Despite recent advances in the treatment of cancer, the issue of therapy resistance remains one of the most significant challenges in the field. In this context, signaling molecules, such as cytokines have emerged as promising targets for drug discovery. Examples of cytokines include macrophage migration inhibitory factor (MIF) and its closely related analogue D-dopachrome tautomerase (D-DT). In this study we aim to develop a new chemical class of D-DT binders and subsequently create a dual-targeted inhibitor that can potentially trigger D-DT degradation via the Proteolysis Targeting Chimera (PROTAC) technology. Here we describe the synthesis of a novel library of 1,2,3-triazoles targeting D-DT. The most potent derivative 19c (IC50 of 0.5 ± 0.04 μM with high selectivity toward D-DT) was attached to a cereblon (CRBN) ligand through aliphatic amides, which were synthesized by a remarkably convenient and effective solvent-free reaction. Enzyme inhibition experiments led to the discovery of the compound 10d, which exhibited moderate inhibitory potency (IC50 of 5.9 ± 0.7 μM), but unfortunately demonstrated no activity in D-DT degradation experiments. In conclusion, this study offers valuable insight into the SAR of D-DT inhibition, paving the way for the development of novel molecules as tools to study D-DT functions in tumor proliferation and, ultimately, new therapeutics for cancer treatment.

Most active pharmaceutical ingredients (APIs) suffer from poor water solubility, often keeping them from reaching patients. To overcome the issues of poor drug solubility and subsequent low bioavailability, amorphous solid dispersions (ASDs) have garnered much attention. Cellulose ester derivatives are of interest for ASD applications as they are benign, sustainable-based, and successful in commercial drug delivery systems, e.g. in osmotic pump systems and as commercial ASD polymers. Synthesis of carboxy-pendant cellulose esters is a challenge, due in part to competing reactions between carboxyls and hydroxyls, forming ester crosslinks. Herein we demonstrate proof-of-concept for a scalable synthetic route to simple, yet highly promising ASD polymers by esterifying cellulose polymers through ring-opening of cyclic succinic or glutaric anhydride. We describe the complexity of such ring-opening reactions, not previously well-described, and report ways to avoid gelation. We report synthesis, characterization, and preliminary in vitro ASD evaluations of fifteen such derivatives. Synthetic routes were designed to accommodate these criteria: no protecting groups, no metal catalysts, mild conditions with standard reagents, simple purification, and one-pot synthesis. Finally, these designed ASD polymers included members that maintained fast-crystallizing felodipine in solution and release it from an ASD at rather high 20 % drug loading (DL).

We present a mild, efficient, and one-pot method for the silyl-promoted transformation of cyclic anhydrides into homo- and hetero-dicarboxylic acid diesters and amide esters. This versatile reaction operates under ambient conditions, on a gram scale, and accommodates a wide range of alcohols, amines, and cyclic anhydrides. The one-pot process involves a two-step sequence, starting with the nucleophilic opening of anhydride by an amine or alcohol, followed by esterification. TMSCl serves a dual role, acting as a sacrificial reagent to remove in situ water and as a Lewis acid to promote the anhydride opening. The reaction proceeds successfully in the absence and presence of a base, as confirmed by NMR and crossover experiments, which validated the formation of dicarboxylic acid monoester and alkyl silyl mixed diester respectively. Controlled experiments have shown that the one-pot process yields higher efficiencies when compared to the same reaction conducted using a two-step process. This is the first comprehensive study demonstrating a broad substrate scope for the conversion of cyclic anhydride into diesters and amide esters. The method finds application in the synthesis of various commercial plasticizers.

Polyesters with a high glass transition temperature above 130 °C were obtained from limonene oxide (LO) or vinylcyclohexene oxide (VCHO) and phthalic anhydride (PA) in the presence of commercial salen-type complexes with different metals-Cr, Al, and Mn-as catalysts in combination with 4-(dimethylamino) pyridine (DMAP), bis-(triphenylphosphorydine) ammonium chloride (PPNCl), and bis-(triphenylphosphoranylidene)ammonium azide (PPNN3) as cocatalysts via alternating ring-opening copolymerization (ROCOP). The effects of the time of precontact between the catalyst and cocatalyst and the polymerization time on the productivity, molar mass (Mw), and glass transition temperature (Tg) were evaluated. The polyesters were characterized by a molar mass (Mw) of up to 14.0 kg/mol, a narrow dispersity Tg of up to 136 °C, and low (<3 mol%) polyether units. For poly(LO-alt-PA) copolymers, biodegradation tests were performed according to ISO 14851 using the respirometric biochemical oxygen demand method. Moreover, the vinyl double bond present in the poly(LO-alt-PA) copolymer chain was functionalized using three different thiols, methyl-3-mercaptopropionate, isooctyl-3-mercaptopropionate, and butyl-3-mercaptopropionate, via a click chemistry reaction. The thermal properties of poly(LO-alt-PA), poly(VCHO-alt-PA) and thiol-modified poly(LO-alt-PA) copolymers were extensively studied by DSC and TGA. Some preliminary compression molding tests were also conducted.

