(5S)-5-Benzylswainsonines as potent and selective inhibitors of Golgi α-mannosidase II: synthesis, enzyme evaluation and molecular modelling.

Development of novel anti-cancer therapeutics based on Golgi α-mannosidase II (GMII) inhibition is considerably impeded by an undesired co-inhibition of lysosomal α-mannosidase leading to severe side-effects. In this contribution, we describe a fully stereoselective synthesis of (5S)-5-[4-(halo)benzyl]swainsonines as highly potent and selective inhibitors of GMII. The synthesis starts from a previously reported aldehyde readily available from l-ribose, and the key features include an intramolecular reductive amination with substrate-controlled stereoselectivity and a late-stage derivatisation of the benzyl group via ipso-substitution. These novel swainsonine analogues were found to be nanomolar inhibitors of the Golgi-type α-mannosidase AMAN-2 (Ki = 23-75 nM) with excellent selectivity (selectivity index = 205-870) over the lysosomal-type Jack bean α-mannosidase. Finally, molecular docking and pKa calculations were performed to provide more insight into the structure of the inhibitor:enzyme complexes, and a pair interaction energy analysis (FMO-PIEDA) was carried out to rationalise the observed potency and selectivity of the inhibitors.

Synthetic Study of Natural Metabolites Containing a Benzo[c]oxepine Skeleton: Heterocornol C and D.

A versatile strategy for the enantioselective synthesis of a benzo[c]oxepine structural core containing natural secondary metabolites was developed. The key steps of the synthetic approach include ring-closing alkene metathesis for seven-member ring construction, the Suzuki-Miyaura cross-coupling reaction for the installation of the double bond and Katsuki-Sharpless asymmetric epoxidation for the introduction of chiral centers. The first total synthesis and absolute configuration assignment of heterocornol D (3a) were achieved. Four stereoisomers, 3a, ent-3a, 3b and ent-3b, of this natural polyketide were prepared, starting with 2,6-dihydroxy benzoic acid and divinyl carbinol. The absolute and relative configuration of heterocornol D was assigned via single-crystal X-ray analysis. The extension of the described synthetic approach is further presented with the synthesis of heterocornol C by applying the ether group reduction method to the lactone.

Bipyridine Ruthenium(II) Complexes with Halogen-Substituted Salicylates: Synthesis, Crystal Structure, and Biological Activity.

Ruthenium complexes currently represent a perspective subject of investigation in terms of potential anticancer therapeutics. Eight novel octahedral ruthenium(II) complexes are the subject of this article. Complexes contain 2,2'-bipyridine molecules and salicylates as ligands, differing in position and type of halogen substituent. The structure of the complexes was determined via X-ray structural analysis and NMR spectroscopy. All complexes were characterized by spectral methods-FTIR, UV-Vis, ESI-MS. Complexes show sufficient stability in solutions. Therefore, their biological properties were studied. Binding ability to BSA, interaction with DNA, as well as in vitro antiproliferative effects against MCF-7 and U-118MG cell lines were investigated. Several complexes showed anticancer effects against these cell lines.

A Universal Strategy for Synthesis of Agropyrenol Family. Total Synthesis of Agropyrenol, Sordarial, and Heterocornol A and B.

A divergent strategy for natural polyketides synthesis has been designed. This synthetic route allowed chemical alterations leading to all stereoisomers of the natural agropyrenol 1, sordarial 2, and heterocornol B 4. Key steps involve desymmetrization of divinylcarbinol using asymmetric Sharpless epoxidation and Heck coupling of an easily available aromatic partner and prepared chiral alkene. The versatility of the synthetic method was demonstrated on the preparation of heterocornol A 3 and sordariol 5. The absolute and relative configurations of prepared natural compounds 2·1/3C6H12 and 4 were confirmed and assigned by single-crystal X-ray analysis.

