Exploiting Co(III)-Cyclopentadienyl Complexes To Develop Anticancer Agents.

In recent years, organometallic complexes have attracted much attention as anticancer therapeutics aiming at overcoming the limitations of platinum drugs that are currently marketed. Still, the development of half-sandwich organometallic cobalt complexes remains scarcely explored. Four new cobalt(III)-cyclopentadienyl complexes containing N,N-heteroaromatic bidentate, and phosphane ligands were synthesized and fully characterized by elemental analysis, spectroscopic techniques, and DFT methods. The cytotoxicity of all complexes was determined in vitro by the MTS assay in colorectal (HCT116), ovarian (A2780), and breast (MDA-MB-231 and MCF-7) human cancer cell lines and in a healthy human cell line (fibroblasts). The complexes showed high cytotoxicity in cancer cell lines, mostly due to ROS production, apoptosis, autophagy induction, and disruption of the mitochondrial membrane. Also, these complexes were shown to be nontoxic in vivo in an ex ovo chick embryo yolk sac membrane (YSM) assay.

Paraptotic Cell Death as an Unprecedented Mode of Action Observed for New Bipyridine-Silver(I) Compounds Bearing Phosphane Coligands.

In this work, we investigated the anticancer activity of several novel silver(I) 2,2'-bipyridine complexes containing either triphenylphosphane (PPh3) or 1,2-bis(diphenylphosphino)ethane (dppe) ligands. All compounds were characterized by diverse analytical methods including ESI-MS spectrometry; NMR, UV-vis, and FTIR spectroscopies; and elemental analysis. Moreover, several compounds were also studied by X-ray single-crystal diffraction. Subsequently, the compounds were investigated for their anticancer activity against drug-resistant and -sensitive cancer cells. Noteworthily, neither carboplatin and oxaliplatin resistance nor p53 deletion impacted on their anticancer efficacy. MES-OV cells displayed exceptional hypersensitivity to the dppe-containing drugs. This effect was not based on thioredoxin reductase inhibition, enhanced drug uptake, or apoptosis induction. In contrast, dppe silver drugs induced paraptosis, a novel recently described form of programmed cell death. Together with the good tumor specificity of this compound's class, this work suggests that dppe-containing silver complexes could be interesting drug candidates for the treatment of resistant ovarian cancer.

Assessment of Halogen Off-Center Point-Charge Models Using Explicit Solvent Simulations.

Compounds containing halogens can form halogen bonds (XBs) with biological targets such as proteins and membranes due to their anisotropic electrostatic potential. To accurately describe this anisotropy, off-center point-charge (EP) models are commonly used in force field methods, allowing the description of XBs at the molecular mechanics and molecular dynamics level. Various EP implementations have been documented in the literature, and despite being efficient in reproducing protein-ligand geometries and sampling of XBs, it is unclear how well these EP models predict experimental properties such as hydration free energies (ΔGhyd), which are often used to validate force field performance. In this work, we report the first assessment of three EP models using alchemical free energy calculations to predict ΔGhyd values. We show that describing the halogen anisotropy using some EP models can lead to a slight improvement in the prediction of the ΔGhyd when compared with the models without EP, especially for the chlorinated compounds; however, this improvement is not related to the establishment of XBs but is most likely due to the improvement of the sampling of hydrogen bonds. We also highlight the importance of the choice of the EP model, especially for the iodinated molecules, since a slight tendency to improve the prediction is observed for compounds with a larger σ-hole but significantly worse results were obtained for compounds that are weaker XB donors.

Recent advances on molecular dynamics-based techniques to address drug membrane permeability with atomistic detail.

Several factors affect the passive membrane permeation of small molecules, including size, charge, pH, or the presence of specific chemical groups. Understanding these features is paramount to identifying or designing drug candidates with optimal ADMET properties and this can be achieved through experimental/knowledge-based methodologies or using computational approaches. Empirical methods often lack detailed information about the underlying molecular mechanism. In contrast, Molecular Dynamics-based approaches are a powerful strategy, providing an atomistic description of this process. This technique is continuously growing, featuring new related methodologies. In this work, the recent advances in this research area will be discussed.

