Hydrogen-Bonding Activation of Gold(I) Chloride Complexes: Enantioselective Synthesis of 3(2H)-Furanones by a Cycloisomerization-Addition Cascade.

Enantioselective synthesis of 3(2H)-furanones has been achieved using the intermolecular H-bonding activation of gold(I) chloride complexes. A DM-BINAP [(R)-(+)-2,2'-Bis[di(3,5-xylyl)phoshino]-1,1'-binaphthyl] digold(I) dichloride complex in combination with a sulfonyl squaramide (SO2Sq) has been identified as the optimal catalytic system. The process involves a 5-endo-dig oxa-cyclization followed by stereocontrolled addition of indoles. Interestingly, the soft L*Au-Cl activation by H-bonding allowed the recovery of both L*Au-Cl and the activator after chromatographic purification.

Silver-Free Gold-Catalyzed Heterocyclizations through Intermolecular H-Bonding Activation.

Modulable monosulfonyl squaramides have been shown to exert activation of gold(I) chloride complexes through H-bonding in an intermolecular way. Combinations of (PPh3)AuCl or IPrAuCl complexes and an optimal sulfonyl squaramide cocatalyst bearing two 3,5-bis(trifluoromethyl)phenyl groups efficiently catalyzed diverse heterocyclizations and a cyclopropanation reaction, avoiding in all cases undesired side reactions. Computational studies indicate that the Au-Cl bond breaks by transligation to the triple bond in a ternary complex formed by the actual AuCl···HBD catalyst and the substrate.

Studies on the Regioselective Rearrangement of Azanorbornanic Aminyl Radicals into 2,8-Diazabicyclo[3.2.1]oct-2-ene Systems.

Aminyl radicals are nitrogen-centered radicals of interest in synthetic strategies involving C-N bond formation due to their high reactivity. These intermediate radicals are generated by the reaction of an organic azide with tributyltin hydride (Bu3SnH) in the presence of substoichiometric amounts of azobisisobutyronitrile (AIBN). In this work, we report the regioselective rearrangement of azanorbornanic ([2.2.1]azabicyclic) aminyl radicals into 2,8-diazabicyclo[3.2.1]oct-2-ene systems. With the aim to establish the structural requirements for this ring expansion, we have studied the effect of different bridgehead atoms of the [2.2.1]bicyclic system and the presence of an alkyl substituent at C4. Attempts to perform this ring expansion on a monocyclic analogue have been also explored to evaluate the influence of the bicyclic skeleton on the rearrangement. A detailed mechanistic proposal supported by computational studies is reported.

Identification of new FK866 analogues with potent anticancer activity against pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases for which chemotherapy has not been very successful yet. FK866 ((E)-N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) is a well-known NAMPT (nicotinamide phosphoribosyltransferase) inhibitor with anti-cancer activities, but it failed in phase II clinical trials. We found that FK866 shows anti-proliferative activity in three PDAC cell lines, as well as in Jurkat T-cell leukemia cells. More than 50 FK866 analogues were synthesized that introduce substituents on the phenyl ring of the piperidine benzamide group of FK866 and exchange its buta-1,4-diyl tether for 1-oxyprop-3-yl, (E)-but-2-en-1,4-diyl and 2- and 3-carbon tethers. The pyridin-3-yl moiety of FK866 was exchanged for chlorinated and fluorinated analogues and for pyrazin-2-yl and pyridazin-4-yl groups. Several compounds showed low nanomolar or sub-nanomolar cell growth inhibitory activity. Our best cell anti-proliferative compounds were the 2,4,6-trimethoxybenzamide analogue of FK866 ((E)-N-(4-(1-(2,4,6-trimethoxybenzoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) (9), the 2,6-dimethoxybenzamide (8) and 2-methoxybenzamide (4), which exhibited an IC50 of 0.16 nM, 0.004 nM and 0.08 nM toward PDAC cells, respectively.

Multifunctional Switch Based on Spin-Labeled Gold Nanoparticles.

The fabrication of multifunctional switches is a fundamental step in the development of nanometer-scale molecular spintronic devices. The anchoring of active organic radicals on gold nanoparticles (AuNPs) surface is little studied and the realization of AuNPs-based switches remains extremely challenging. We report the first demonstration of a surface molecular switch based on AuNPs decorated with persistent perchlorotriphenylmethyl (PTM) radicals. The redox properties of PTM are exploited to fabricate electrochemical switches with optical and magnetic responses, showing high stability and reversibility. Electronic interaction between the radicals and the gold surface is investigated by UV-vis, showing a very broad absorption band in the near-infrared (NIR) region, which becomes more intense when PTMs are reduced to anionic phase. By using multiple experimental techniques, we demonstrate that this interaction is likely favored by the preferentially flat orientation of PTM ligands on the metallic NP surface, as confirmed by first-principles simulations.

Catalytic enantioselective synthesis of perfluoroalkyl-substituted ß-lactones via a concerted asynchronous [2 + 2] cycloaddition: a synthetic and computational study.