Autotandem Catalysis: Inexpensive and Green Access to Functionalized Ketones by Intermolecular Iron-Catalyzed Amidoalkynylation/Hydration Cascade Reaction via N-Acyliminium Ion Chemistry.

Iron-based catalysts were applied in cascade-type reactions for the synthesis of different carbonyl compounds. The reactions proceeded by a new iron-catalyzed cascade of alkynylation/hydration by using both the σ- and π-Lewis acid properties of iron salts. The alkynylation reactions of several endo and exocyclic acetoxylactams were achieved with three different catalysts including FeCl3 ⋅ 6H2 O, FeCl3 , and Fe(OTf)3 showing the efficiency of σ-Lewis acidity of iron (III) salts in catalyzing the alkynylation reaction. We also demonstrated that the reaction sequence could be shortened by the direct use of hydroxylactams, leading to an environmentally friendly protocol, avoiding the need to perform unnecessary lengthy steps. A combination of the hard/soft iron Lewis acid properties was then used to implement an unprecedented tandem intermolecular alkynylation/intramolecular hydration sequence allowing expedient access to a new carbonyl structures from trivial materials.

Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation.

A new highly diastereoselective synthesis of the polyhydroxylated pyrrolidine alkaloid (±)-codonopsinol B and its N-nor-methyl analogue, starting from achiral materials, is presented. The strategy relies on the trans-stereoselective epoxidation of 2,3-dihydroisoxazole with in situ-generated DMDO, the syn-selective α-chelation-controlled addition of vinyl-MgBr/CeCl3 to the isoxazolidine-4,5-diol intermediate, and the substrate-directed epoxidation of the terminal double bond of the corresponding γ-amino-α,ß-diol with aqueous hydrogen peroxide catalyzed by phosphotungstic heteropoly acid. Each of the key reactions proceeded with an excellent diastereoselectivity (dr > 95:5). (±)-Codonopsinol B was prepared in 10 steps with overall 8.4% yield. The antiproliferative effect of (±)-codonopsinol B and its N-nor-methyl analogue was evaluated using several cell line models.

Effect of the Distant Substituent to Slow Magnetic Relaxation of Pentacoordinate Fe(III) Complexes.

Pentacoordinate Fe(III) complexes [Fe(LMeO)2X] and [Fe(LEtO)2X], X = Cl and Br, show the slow magnetic relaxation that is enhanced by the applied static magnetic field. A substitution of the distant ethoxy group to the methoxy group residing at the phenyl ring of a Schiff base N,O-donor ligand (LMeO vs LEtO) considerably influences the relaxation characteristics. In the chlorido complex [Fe(LMeO)2Cl], the following three slow relaxation channels are recognized as possessing different relaxation times: τLF = 0.47 s, τIF = 13 ms, and τHF = 26 µs at the static field BDC = 0.2 T and T = 1.9 K. In the bromido complex [Fe(LMeO)2Br], only the following two relaxation channels are seen: τLF = 0.30 ms and τHF = 139 µs at BDC = 0.15 T and T = 1.9 K. Due to D > 0, the Orbach relaxation mechanism does not apply, and the temperature dependence of the high-frequency relaxation time can be described by two Raman-like terms.

Synthesis and sequential diastereoselective incorporation of hydroxyl groups into hexahydrofuro[3,2-f]indolizin-7(2H)-one to give mono-, di- and tetra-hydroxyfuroindolizidines.

Dihydrofuro[2,3-f]indolizidinone obtained from biosourced reagents even at multigram-scale was used as an advanced building-block with up to five points of chemical diversification. This resulted in the sequential synthesis of a series of mono-, di- and tetra-hydroxyfuranoindolizidines belonging to a very scarce and elaborate tetrahydrofuran-fused indolizidine family with up to six controlled stereogenic centers. These sequences include, among others, diastereoselective olefin epoxidation, stereoselective epoxide ring opening into tetrahydrofuran trans-diols, their protection as an ester or acetonide, and lactam carbonyl reduction ultimately followed by acetate or acetonide deprotection.