C-H functionalization of quinoline N-oxides catalyzed by Pd(II) complexes: a computational study.

Pd(II) catalysts, particularly the acetate salt in acetic acid, tended to favor regioselective C-H activation of quinoline N-oxides (QOs) at the C2 position. However, Pd(II)Cl2 was shown to catalyze their C-H activation at C8 and, in the presence of water, C8-H activation was accompanied by the formation of 2-quinolinones. The aim of the DFT study described in this work was to shed light on the complete mechanism of these competing catalytic reactions, when PdCl2 reacts with QO and benzaldehyde in dichloroethane. C-H activation of QO was the first step of the reaction and involved either a metallacycle, with a CQO-Pd(II) σ-bond and a C(8)-H-Pd(II) agostic bond, or an η3-QO complex, with three carbon atoms of the heteroring of QO binding PdCl2. The first situation led to the unusual C8 activation and the second to C2 activation. The σ-metallacycle undergoes C8-H activation and the energy of the TOF determining the transition state to form the product is ∼17 kcal mol-1, while for the reaction through the π-metallacycle (C2-H activation) the corresponding energy is higher (∼29 kcal mol-1) and thus is not competitive under the same conditions. The reaction proceeding through the σ-complex, activating the C8 position, is preferred, in agreement with experimental results. Both reactions involve oxidation of Pd(II) to Pd(IV) and the catalyst is regenerated. When small amounts of water are added to the reaction mixture, C8-H activation (acylation) results from the same σ-metallacycle with the same barrier, but the simultaneous formation of 2-quinolinones is more complicated. It starts with OH- attack at the C2 position, and is followed by the migration of two hydrogen atoms, and the final reductive elimination step ends with Pd(0). The higher barriers for the migration and reoxidation of Pd(0) are associated with the more demanding reaction conditions. The different reactivity of Pd(II)(OAc)2 under analogous conditions is clarified, as it is only capable of forming the above mentioned π-complex and thus of activating the C2 position of QO. This catalyst can preferentially activate the C8-H bond under rather different conditions, including in particular acetic acid medium, as shown by other authors.

Intrinsic bond strength index as a halogen bond interaction energy predictor.

Halogen bonds (XBs) have become increasingly popular over the past few years with numerous applications in catalysis, material design, anion recognition, and medicinal chemistry. To avoid a post factum rationalization of XB trends, descriptors can be tentatively employed to predict the interaction energy of potential halogen bonds. These typically comprise the electrostatic potential maximum at the tip of the halogen, VS,max, or properties based on the topological analysis of the electronic density. However, such descriptors either can only be used with confidence for specific families of halogen bonds or require intense computations and, therefore, are not particularly attractive for large datasets with diverse compounds or biochemical systems. Therefore, the development of a simple, widely applicable, and computationally cheap descriptor remains a challenge as it would facilitate the discovery of new XB applications while also improving the existing ones. Recently, the Intrinsic Bond Strength Index (IBSI) has been proposed as a new tool to evaluate any bond strength, however, it has not been extensively explored in the context of halogen bonding. In this work, we show that IBSI values linearly correlate with the interaction energy of diverse sets of closed-shell halogen-bonded complexes in the ground state, and therefore, can be used to quantitatively predict this property. Although the linear fit models that use quantum-mechanics-based electron density provided MAEs typically below 1 kcal mol-1, this type of calculation might still be computationally heavy in large sets or systems. Therefore, we also explored the exciting possibility of using a promolecular density approach (IBSIPRO), which only requires the geometry of the complex as an input, being computationally cheap. Surprisingly, the performance was comparable to the QM-based methods, thus opening the door for the usage of IBSIPRO as a fast, yet accurate, XB energy descriptor in large datasets but also in biomolecular systems such as protein-ligand complexes. We also show that the δgpair descriptor emerging from the Independent Gradient Model that leads to IBSI can be seen as a term proportional to the overlapping van der Waals volume of the atoms at a given interaction distance. Overall, ISBI can be thought of as a complementary descriptor to VS,max for situations where the geometry of the complex is available and QM calculations are not feasible whereas the latter still remains a hallmark of XB descriptors.

