BOSS-Group

Organocatalytic asymmetric transformation of common aromatic heterocycles via in situ formation of highly reactive dearomatized ortho-quinodimethane diene species and subsequent [4+2] cycloaddition with suitable dienophiles has become a powerful tool to enter cyclohexane-fused heterocycles. Most of these reactions were previously applied to benzofused heterocycles or poorly aromatic rings. Herein, we disclose how previously intractable aromatic imidazole rings, equipped with removable methylidene malononitrile activating handle, could be involved as competent cycloaddends with β-aryl enals in efficient eliminative [4+2] cycloadditions under mild organocatalytic conditions. This method allowed the efficient and direct preparation of scantly represented 6,7-dihydrobenzo[d]imidazoles with optimal enantio- and regioselectivities. Post-cycloaddition chemical editing provided imidazole-based ring systems with diverse oxidation state and functional groups. 

Though the bulk of the COVID-19 pandemic is behind, the search for effective and safe anti-SARS-CoV-2 drugs continues to be relevant. A highly pursued approach for antiviral drug development involves targeting the viral spike (S) protein of SARS-CoV-2 to prevent its attachment to the cellular receptor ACE2. Here, we exploited the core structure of polymyxin B, a naturally occurring antibiotic, to design and synthesize unprecedented peptidomimetics (PMs), intended to target contemporarily two defined, non-overlapping regions of the S receptor-binding domain (RBD). Monomers 1, 2, and 8, and heterodimers 7 and 10 bound to the S-RBD with micromolar affinity in cell-free surface plasmon resonance assays (KD ranging from 2.31 μM to 2.78 μM for dimers and 8.56 μM to 10.12 μM for monomers). Although the PMs were not able to fully protect cell cultures from infection with authentic live SARS-CoV-2, dimer 10 exerted a minimal but detectable inhibition of SARS-CoV-2 entry in U87.ACE2+ and A549.ACE2.TMPRSS2+ cells. These results validated a previous modeling study and provided the first proof-of-feasibility of using medium-sized heterodimeric PMs for targeting the S-RBD. Thus, heterodimers 7 and 10 may serve as a lead for the development of optimized compounds, which are structurally related to polymyxin, with improved S-RBD affinity and anti-SARS-CoV-2 potential. 

The mechanism of the previously reported stereoselective (4+2) cycloaddition of N-protected 6-methyluracil-5-carbaldehydes and (E)-β-nitrostyrenes catalyzed by Takemoto's tertiary amine/thiourea organocatalyst was explored, using density functional theory (DFT) calculations on a model representative reaction. The cyclization reaction, which afforded notable enantioenriched carbocycle-fused uracils embedding three contiguous stereocenters, was here proven to be the result of a four-step sequence comprising a key stereo-defining Michael addition, followed by a completely diastereoselective intramolecular Henry reaction. Going beyond the hitherto reported activation modes, a complex and unprecedented network of hydrogen-bonding interactions between the chiral catalyst and the reaction partners has been disclosed, in which the protonated tertiary amine and the thiourea moiety of the catalyst simultaneously activate both the electrophile and the nucleophile components. By applying the Energetic Span Model (ESM) to four competitive energetic profiles, we unveiled the most plausible reaction pathways best fitting the experimental data, with close correlation with the observed enantiomeric ratio of the product. 

Growth factors and cytokines released in the lung cancer microenvironment promote an epithelial-to-mesenchymal transition (EMT) that sustains the progression of neoplastic diseases. TGFβ is one of the most powerful inducers of this transition, as it induces overexpression of the fibronectin receptor, αvβ6 integrin, in cancer cells which, in turn, is strongly associated with EMT. Thus, αvβ6 integrin receptors may be exploited as a target for the selective delivery of anti-tumor agents. We introduce three novel synthesized conjugates, in which a selective αvβ6 receptor ligand is linked to nintedanib, a potent kinase inhibitor used to treat advanced adenocarcinoma lung cancer in clinics. The αvβ6 integrin ligand directs nintedanib activity to the target cells of the tumor microenvironment, avoiding the onset of negative side effects in normal cells. We found that the three conjugates inhibit the adhesion of cancer cells to fibronectin in a concentration-dependent manner and that αvβ6-expressing cells internalized the conjugated compounds, thus permitting nintedanib to inhibit 2D and 3D cancer cell growth and suppress the clonogenic ability of the EMT phenotype as well as intervening in other aspects associated with the EMT transition. These results highlight αvβ6 receptors as privileged access points for dual-targeting molecular conjugates engaged in an efficient and precise strategy against non-small cell lung cancer.