Deposition of Tetracoordinate Co(II) Complex with Chalcone Ligands on Graphene.

Studying the properties of complex molecules on surfaces is still mostly an unexplored research area because the deposition of the metal complexes has many pitfalls. Herein, we probed the possibility to produce surface hybrids by depositing a Co(II)-based complex with chalcone ligands on chemical vapor deposition (CVD)-grown graphene by a wet-chemistry approach and by thermal sublimation under high vacuum. Samples were characterized by high-frequency electron spin resonance (HF-ESR), XPS, Raman spectroscopy, atomic force microscopy (AFM), and optical microscopy, supported with density functional theory (DFT) and complete active space self-consistent field (CASSCF)/N-electron valence second-order perturbation theory (NEVPT2) calculations. This compound's rationale is its structure, with several aromatic rings for weak binding and possible favorable π-π stacking onto graphene. In contrast to expectations, we observed the formation of nanodroplets on graphene for a drop-cast sample and microcrystallites localized at grain boundaries and defects after thermal sublimation.

Phenyliodine(III) Diacetate/I2 -Mediated Domino Approach for Pyrrolo[1,4]Thiazines and 1,4-Thiazines by a One-Pot Morin Rearrangement of N,S-Acetals.

An efficient domino transformation using a phenyliodine(III) diacetate (PIDA)/I2 combination towards Morin 1,4-thiazine compounds has been developed starting from N,S-acetals. The latter leads to "one-step" regioselective methylene insertion without the need for traditional sulfoxide intermediates in good yields. The reaction involves easily accessible N,S-acetals obtained from cost-effective basic ketones and cysteamine as starting materials. This process ultimately leads to 1,4-thiazines related to natural product and fused derivatives necessary for further QSAR study.

Total Synthesis of Berkeleylactone A.

The first total synthesis of the potent antibiotic berkeleylactone A is described in 10 steps with an overall yield of 9.5%. A key step of our concise route is a late-stage, highly diastereoselective, sulfa-Michael addition. The 16-membered macrocyclic lactone was formed via ring closing metathesis and subsequent chemoselective reduction. The absolute stereochemical configuration was confirmed by single-crystal X-ray analysis. Synthetic berkeleylactone A was tested against several methicillin-resistant Staphylococcus aureus strains, and its potent antibacterial activity was verified.

First Total Synthesis of Varioxiranol A.

The paper describes the first total synthesis of natural varioxiranol A by chiral pool approach and confirmation of its absolute configuration by single-crystal X-ray analysis. The target varioxiranol A and its 4-epimer were obtained after 10 steps from single and available chiral source 1,2-O-isopropylidene-d-glyceraldehyde in an overall yield of 10% and 6%, respectively. A synthetic strategy based on the Julia⁻Kocienski coupling reaction between aromatic sulfone and corresponding aldose derivative makes it possible to prepare other interesting polyketide derivatives (varioxiranols B-G, varioxirane, varioxiranediols).

Impact of Substituent Variation on the Presence of Thermal Spin Crossover in a Series of Mononuclear Iron(III) Schiff Base Complexes with Terminal Pseudohalido Co-ligands.