DIS3L2 knockdown impairs key oncogenic properties of colorectal cancer cells via the mTOR signaling pathway.

DIS3L2 degrades different types of RNAs in an exosome-independent manner including mRNAs and several types of non-coding RNAs. DIS3L2-mediated degradation is preceded by the addition of nontemplated uridines at the 3'end of its targets by the terminal uridylyl transferases 4 and 7. Most of the literature that concerns DIS3L2 characterizes its involvement in several RNA degradation pathways, however, there is some evidence that its dysregulated activity may contribute to cancer development. In the present study, we characterize the role of DIS3L2 in human colorectal cancer (CRC). Using the public RNA datasets from The Cancer Genome Atlas (TCGA), we found higher DIS3L2 mRNA levels in CRC tissues versus normal colonic samples as well as worse prognosis in patients with high DIS3L2 expression. In addition, our RNA deep-sequencing data revealed that knockdown (KD) of DIS3L2 induces a strong transcriptomic disturbance in SW480 CRC cells. Moreover, gene ontology (GO) analysis of significant upregulated transcripts displays enrichment in mRNAs encoding proteins involved in cell cycle regulation and cancer-related pathways, which guided us to evaluate which specific hallmarks of cancer are differentially regulated by DIS3L2. To do so, we employed four CRC cell lines (HCT116, SW480, Caco-2 and HT-29) differing in their mutational background and oncogenicity. We demonstrate that depletion of DIS3L2 results in reduced cell viability of highly oncogenic SW480 and HCT116 CRC cells, but had little or no impact in the more differentiated Caco-2 and HT-29 cells. Remarkably, the mTOR signaling pathway, crucial for cell survival and growth, is downregulated after DIS3L2 KD, whereas AZGP1, an mTOR pathway inhibitor, is upregulated. Furthermore, our results indicate that depletion of DIS3L2 disturbs metastasis-associated properties, such as cell migration and invasion, only in highly oncogenic CRC cells. Our work reveals for the first time a role for DIS3L2 in sustaining CRC cell proliferation and provides evidence that this ribonuclease is required to support the viability and invasive behavior of dedifferentiated CRC cells.

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives.

The synthesis and biological evaluation of novel guanidino sugars as isonucleoside analogs is described. 5-Guanidino xylofuranoses containing 3-O-saturated/unsaturated hydrocarbon or aromatic-containing moieties were accessed from 5-azido xylofuranoses via reduction followed by guanidinylation with N,N'-bis(tert-butoxycarbonyl)-N''-triflylguanidine. Molecules comprising novel types of isonucleosidic structures including 5-guanidino 3-O-methyl-branched N-benzyltriazole isonucleosides and a guanidinomethyltriazole 3'-O-dodecyl xylofuranos-5'-yl isonucleoside were accessed. The guanidinomethyltriazole derivative and a 3-O-dodecyl (N-Boc)guanidino xylofuranose were revealed as selective inhibitors of acetylcholinesterase (Ki =22.87 and 7.49 µM, respectively). The latter also showed moderate antiproliferative effects in chronic myeloid leukemia (K562) and breast cancer (MCF-7) cells. An aminomethyltriazole 5'-isonucleoside was the most potent molecule with low micromolar GI50 values in both cells (GI50 =6.33 µM, 8.45 µM), similar to that of the drug 5-fluorouracil in MCF-7 cells. Moreover, the most bioactive compounds showed low toxicity in human fibroblasts, further indicating their interest as promising lead molecules.

Tau mRNA Metabolism in Neurodegenerative Diseases: A Tangle Journey.