In recent years, the principle of vinylogy and its applications in synthesis have intersected the world of organocatalysis, with rewarding benefits for both domains. The remarkable development of activation modalities using organocatalysis has been applied agreeably to vinylogous substrates such as polyunsaturated carbonyl- and carboxyl-level compounds, thus launching new reaction pathways and leading to panels of highly diversified products with excellent levels of chemo-, regio-, and stereocontrol. The selection of outstanding examples of organocatalyzed asymmetric, vinylogy-based reactions collected here bear witness to this strategic merger.

Melanoma is the deadliest form of skin cancer, and more than 150,000 cases are diagnosed every year in Europe. New strategies in treatment approved over the past decade, such as immunotherapy and targeted therapy, have prolonged life expectation even in stage IV melanoma patients. However, due to the increasing incidence of this cancer, the development of new therapeutic strategies remains urgent. Recent studies revealed the combination of nintedanib, a tyrosine kinase inhibitor approved as an antifibrotic drug, and immuno- and/or targeted therapy drugs to be promising. Here we present three new dual covalent conjugates, in which a nintedanib unit is permanently linked to a cyclopeptidomimetic ligand for the αVβ3 integrin, a transmembrane receptor involved in cell survival, proliferation and migration, which is overexpressed by tumour cells, and therefore recognized as marker for tumour targeting. In vitro assays on human melanoma tumour cells confirmed the high binding affinity of these conjugates for αVβ3 integrin-positive melanoma cells, as well as their integrin-mediated cell internalization. Two of these conjugates were efficient in inhibiting the mitogen activated protein kinase (MAPK) signalling pathway, common to both integrin- and growth factor- biological targets. Such targeted conjugates could therefore be of special interest in melanoma treatment alone or in combination with other anticancer drugs. 

Quinazoline-2,4-diones represent a prominent class of 5,6-fused-uracil derivatives which have attracted appreciable attention in the field of medicinal chemistry owing to their peculiar structure and multifaceted pharmacological profile. Within this heterocyclic class, the subdomain of chiral functionalized dihydro- and tetrahydroquinazoline derivatives, embedding in-cycle stereogenic elements, has emerged as an intriguing, yet underestimated, class of compounds, whose challenging structure and potential usefulness as drug-like pharmacophores has stimulated the development of versatile and efficient strategies toward their synthesis. After notable pioneering studies dating back to early 1980s, accessing these compounds in racemic format, substantial stagnation of innovative enantioselective synthesis proceduresto access these ring systems occurred, thus precluding their exploitation in medicinal chemistry programmes. Quite recently, the implementation of asymmetric, organocatalytic strategies towards these products, and based on stepwise [4+2]-cycloadditions has renewed the interest toward this fascinating class of chiral compounds, possibly paving the way to the study of their biological activities in the years to come. This account highlights strategies to the chemical synthesis of chiral dihydro- and tetrahydroquinazoline-2,4-dione ring systems in both racemic and enantioenriched formats via [4+2]-cyclization between elusive uracil-based ortho-quinodimethane dienes and suitable dienophile components. 

αVβ6 Integrin plays a fundamental role in the activation of transforming growth factor-β (TGF-β), the major profibrotic mediator; for this reason, αVβ6 ligands have recently been forwarded to clinical phases for the therapy of fibrotic diseases. Herein, we report the synthesis and in vitro biological evaluation as antifibrotic agents of three new covalent conjugates, constituted by c(AmpLRGDL), an αVβ6 integrin-recognizing small cyclopeptide, and nintedanib, a tyrosine kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF) treatment. One of these conjugates recapitulates optimal in vitro antifibrotic properties of the two active units. The integrin ligand portion within the conjugate plays a role in inhibiting profibrotic stimuli, potentiating the nintedanib effect and favoring the selective uptake of the conjugate in cells overexpressing αVβ6 integrin. These results may open a new perspective on the development of dual conjugates in the targeted therapy of IPF. 