A series of novel iron(III) complexes of the general formula [Fe(L)X] (where L is a dianion of pentadentate Schiff base ligand N,N'-bis({2-hydroxy-3,5-dimethylphenyl}phenyl)methylidene-1,6-diamino-3-azapentane=H2 L1 for 1 and 2; N,N'-bis({2-hydroxy-3-ethoxyphenyl}methylidene)-1,6-diamino-3-azapentane=H2 L2 for 3 and 3⋅C3 H6 O) and X is terminal pseudohalido ligand (X=N3 for 1, X=NCS for 2, and X=NCSe for 3 and 3⋅C3 H6 O) were synthesized and thoroughly characterized. Magnetic measurements revealed the above room temperature spin crossover for isomorphic complexes 1 and 2 (T1/2 =441 K and T1/2 =435 K, respectively), whereas the solvent-free complex 3 showed a half complete spin crossover (T1/2 =250 K), which was detected by variable temperature crystallography as well. On the other hand, solvated complex 3⋅C3 H6 O exhibited permanent high spin state behaviour and either recrystallization or in situ thermal desolvation converts 3⋅C3 H6 O to solvent-free and spin-crossover-active form 3. Magnetic properties of all the reported complexes were also supported by EPR spectroscopy experiments and in addition, DFT and ab initio calculations were employed for the evaluation of the g-factor and zero field splitting parameters.

Breaking the Magic Border of One Second for Slow Magnetic Relaxation of Cobalt-Based Single Ion Magnets.

Instead of assembling complex clusters and/or expensive lanthanide-based systems as single ion magnets, we are focusing on mononuclear cobalt(II) systems among which the complex under study, [Co( pydca)( dmpy)]2·H2O (1), shows a field supported slow magnetic relaxation on the order of seconds at low temperature ( pydca = pyridine-2,6-dicarboxylato, dmpy = 2,6-dimethanolpyridine). The low-frequency relaxation time is as slow as τ(LF) = 1.35(6) s at T = 1.9 K and BDC = 0.4 T. The properties of 1 are compared to the previously reported nickel and copper analogues which were the first examples of single ion magnets in the family of Ni(II) and Cu(II) complexes.

Octahedral-Tetrahedral Systems [Co( dppm O, O)3]2+[CoX4]2- Showing Slow Magnetic Relaxation with Two Relaxation Modes.

Three compounds with octahedral-tetrahedral Co(II) moieties of [Co( dppm O, O)3][CoX4] type, where X = SCN (1), Cl (2), or I (4) have been synthesized and characterized by the X-ray structure analysis (1 and 4), and spectroscopic methods. The dc magnetic measurements show high magnetic anisotropy for octahedral centers whereas tetrahedral sites possess moderate D values. These results are confirmed by the ab initio calculations. The ac susceptibility data reveals a slow magnetic relaxation for 2 and 4, similar to that of the X = Br analogue (3), whereas 1 displays no ac-absorption signal. There are two relaxation channels; the slower for 2 (4) possesses a relaxation time as long as τLF= 178 (588) ms at T = 1.9 K and Bdc = 0.7 T. Also, the half-Zn analogue, [Co( dppm O, O)3][ZnI4], shows slow magnetic relaxation with two relaxation channels conditioned by the cationic unit [Co( dppm O, O)3]2+.

Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their evaluation as inhibitors of GH38 α-mannosidases.

A synthetic approach to 1,4-imino-L-lyxitols with various modifications at the C-5 position is reported. These imino-L-lyxitol cores were used for the preparation of a series of N-(4-halobenzyl)polyhydroxypyrrolidines. An impact of the C-5 modification on the inhibition and selectivity against GH38 α-mannosidases from Drosophila melanogaster, the Golgi (GMIIb) and lysosomal (LManII) mannosidases and commercial jack bean α-mannosidase from Canavalia ensiformis was evaluated. The modification at C-5 affected their inhibitory activity against the target GMIIb enzyme. In contrast, no inhibition effect of the pyrrolidines against LManII was observed. The modification of the imino-L-lyxitol core is therefore a suitable motif for the design of inhibitors with desired selectivity against the target GMIIb enzyme.

Structure-Based Kinetic Control in a Domino Process: A Powerful Tool Toward Molecular Diversity in Chromone Series.