Tau proteins are known to be mainly involved in regulation of microtubule dynamics. Besides this function, which is critical for axonal transport and signal transduction, tau proteins also have other roles in neurons. Moreover, tau proteins are turned into aggregates and consequently trigger many neurodegenerative diseases termed tauopathies, of which Alzheimer's disease (AD) is the figurehead. Such pathological aggregation processes are critical for the onset of these diseases. Among the various causes of tau protein pathogenicity, abnormal tau mRNA metabolism, expression and dysregulation of tau post-translational modifications are critical steps. Moreover, the relevance of tau function to general mRNA metabolism has been highlighted recently in tauopathies. In this review, we mainly focus on how mRNA metabolism impacts the onset and development of tauopathies. Thus, we intend to portray how mRNA metabolism of, or mediated by, tau is associated with neurodegenerative diseases.

Starch flow behavior alone and under different glidants action using the shear cell method.

The objective of this work was to analyze the flow behavior of a commonly used filler (pregelatinised starch) and the effect of two of the most used lubricants (talc and colloidal silicon dioxide). The studies were carried out according to the conventional methods (Angle of Repose, Bulk and Tapped densities and from these the Compressibility Index) and shear cell methods (Brookfield Powder Flow Tester apparatus) described in European Pharmacopeia (Ph. Eur.). The results showed some surprising and unexpected values for the flow behavior of this filler under influence of the methods and the used glidants. Regarding pure starch and mixtures containing talc, the flow behavior was similar between them and the Flow Index (ffc) values varied between 1.8 and 4 (very cohesive and cohesive) as consolidation stress (σ1) increased. In this case, the glidant effect was not observed. However, for the mixtures of starch with colloidal silicon dioxide this effect was observed providing Flow Index (ffc) values between 2.6 and 8.9 (cohesive and easy-flowing) as consolidation stress (σ1) increased. Other parameters that are also used to characterize flow properties, more specifically, within silos, chutes and hoppers, such as effective angle of internal friction (φe), effective angle of wall friction (φx), critical arching and critical rathole values, provided similar information. Based in the obtained results from all tests it can be said that the talc did not induce improvement on the starch flow behavior in the used conditions in opposition to the effect produced by colloidal silicon dioxide.HighlightsExample 1. A good flowability of powders is needed in order to be compressed/filled;Example 2. The overcome the poor flow it is usual to use glidants;Example 3. CSD improved the pregelatinised starch (Starch 1500®) flow;Example 4. Talc do not have relevant effect in the pregelatinised starch (Starch 1500®) flow;Example 5. Powder FlowTester method showed more complete and consistent results.

Alumination of aryl methyl ethers: switching between sp2 and sp3 C-O bond functionalisation with Pd-catalysis.

The reaction of [{(ArNCMe)2CH}Al] (Ar = 2,6-di-iso-propylphenyl) with aryl methyl ethers proceeded with alumination of the sp3 C-O bond. The selectivity of this reaction could be switched by inclusion of a catalyst. In the presence of [Pd(PCy3)2], chemoselective sp2 C-O bond functionalisation was observed. Kinetic isotope experiments and DFT calculations support a catalytic pathway involving the ligand-assisted oxidative addition of the sp2 C-O bond to a Pd-Al intermetallic complex.

Transmembrane Anion Transport Mediated by Halogen Bonds: Using Off-Center Charges.

Synthetic anion transporters are promising therapeutic agents designed to emulate the specialized role of certain transmembrane proteins that maintain the ion concentration in cells. In the last few years, besides hydrogen bonds and ion pairs, halogen bonds have also been explored to promote the association between the synthetic molecule and the anion and their subsequent transport. This interaction is due to an anisotropic charge distribution on the halogen, and therefore, modeling halogen bonds is not a trivial task using classical force field methods that typically rely on point-charge models.Herein, a computational protocol capable of dealing with halogen bonds is presented. This protocol takes advantage of the addition of an off-center particle during the charge fitting procedure, and the resulting set of charges can be used along with the classical force field parameters from GAFF or GROMOS 54A7.

