stronger activity against HSV-1 replication than that of the gallotannins. Six of the tested ellagitannins manifested a well-pronounced activity: epiacutissimin B (selectivity index, SI>60.6), epiacutissimin A (SI>55.5), acutissimin A (SI>34.8), mongolicain (SI>32.5), VgSBuSH (SI>24.6) and VgOMe (SI>22.0). Four gallotannin-type compounds inhibited the replication of HSV-1 at a lower but still significant extent: Gal-04B (SI>35.7), Gal-04A (SI>28.5), Gal-11M (tannic acid) (SI>25) and Gal-05M (SI=15.6).

Quench ionic flash nano precipitation as a simple and tunable approach to decouple growth and functionalization for the one-step synthesis of functional LnPO4-based nanoparticles in water.

A novel, one-step method for the synthesis of functional, organic-inorganic hybrid nanoparticles is reported. The quench ionic Flash NanoPrecipitation (qiFNP) method enables the straightforward synthesis of nanoparticles by decoupling the formation of the inorganic core and surface functionalization. As a proof-of-concept, the qiFNP method was successfully applied for the tunable and highly controlled synthesis of various LnPO4-based nanomaterials for bioimaging applications.

Copper(I)-USY as a Ligand-Free and Recyclable Catalyst for Ullmann-Type O-, N-, S-, and C-Arylation Reactions: Scope and Application to Total Synthesis.

The copper(I)-doped zeolite CuI-USY proved to be a versatile, efficient, and recyclable catalyst for various Ullmann-type coupling reactions. Easy to prepare and cheap, this catalytic material enables the arylation and heteroarylation of diverse O-, N-, S-, and C-nucleophiles under ligand-free conditions while exhibiting large functional group compatibility. The facility of this catalyst to promote C-O bond formation was further demonstrated with the total synthesis of 3-methylobovatol, a naturally occurring diaryl ether of biological relevance. From a mechanistic viewpoint, two competitive pathways depending on the nature of the nucleophile and consistent with the obtained results have been proposed.

Asymmetric Alkynylation of ß-Ketoesters and Naphthols Promoted by New Chiral Biphenylic Iodanes.

The preparation of new chiral biphenylic λ3 -iodane reagents bearing transferable alkynyl ligands is described. These reagents transfer their carbon-based ligands onto ß-ketoesters with an enantiomeric excess (ee) up to 68 %, and most remarkably, enable the dearomative alkynylation of naphthols in good to high yields up to 84 % ee.

ortho-Quinol Acetate Chemistry: Reactivity toward Aryl-Based Nucleophiles and Applications to the Synthesis of Natural Products.

Two model ortho-quinol acetates were easily prepared by iodane-mediated acetoxylative phenol dearomatization and evaluated for their reactivity toward various aryl-based nucleophiles, i.e., aryl metallic reagents and phenolic derivatives. Novel modes of reactivity, allowing the formation of biaryl linkages, were revealed and here exploited for the synthesis of two natural phenolics.

Triazolophthalazines: Easily Accessible Compounds with Potent Antitubercular Activity.

Tuberculosis (TB) remains one of the major causes of death worldwide, in particular because of the emergence of multidrug-resistant TB. Herein we explored the potential of an alternative class of molecules as anti-TB agents. Thus, a series of novel 3-substituted triazolophthalazines was quickly and easily prepared from commercial hydralazine hydrochloride as starting material and were further evaluated for their antimycobacterial activities and cytotoxicities. Four of the synthesized compounds were found to effectively inhibit the Mycobacterium tuberculosis (M.tb) H37 Rv strain with minimum inhibitory concentration (MIC) values <10 µg mL(-1) , whereas no compounds displayed cytotoxicity against HCT116 human cell lines (IC50 >100 µm). More remarkably, the most potent compounds proved to be active to a similar extent against various multidrug-resistant M.tb strains, thus uncovering a mode of action distinct from that of standard antitubercular agents. Overall, their ease of preparation, combined with their attractive antimycobacterial activities, make such triazolophthalazine-based derivatives promising leads for further development.