Two successive original routes leading to two novel families of polyheterocycles starting from the versatile chromone-based Michael acceptors platform are reported herein. The major aspect of this work is the selective access to these frameworks by changing the course of the domino process involved in their formation. First, enaminochromanones were selectively accessed under uncommon kinetic control. In this study, we showed that the tuning of the selectivity toward the kinetic product could be achieved by key structural modifications of the different reaction partners involved in the domino process. Once selectivity was efficiently controlled, enaminochromanones were ultimately transformed into a more complex family of polyheterocycles containing the pyrrolo-oxazinone framework. Here, the modulation of the domino sequence toward these particularly scarce structures was enabled by a pivotal switch in reactivity induced by aryl-λ3-iodanes.

Total Synthesis, Configuration Assignment, and Cytotoxic Activity Evaluation of Protulactone A.

The first total synthesis and absolute configuration assignment of protulactone A (1) has been achieved. Four stereoisomers, 1a, ent-1a, 1b, and ent-1b, of this natural polyketide were prepared by chiral pool synthesis starting from l- and d-arabinose, respectively. The absolute and relative configurations of all isomers were assigned by single-crystal X-ray analysis. Target compounds were screened for their in vitro cytotoxicity toward certain human tumor cells (NCI60 cancer cell line panel).

Synthesis, crystal structure, spectroscopic properties and potential biological activities of salicylate‒neocuproine ternary copper(II) complexes.

Mixed ligand copper(II) complexes containing derivatives of salicylic acid and heterocyclic ligands with nitrogen donor atoms have been the subject of various studies and reviews. In this paper, synthesis and characterization of the ternary copper(II) complexes of neocuproine (2,9-dimethyl-1,10-phenanthroline, Neo) and salicylate ligands (Sal) are reported. In addition, the crystal structures of ([Cu(H2O)(5-Cl-Sal)(Neo)] (1), [Cu(µ-Sal)(Neo)]2 (2), Cu2(µ-5-Cl-Sal)(5-Cl-HSal)2(Neo)2]·EtOH (3)) were determined. In order to compare structural and biological properties of the prepared complexes, spectroscopic and biological studies were performed. Results of X-ray diffraction show that prepared complexes form three types of crystal structures in a given system: monomeric, dimeric and dinuclear complex. The preliminary study on the DNA cleavage activity has shown that the complexes under study behave as the chemical nucleases in the presence of added hydrogen peroxide with slight differences in the activity (1 > 2 > 3). The complexes 1 and 2 exhibited nuclease activity itself indicating the interaction of complexes with the DNA. It has been proposed that the enhanced destructive effect of the complexes 1 and 2 on the DNA is a result of two possible mechanisms of action: (i) the conversion of closed circular DNA (form I) to the nicked DNA (form II) caused by the copper complex itself and (ii) damage of DNA by Reactive Oxygen Species (ROS)-products of the interaction of copper with hydrogen peroxide by means of Fenton reaction (hydroxyl radicals). Thus the biological activity of the prepared Cu(II) complexes containing derivatives of salicylic acid and phenanthroline molecules is substantiated by two independent mechanisms. While derivatives of salicylic acids in the coordination sphere of copper complexes are responsible for radical-scavenging activity (predominantly towards superoxide radical anion), the presence of chelating ligand 2,9-dimethyl-1,10-phenanthroline significantly enhances capability of Cu(II) complexes binding to DNA via intercalation.

Synthesis, physicochemical properties and antimicrobial activity of mono-/dinitroxyl amides.

Two comparative sets of mono-/dinitroxyl amides were designed and prepared. The novel TEMPO and/or PROXYL derivatives were fully characterised and their spin, redox and antimicrobial properties were determined. Cyclic voltammetry revealed (quasi)reversible redox behavior for most of the studied radicals. Moreover, the electron-withdrawing substituents increased the oxidation potential of nitroxides in comparison to electron-donating groups. While EPR spectra of monoradicals featured the typical three-line signal, the spectra of biradicals showed more complex splitting patterns. The in vitro biological assay revealed that unlike pyrrolidinyl derivatives, the piperidinyl nitroxides significantly inhibited the growth of Staphylococcus sp.