Optimized Halogen Atomic Radii for PBSA Calculations Using Off-Center Point Charges.

In force-field methods, the usage of off-center point charges, also called extra points (EPs), is a common strategy to tackle the anisotropy of the electrostatic potential of covalently bonded halogens (X), thus allowing the description of halogen bonds (XBs) at the molecular mechanics/molecular dynamics (MM/MD) level. Diverse EP implementations exist in the literature differing on the charge sets and/or the X-EP distances. Poisson-Boltzmann and surface area (PBSA) calculations can be used to obtain solvation free energies (ΔGsolv) of small molecules, often to compute binding free energies (ΔGbind) at the MM-PBSA level. This method depends, among other parameters, on the empirical assignment of atomic radii (PB radii). Given the multiplicity of off-center point-charge models and the lack of specific PB radii for halogens compatible with such implementations, in this work, we assessed the performance of PBSA calculations for the estimation of ΔGsolv values in water (ΔGhyd), also conducting an optimization of the halogen PB radii (Cl, Br, and I) for each EP model. We not only expand the usage of EP models in the scope of the general AMBER force field (GAFF) but also provide the first optimized halogen PB radii in the context of the CHARMM general force field (CGenFF), thus contributing to improving the description of halogenated compounds in PBSA calculations.

Binding of RuCp complexes with human apo-transferrin: fluorescence spectroscopy and molecular docking methods.

The interaction between human serum transferrin (hTf) and three promising organometallic Ru (II)- (η5-C5H5) derived complexes, that have already shown strong in vitro cytotoxicity towards human cancer cell lines, has been investigated using fluorescence spectroscopic techniques. The results suggested that the formation of Ru-hTf systems involves a dynamic collision. The binding process occurs spontaneously (ΔG < 0), mainly driven by hydrophobic interactions. Additional docking studies show that all complexes bind preferably to a specific hydrophobic pocket in the C2-subdomain as already observed for other metal-cyclopentadienyl (MCp) complexes and are in agreement with the experimental results. With these studies we hope to contribute to the understanding of the mechanism of action of these promising cytotoxic agents, thus providing clues for a more rational design.

Stimuli-responsive hydrogels for intratumoral drug delivery.

The ability of some hydrogels to exhibit a phase transition or change their structure in response to stimuli has been extensively explored for drug depot formation and controlled drug release. Taking advantage of the unique features of the tumor microenvironment (TME) or externally applied triggers, several injectable stimuli-responsive hydrogels have been described as promising candidates for intratumoral drug delivery. In this review, we provide a brief overview of the TME and highlight the advantages of intratumoral administration, followed by a summary of the reported strategies to endow hydrogels with responsiveness to physical (temperature and light), chemical (pH and redox potential), or biological (enzyme) stimuli.

Halogen Bonding: An Underestimated Player in Membrane-Ligand Interactions.

Halogen bonds (XBs) are noncovalent interactions where halogen atoms act as electrophilic species interacting with Lewis bases. These interactions are relevant in biochemical systems being increasingly explored in drug discovery, mainly to modulate protein-ligand interactions, but are also found in engineered protein or nucleic acid systems. In this work, we report direct evidence for the existence of XBs in the context of biological membrane systems, thus expanding the scope of application of these interactions. Indeed, our molecular dynamics simulations show the presence of favorable interactions between halobenzene derivatives and both phosphate or ester oxygen acceptors from a model phospholipid bilayer, thus supporting the existence of XB-mediated phospholipid-halogen recognition phenomena influencing the membrane insertion profile of the ligands and their orientational preferences. This represents a relevant interaction, previously overlooked, eventually determining the pharmacological or toxicological activity of halogenated compounds and hence with potential implications in drug discovery and development, a place where such species account for a significant part of the chemical space. We also provide insights into a potential role for XBs in the water-to-membrane insertion of halogenated ligands as XBs are systematically observed during this process. Therefore, our data strongly suggest that, as the ubiquitous hydrogen bond, XBs should be accounted for in the development of membrane partition models.