The enantioselective preparation of a range of perfluoroalkyl-substituted ß-lactones through an isothiourea (HyperBTM) catalysed reaction using symmetric anhydrides as ammonium enolate precursors and perfluoroalkylketones (RF = CF3, C2F5, C4F9) is reported. Following optimisation, high diastereo- and enantioselectivity was observed for ß-lactone formation using C2F5- and C4F9-substituted ketones at room temperature (26 examples, up to >95 : 5 dr and >99 : 1 er), whilst -78 °C was necessary for optimal dr and er with CF3-substituted ketones (11 examples, up to >95 : 5 dr and >99 : 1 er). Derivatisation of the ß-lactones through ring-opening, as well as a two-step conversion to give perfluoroalkyl-substituted oxetanes, is demonstrated without loss of stereochemical integrity. Density functional theory computations, alongside 13C natural abundance KIE studies, have been used to probe the reaction mechanism with a concerted asynchronous [2 + 2]-cycloaddition pathway favoured over a stepwise aldol-lactonisation process.

Discovery of a Potent α-Galactosidase Inhibitor by in Situ Analysis of a Library of Pyrrolizidine-(Thio)urea Hybrid Molecules Generated via Click Chemistry.

The parallel synthesis of a 26-membered-library of aromatic/aliphatic-(thio)urea-linked pyrrolizidines followed by in situ biological evaluation toward α-galactosidases has been carried out. The combination of the (thio)urea-forming click reaction and the in situ screening is pioneer in the search for glycosidase inhibitors and has allowed the discovery of a potent coffee bean α-galactosidase inhibitor (IC50 = 0.37 µM, Ki = 0.12 µM) that has also showed inhibition against human lysosomal α-galactosidase (α-Gal A, IC50 = 5.3 µM, Ki = 4.2 µM).

Induction of cell killing and autophagy by amphiphilic pyrrolidine derivatives on human pancreatic cancer cells.

We have synthesized a wide array of structurally related amphiphilic compounds, containing a functionalized pyrrolidine polar group coupled to different ether-linked hydrocarbon chains, to generate novel structures with antitumor activity. These newly synthesized amphiphilic pyrrolidine-derived compounds were classified in three different sub-libraries regarding the number of hydroxyl groups substituting the pyrrolidine moiety at C3 and C4. Pyrrolidine compounds with one or none hydroxyl groups showed a potent cell killing activity against pancreatic cancer cells, but they lacked selectivity for tumor cells. Pyrrolidine compounds with two hydroxyl groups induced cell death in a wide variety of pancreatic cancer cell lines, and they were somewhat less cytotoxic to normal non-tumor cells. Among these latter compounds, the diol-derived pyrrolidine 20 ((2R,3R,4S)-2-{(9Z)-hexadec-9-en-1-yloxy]methyl}pyrrolidine-3,4-diol) induced autophagy and a potent apoptotic response in pancreatic ductal adenocarcinoma cells, which was inhibited by Bcl-XL overexpression and by caspase inhibition, in a way similar to that of the amphiphilic ether lipid edelfosine, with which it was compared. Pharmacological and genetic inhibition of autophagy potentiated 20-mediated apoptosis. These structure-activity relationship studies point out the importance of the diol polar group and aliphatic side chain of 20 in promoting apoptosis against pancreatic cancer cells in a rather controlled way, and some additional subtle modifications were found to be potential modulators of the cytotoxic activity.

Epididymal α-l-fucosidase and its possible role in remodelling the surface of bull spermatozoa.

The mammalian epididymis provides an appropriate environment for sperm maturation. During the epididymal transit, spermatozoa undergo biochemical and morphological changes that lead to the acquisition of the fertilizing capacity. In this study we analysed the fucosylation status of membrane glycoproteins in the spermatozoa obtained from different regions of the bull epididymis. High amounts of fucose were detected on caput spermatozoa (R.F.I. = 1010 ± 20.35), mostly located in the post-acrosome zone. A significant decrease in the fucose levels was detected toward the cauda (R.F.I. = 540.5 ± 49.93) (P < 0.05). This decrease was in line with the increased activity of α-l-fucosidase in the cauda fluid. In sperm from the cauda, the defucosylation occurred in some proteins, whereas others showed higher fucosylation rates. A significant decrease of fucose in the gametes was observed upon incubation of crude cauda fluid with caput spermatozoa (from R.F.I. = 1.45 ± 0.08 to 1.06 ± 0.03) (P < 0.05) indicating that the α-l-fucosidase present in the epididymal fluid is active on spermatozoa. Moreover, this effect was blocked with specific enzyme inhibitors. These results provide direct evidence that the α-l-fucosidase from epididymal fluid participates in the fucose removal from spermatozoa, as a step of sperm maturation in the bull epididymis.

Rapid discovery of potent α-fucosidase inhibitors by in situ screening of a library of (pyrrolidin-2-yl)triazoles.

The synthesis of a small library of (pyrrolidin-2-yl)triazoles via copper catalysed cycloaddition of an alkynyl iminocyclopentitol and a set of commercial and synthetic azides has been achieved. The in situ screening for the activity towards α-fucosidase of the resulting triazoles has allowed the identification of one of the most potent and selective pyrrolidine derived inhibitors of this enzyme (Ki = 4 nM).