Cu(I)-USY as a Ligand-Free and Recyclable Catalytic System for the Ullmann-Type Diaryl Ether Synthesis.

The catalytic potential of copper(I)-exchanged zeolites was evaluated in the Ullmann-type synthesis of diaryl ethers. Among four investigated zeolites (i.e., USY, MOR, ß, and ZSM5), Cu(I)-USY was the best catalyst and proved efficient under ligand-free conditions in toluene at 120 °C. Cu(I)-USY was also easy to recover and was recyclable up to five times without significant loss of activity.

Synthesis and biological evaluation of analogs of the marine alkaloids granulatimide and isogranulatimide.

A series of pyrrolic analogs and two series of regioisomeric pyrazolic analogs of the marine alkaloids granulatimide and isogranulatimide were prepared. The synthesis of the two first ones was based on the condensation reaction of diversely 5-substituted 3-bromoindoles with pyrrole or pyrazole followed by addition of the intermediates on maleimide or dibromomaleimide, respectively, the so-obtained acyclic adducts being finally photocyclized to the desired analogs. Compounds of the last series were obtained by reacting different 5-substituted-indole-3-glyoxylates with N-Boc-pyrazole-3-acetamide and subsequent photochemical cyclization of the adducts. All the compounds were evaluated for their in vitro growth inhibitory properties toward eight cancer cell lines. Several compounds were also assayed for their ability to abrogate the G2-cell cycle checkpoint or to inhibit a panel of Ser/Thr kinases. Lastly, computer-assisted phase-contrast microscopy (quantitative videomicroscopy) revealed that the three most potent compounds (4a, 9a, 9e), with IC(50) growth inhibitory concentrations ranging between 10 and 20 µM, displayed cytostatic, not cytotoxic, anticancer effects.

Characterization of the antiproliferative activity of Xylopia aethiopica.

BACKGROUND: Xylopia aethiopica, a plant found throughout West Africa, has both nutritional and medicinal uses. The present study aims to characterize the effects of extracts of this plant on cancer cells. RESULTS: We report that X. aethiopica extract prepared with 70% ethanol has antiproliferative activity against a panel of cancer cell lines. The IC50 was estimated at 12 µg/ml against HCT116 colon cancer cells, 7.5 µg/ml and > 25 µg/ml against U937 and KG1a leukemia cells, respectively. Upon fractionation of the extract by HPLC, the active fraction induced DNA damage, cell cycle arrest in G1 phase and apoptotic cell death. By using NMR and mass spectrometry, we determined the structure of the active natural product in the HPLC fraction as ent-15-oxokaur-16-en-19-oic acid. CONCLUSION: The main cytotoxic and DNA-damaging compound in ethanolic extracts of Xylopia aethiopica is ent-15-oxokaur-16-en-19-oic acid.

Recent advances in the development of cinnamic-like derivatives as antituberculosis agents.

INTRODUCTION: The high susceptibility of human immunodeficiency virus-infected people to tuberculosis (TB), the emergence of multi-drug-resistant (MDR-TB) strains and extensively drug-resistant (XDR-TB) ones, has brought TB into the focus of urgent scientific interest. As a result, there has been an upsurge in recent years to find new anti-TB agents, with the cinnamoyl moiety having been identified as a particularly simple and effective pharmacophore for this purpose. AREAS COVERED: This review aims at highlighting the potential of (non)natural cinnamic derivatives to treat TB. It provides an overview of the worldwide recent patent and literature surrounding this type of easy-to-prepare small molecules. There is a special focus on their salient structural and chemical features involved in the reported anti-TB activities. EXPERT OPINION: Cinnamic derivatives clearly appear as attractive drug candidates to combat TB. So far, literature has reported that they are easy to synthesize and have promising anti-TB activities. Nevertheless, the mode(s) of action of these small molecules remain(s) to date obscure, which is why the implicated molecular mechanisms deserve to be investigated in further detail in the near future.

Copper and heme-mediated Abeta toxicity: redox chemistry, Abeta oxidations and anti-ROS compounds.