Oromucosal precursors of in loco hydrogels for wound-dressing and drug delivery in oral mucositis: Retain, resist, and release.

Oromucosal films and tablets were developed as multifunctional biomaterials for the treatment of oral mucositis. These are intended to function as a hybrid, performing as a controlled drug delivery system and as a wound-dressing device. The dosage forms are precursors for in loco hydrogels that are activated by the saliva. An anti-inflammatory and anesthetic activity is attained from budesonide tripartite polymeric nanoparticles and lidocaine, while the polymeric network allows the protection and cicatrization of the wound. Different biomaterials and blends were investigated, focusing on the capacity to retain and resist on-site, as well as achieve a long-lasting controlled release. As the limiting factor, the choice was made according to the films' results. A polymer mix of Methocel™ K100M and Carbopol® (974P, EDT 2020, or Ultrez 10) blends were used. Overall, regrading critical factors, Carbopol® increased films' elasticity and flexibility, mucoadhesion, and the strength of the hydrogels, while higher concentrations led to thicker, more opaque, and lower strain resistance products. Whereas 974P and Ultrez 10 performed similarly, EDT 2020 led to uniformity problems and weaker films, hydrogels and bioadhesion. The optimized products were enhanced with sodium hyaluronate and drug-loaded for further characterization. Concerning the dosage form, the films' hydrogels were more resilient, while the tablets had higher mucoadhesiveness and longer swelling. Although through different networks and mechanisms, both dosage forms and grades revealed similar release profiles. A Case II time-evolving stereoselectivity for the 22R and 22S budesonide epimers was found, and Fickian-diffusion for lidocaine. Ultimately, the developed formulations show great potential to be used in OM management. Both of the selected grades at 0.6% displayed excellent performance, while Ultrez 10 can be preferable for the films' production due to its lower viscosity before neutralization and higher after activation. Where the tablets are easier to produce and offer better adhesion, the films are more customizable post-production and have higher rheological performance for wound-dressing.

Synthesis of Triazole-Containing Furanosyl Nucleoside Analogues and Their Phosphate, Phosphoramidate or Phoshonate Derivatives as Potential Sugar Diphosphate or Nucleotide Mimetics.

The synthesis of stable and potentially bioactive xylofuranosyl nucleoside analogues and potential sugar diphosphate or nucleotide mimetics comprising a 1,2,3-triazole moiety is reported. 3'-O-Methyl-branched N-benzyltriazole isonucleosides were accessed in 5-7 steps and 42-54 % overall yields using a Cu(I)-catalyzed cycloaddition of 3-O-propargyl-1,2-O-isopropylidene-α-D-xylofuranose with benzyl azide as key step. Related isonucleotides were obtained by 5-O-phosphorylation of acetonide-protected 3-O-propargyl xylofuranose and further "click" cycloaddition or by Staudinger-phosphite reaction of a 5-azido N-benzyltriazole isonucleoside. Hydroxy-, amino- or bromomethyl triazole 5'-isonucleosides were synthesized by thermal cycloaddition of 5-azido 3-O-benzyl/dodecyl xylofuranoses with propargyl alcohol, propargylamine or propargyl bromide. Better yields (82-85 %) were obtained when using propargyl alcohol and a high 1,4-regioselectivity was attained with propargyl bromide. Further O/N-phosphorylation or Arbuzov reaction led to (triazolyl)methyl phosphates, phosphoramidates or phosphonates. The latter were converted into uracil nucleoside 5'-(triazolyl)methyl phosphonates as prospective nucleoside diphosphate mimetics.

A New Family of Iron(II)-Cyclopentadienyl Compounds Shows Strong Activity Against Colorectal and Triple Negative Breast Cancer Cells.