The present work aims to develop thermosetting resins using epoxidized hemp oil (EHO) as a bio-based epoxy matrix and a mixture of methyl nadic anhydride (MNA) and maleinized hemp oil (MHO) in different ratios as hardeners. The results show that the mixture with only MNA as a hardener is characterized by high stiffness and brittleness. In addition, this material is characterized by a high curing time of around 170 min. On the other hand, as the MHO content in the resin increases, the mechanical strength properties decrease and the ductile properties increase. Therefore, it can be stated that the presence of MHO confers flexible properties to the mixtures. In this case, it was determined that the thermosetting resin with balanced properties and high bio-based content contains 25% MHO and 75% MNA. Specifically, this mixture obtained a 180% higher impact energy absorption and a 195% lower Young\'s modulus than the sample with 100% MNA. Also, it has been observed that this mixture has significantly shorter times than the mixture containing 100% MNA (around 78 min), which is of great concern at an industrial level. Therefore, thermosetting resins with different mechanical and thermal properties can be obtained by varying the MHO and MNA content.

The development of new strategies for producing polyesters can expand the category of biodegradable materials. Here, we disclose the alternating copolymerization of cyclic acetals (made from formaldehyde and diols) and anhydrides for the first time, using 5 cyclic acetals and 9 anhydrides to afford 45 unprecedented polyesters. At a wide range of reaction temperatures (25 to 140 °C), diverse metal-free Lewis/Brønsted acids are highly active catalysts for these copolymerizations via the cationic mechanism. Of interest, kinetic studies indicate that the copolymerization of cyclic acetals and anhydrides shifts the chemical equilibrium of \"cyclic acetals ⇌ polyacetals\" to the left, thus yielding polyesters with up to >99 % alternating degree. The obtained polyesters possess high oxygen content ([O] : [C] up to 6 : 7), molecular weights of 2.0-33.3 kDa, narrow polydispersities of 1.2-1.5, low glass transition temperatures (-64 to -27 °C), as well as high decomposition temperatures (275 to 324 °C).

The catalytic activity and high selectivity reported by bimetallic heteroscorpionate acetate zinc complexes in ring-opening copolymerization (ROCOP) reactions involving CO2 as substrate encouraged us to expand their use as catalysts for ROCOP of cyclohexene oxide (CHO) and cyclic anhydrides. Among the catalysts tested for the ROCOP of CHO and phthalic anhydride at different reaction conditions, the most active catalytic system was the combination of complex 3 with bis(triphenylphosphine)iminium as cocatalyst in toluene at 80 °C. Once the optimal catalytic system was determined, the scope in terms of other cyclic anhydrides was broadened. The catalytic system was capable of copolymerizing selectively and efficiently CHO with phthalic, maleic, succinic and naphthalic anhydrides to afford the corresponding polyester materials. The polyesters obtained were characterized by spectroscopic, spectrometric, and calorimetric techniques. Finally, the reaction mechanism of the catalytic system was proposed based on stoichiometric reactions.

An anion-binding approach to the problem of preparing enantioenriched γ-lactams from enolisable anhydrides and imines is reported. A simple bisurea catalyst promotes the cycloaddition between α-aryl succinic anhydrides and either PMP- or benzhydryl-protected aldimines to provide γ-lactams with two contiguous stereocentres (one quaternary) with complete diastereocontrol and high to excellent enantioselectivity for the first time. A DFT study has provided insight into the catalyst mode of action and the origins of the observed stereocontrol.

The first broad-scope catalytic asymmetric Tamura cycloaddition reactions are reported. Under the influence of anion-binding bifunctional catalysis a wide range of α,β-unsaturated N-trityl imines undergo reactions with enolisable anhydrides to form highly synthetically useful α-tetralone structures with excellent enantio- and -diastereocontrol. In stark contrast to the previous literature benchmarks, doubly activated or highly electron deficient alkenes are not required. A facile two-step, high yielding sequence can convert the cycloadducts to α-haloketones (challenging to generate catalytically by other means) with the net formation of two new C-C bonds and three new contiguous stereocentres with exquisite stereocontrol. A DFT study has provided insight into the catalyst mode of action and the origins of the observed enantiocontrol.

The alternating copolymerization of epoxides with cyclic anhydrides (CAs) is a highly diverse synthetic method for polyesters as the polymers\' architectures and properties can be easily controlled depending on the combination of two monomers. Thus, a variety of catalyst designs has been reported to prepare the desired copolymers efficiently. We herein report dinuclear cobalt-salen complexes with a benzene ring as a linker and their activities in copolymerization reactions. The dinuclear cobalt complexes showed a higher catalytic activity for the copolymerization of propylene oxide with phthalic anhydride than the corresponding mononuclear cobalt-salen complex and achieved one of the highest turnover frequencies ever reported. A variety of epoxides and CAs were also found to be copolymerized successfully by the dinuclear cobalt complex with a high catalytic activity.