Oxidative stress mediated by reactive oxygen or nitrogen species (ROS/RNS) seems to be implicated in several diseases including neurodegenerative ones. In one of them, namely Alzheimer's disease, there is a large body of evidence that the aggregation of the peptide amyloid-beta (Abeta) is implicated in the generation of the oxidative stress. Redox active metal ions play a key role in oxidative stress, either in the production of ROS/RNS by enzymes or loosely bound metals or in the protection against ROS, mostly as catalytic centers in enzymes. In Alzheimer's disease, it is thought that metals (mostly Cu, Fe and heme) can bind to amyloid-beta and that such systems are involved in the generation of oxidative stress. In the present article, we review the role of ROS/RNS produced by redox active Cu ions and heme compounds in the context of the amyloid cascade. We focus on (i) the coordination chemistry of Cu and heme to Abeta; (ii) the role of the corresponding Abeta adducts in the (catalytic) production of ROS/RNS; (iii) the subsequent degradation of Abeta by these reactive species and (iv) the use of antioxidants, in particular metal sequestering compounds and direct antioxidants like polyphenols as a therapeutic strategies.

Retrochalcone derivatives are positive allosteric modulators at synaptic and extrasynaptic GABA(A) receptors in vitro.

BACKGROUND AND PURPOSE: Flavonoids, important plant pigments, have been shown to allosterically modulate brain GABA(A) receptors (GABA(A)Rs). We previously reported that trans-6,4'-dimethoxyretrochalcone (Rc-OMe), a hydrolytic derivative of the corresponding flavylium salt, displayed nanomolar affinity for the benzodiazepine binding site of GABA(A)Rs. Here, we evaluate the functional modulations of Rc-OMe, along with two other synthetic derivatives trans-6-bromo-4'-methoxyretrochalcone (Rc-Br) and 4,3'-dimethoxychalcone (Ch-OMe) on GABA(A)Rs. EXPERIMENTAL APPROACH: Whole-cell patch-clamp recordings were made to determine the effects of these derivatives on GABA(A)Rs expressed in HEK-293 cells and in hippocampal CA1 pyramidal and thalamic neurones from rat brain. KEY RESULTS: Rc-OMe strongly potentiated GABA-evoked currents at recombinant α(1-4)ß(2)γ(2s) and α(4)ß(3)δ receptors but much less at α(1)ß(2) and α(4)ß(3). Rc-Br and Ch-OMe potentiated GABA-evoked currents at α(1)ß(2)γ(2s). The potentiation by Rc-OMe was only reduced at α(1)H101Rß(2)γ(2s) and α(1)ß(2)N265Sγ(2s), mutations known to abolish the potentiation by diazepam and loreclezole respectively. The modulation of Rc-OMe and pentobarbital as well as by Rc-OMe and the neurosteroid 3α,21-dihydroxy-5α-pregnan-20-one was supra-additive. Rc-OMe modulation exhibited no apparent voltage-dependence, but was markedly dependent on GABA concentration. In neurones, Rc-Br slowed the decay of spontaneous inhibitory postsynaptic currents and both Rc-OMe and Rc-Br positively modulated synaptic and extrasynaptic diazepam-insensitive GABA(A)Rs. CONCLUSIONS AND IMPLICATIONS: The trans-retrochalcones are powerful positive allosteric modulators of synaptic and extrasynaptic GABA(A)Rs. These novel modulators act through an original mode, thus making them putative drug candidates in the treatment of GABA(A)-related disorders in vivo.

13C NMR discrimination of regioisomeric bispyrroloquinone/bispyrroloiminoquinone ring systems.

The structural assignment of bispyrroloquinone and bispyrroloiminoquinone regioisomers was achieved using (13)C NMR spectral data. In the case of bispyrroloiminoquinones, the carbonyl group in the regioisomer possessing a nitrogen atom in both alpha-positions was systematically less deshielded than the carbonyl group in the other regioisomer. In the case of bispyrroloquinones, the most deshielded carbonyl group in the regioisomer with a nitrogen atom in both alpha-positions was more deshielded than the same carbonyl group in the other regioisomer.