Integrin α4β1 belongs to the leukocyte integrin family and represents a therapeutic target of relevant interest given its primary role in mediating inflammation, autoimmune pathologies and cancer-related diseases. The focus of the present work is the design, synthesis and characterization of new peptidomimetic compounds that are potentially able to recognize α4β1 integrin and interfere with its function. To this aim, a collection of seven new cyclic peptidomimetics possessing both a 4-aminoproline (Amp) core scaffold grafted onto key α4β1-recognizing sequences and the (2-methylphenyl)ureido-phenylacetyl (MPUPA) appendage, was designed, with the support of molecular modeling studies. The new compounds were synthesized through SPPS procedures followed by in-solution cyclization maneuvers. The biological evaluation of the new cyclic ligands in cell adhesion assays on Jurkat cells revealed promising submicromolar agonist activity in one compound , namely, the c[Amp(MPUPA)Val-Asp-Leu] cyclopeptide. Further investigations will be necessary to complete the characterization of this class of compounds. 

In recent years, targeted therapies have raised increasing interest as effective strategies to improve therapeutic efficiency, reduce the impact of adverse side effects, and overcome drug resistance, particularly in the field of cancer chemotherapeutics. Many examples of RGD (Arg‐Gly‐Asp) peptide‐drug conjugates (PDCs) have been proposed as targeted drug delivery systems. These molecular hybrids embody high affinity ligands targeting disease signatures (overexpressed integrin receptors or specific integrin‐related pathways within diseased cells/tissues) connected to recognized therapeutic units by means of carefully designed linker‐spacer combinations, to ultimately control stability, physico‐chemical properties, timing, and localization of drug release. This account has collected and critically surveyed relevant contributions from the period of 2015 to the present day, wishing to provide a window open on new synthesis strategies facing the challenging issues of site‐selective drug delivery and dual drug targeting. 

The peculiar versatility of remotely enolizable 6‐methyluracil‐5‐carbaldehydes as useful vinylogous pronucleophiles in direct, asymmetric [4+2] cyclizations with suitable nitroolefins has been demonstrated. Under the strategic exploitation of noncovalent bifunctional organocatalysis, a dearomative remote enolization strategy was implemented, to generate oQDM‐type dienolate intermediates that were efficiently and stereoselectively trapped by either aromatic or aliphatic nitroolefins. A series of functionalized, chiral carbocycle‐fused uracils embedding three contiguous stereocenters were thus collected in one step in good yields, with generally good levels of enantioselectivity, and complete diastereocontrol. Furthermore, the ability to provide enantiopure products via simple one‐cycle recrystallizations and the possibility to further functionalize these scaffolds without losing their chiral integrity were demonstrated. 

The discovery of chemical methods enabling the construction of carbocycle‐fused uracils which embody a three‐dimensional and functional‐group‐rich architecture is a useful tool in medicinal chemistry oriented synthesis. In this work, an unprecedented amine‐catalyzed [4+2] cross‐cycloaddition is documented; it involves remotely enolizable 6‐methyluracil‐5‐carbaldehydes and β‐aryl enals, and chemoselectively produces two novel bicyclic and tricyclic fused uracil chemotypes in good yields with a maximum level of enantiocontrol. In‐depth mechanistic investigations and control experiments support an intriguing homo‐synergistic organocatalytic approach, where the same amine organocatalyst concomitantly engages both aldehyde partners in a stepwise eliminative [4+2] cycloaddition, whose vinylogous iminium ion intermediate product may diverge—depending upon conditions—to either bicyclic targets by hydrolysis or tricyclic products by a second homo‐synergistic trienamine‐mediated stepwise [4+2] cycloaddition.