A family of compounds with the general formula [Fe(η5-C5H5)(CO)(PPh3)(NCR)]+ has been synthesized (NCR = benzonitrile (1); 4-hydroxybenzonitrile (2); 4-hydroxymethylbenzonitrile (3); 4-aminobenzonitrile (4); 4-bromobenzonitrile (5); and, 4-chlorocinnamonitrile (6)). All of the compounds were obtained in good yields and were completely characterized by standard spectroscopic and analytical techniques. Compounds 1, 4, and 5 crystallize in the monoclinc P21/c space group and packing is determined by short contacts between the phosphane phenyl rings and cyclopentadienyl (compounds 1 and 4) or π-π lateral interactions between the benzonitrile molecules (complex 5). DFT and TD-DFT calculations were performed to help in the interpretation of the experimental UV-Vis. data and assign the electronic transitions. Cytotoxicity studies in MDA-MB-231 breast and SW480 colorectal cancer-derived cell lines showed IC50 values at a low micromolar range for all of the compounds in both cell lines. The determination of the selectivity index for colorectal cells (SW480 vs. NCM460, a normal colon-derived cell line) indicates that the compounds have some inherent selectivity. Further studies on the SW480 cell line demonstrated that the compounds induce cell death by apoptosis, inhibit proliferation by inhibiting the formation of colonies, and affect the actin-cytoskeleton of the cells. These results are not observed for the hydroxylated compounds 2 and 3, where an alternative mode of action might be present. Overall, the results indicate that the substituent at the nitrile-based ligand is associated to the biological activity of the compounds.

Catalyst control of selectivity in the C-O bond alumination of biomass derived furans.

Non-catalysed and catalysed reactions of aluminium reagents with furans, dihydrofurans and dihydropyrans were investigated and lead to ring-expanded products due to the insertion of the aluminium reagent into a C-O bond of the heterocycle. Specifically, the reaction of [{(ArNCMe)2CH}Al] (Ar = 2,6-di-iso-propylphenyl, 1) with furans proceeded between 25 and 80 °C leading to dearomatised products due to the net transformation of a sp2 C-O bond into a sp2 C-Al bond. The kinetics of the reaction of 1 with furan were found to be 1st order with respect to 1 with activation parameters ΔH ‡ = +19.7 (±2.7) kcal mol-1, ΔS ‡ = -18.8 (±7.8) cal K-1 mol-1 and ΔG ‡ 298 K = +25.3 (±0.5) kcal mol-1 and a KIE of 1.0 ± 0.1. DFT calculations support a stepwise mechanism involving an initial (4 + 1) cycloaddition of 1 with furan to form a bicyclic intermediate that rearranges by an α-migration. The selectivity of ring-expansion is influenced by factors that weaken the sp2 C-O bond through population of the σ*-orbital. Inclusion of [Pd(PCy3)2] as a catalyst in these reactions results in expansion of the substrate scope to include 2,3-dihydrofurans and 3,4-dihydropyrans and improves selectivity. Under catalysed conditions, the C-O bond that breaks is that adjacent to the sp2C-H bond. The aluminium(iii) dihydride reagent [{(MesNCMe)2CH}AlH2] (Mes = 2,4,6-trimethylphenyl, 2) can also be used under catalytic conditions to effect a dehydrogenative ring-expansion of furans. Further mechanistic analysis shows that C-O bond functionalisation occurs via an initial C-H bond alumination. Kinetic products can be isolated that are derived from installation of the aluminium reagent at the 2-position of the heterocycle. C-H alumination occurs with a KIE of 4.8 ± 0.3 consistent with a turnover limiting step involving oxidative addition of the C-H bond to the palladium catalyst. Isomerisation of the kinetic C-H aluminated product to the thermodynamic C-O ring expansion product is an intramolecular process that is again catalysed by [Pd(PCy3)2]. DFT calculations suggest that the key C-O bond breaking step involves attack of an aluminium based metalloligand on the 2-palladated heterocycle. The new methodology has been applied to important platform chemicals from biomass.