Pd-Catalyzed Miyaura Borylation and Telescopic Borylation/Suzuki-Miyaura Cross-Coupling Processes in Deep-Eutectic Solvents.

We report an efficient procedure to carry out palladium-catalyzed Miyaura borylation reactions of (hetero)aromatic halides and triflates in choline chloride (ChCl)-based deep eutectic solvents (DESs). The procedure employs bis(pinacolato)diboron as a boron source and a catalyst prepared in situ from readily available Pd(dba) and the phosphine ligand XPhos. Reactions proceed well in different ChCl-based DESs, among which the best results were provided by environmentally friendly and biodegradable mixtures with glycerol and glucose.

A novel bioresponsive self-immolative spacer based on aza-quinone methide reactivity for the controlled release of thiols, phenols, amines, sulfonamides or amides.

A stimuli-sensitive linker is one of the indispensable components of prodrugs for cancer therapy as it covalently binds the drug and releases it upon external stimulation at the tumour site. Quinone methide elimination has been widely used as the key transformation to release drugs based on their nucleofugacity. The usual approach is to bind the drug to the linker as a carbamate and release it as a free amine after a self-immolative 1,6-elimination.

Targeting GLI1 and GLI2 with small molecule inhibitors to suppress GLI-dependent transcription and tumor growth.

Aberrant activation of Hedgehog (HH) signaling in cancer is the result of genetic alterations of upstream pathway components (canonical) or other oncogenic mechanisms (noncanonical), that ultimately concur to activate the zinc-finger transcription factors GLI1 and GLI2. Therefore, inhibition of GLI activity is a good therapeutic option to suppress both canonical and noncanonical activation of the HH pathway. However, only a few GLI inhibitors are available, and none of them have the profile required for clinical development due to poor metabolic stability and aqueous solubility, and high hydrophobicity.

A Self-Immolative Linker for the pH-Responsive Release of Amides.

The administration of therapeutics using bioconjugation has been mainly limited to drugs containing amine, alcohol, or thiol functional groups. Here, we report a general procedure for the preparation of benzylic N-acyl carbamates suitable for masking the amide group in important drugs such as Linezolid, Enzalutamide, or Tasimelteon in good to acceptable yields. These N-acyl carbamates appear to be stable in plasma, while a qualitative analysis of further drug uncage demonstrates that, at pH values of 5.

A pH-responsive crosslinker platform for antibody-drug conjugate (ADC) targeting delivery.

We report a new 1-6 self-immolative, traceless crosslinker derived from the natural product gallic acid. The linker acts through a pH-dependent mechanism for drug release. This 5-(hydroxymethyl)pyrogallol orthoester derivative (HMPO) was stable for 24 hours at pH values of 7.

An Intramolecular Hydroaminomethylation-Based Approach to Pyrrolizidine Alkaloids under Microwave-Assisted Heating.

A general method for the synthesis of pyrrolizidine derivatives using an intramolecular hydroaminomethylation protocol (HAM) under microwave (MW) dielectric heating is reported. Starting from a 3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-vinylpyrrolidine, MW-assisted intramolecular HAM in the presence of gaseous H and CO gave the natural alkaloid hyacinthacine A protected as benzyl ether. The same approach gave a lentiginosine analogue starting from the corresponding vinyl -hydroxypyrrolidine.

Synthesis of 2-Substitued Indoles via Pd-Catalysed Cyclization in an Aqueous Micellar Medium.

The synthesis of 2-substituted indoles starting from the corresponding unprotected 2-alkynylanilines was made possible in 3% TPGS-750-M water using Pd(OAc) alone as the catalyst. The reaction was sensitive to the heating mode respect to the nature of the starting material as, in many cases, convectional heating was better than microwave dielectric heating. The MW (microwave) delivery mode had also an influence in the formation of by-products and, consequently, product yields.

Antibody drug conjugates with hydroxamic acid cargos for histone deacetylase (HDAC) inhibition.

Antitumor hydroxamates SAHA and Dacinostat have been linked to cetuximab and trastuzumab through a non-cleavable linker based on the p-mercaptobenzyl alcohol structure. These antibody drug conjugates (ADCs) were able to inhibit HDAC in several tumour cell lines. The cetuximab based ADCs block human lung adenocarcinoma cell proliferation, demonstrating that bioconjugation with antibodies is a suitable approach for targeted therapy based on hydroxamic acid-containing drugs.

Pharmacophore-Based Virtual Screening for Identification of Negative Modulators of GLI1 as Potential Anticancer Agents.

Starting from known GLI1 inhibitors, a pharmacophore-based virtual screening approach was applied to databases of commercially available compounds with the aim of identifying new GLI1 modulators. As a result, three different chemical scaffolds emerged that were characterized by a significant ability to reduce the transcriptional activity of the endogenous Hedgehog-GLI pathway and GLI1 protein level in murine NIH3T3 cells. They also showed a micromolar antiproliferative activity in human melanoma (A375) and medulloblastoma (DAOY) cell lines, without cytotoxicity in non-neoplastic mammary epithelial cells.

ErbB2 Targeted Epigenetic Modulation: Anti-tumor Efficacy of the ADC Trastuzumab-HDACi ST8176AA1.

Targeted therapy using monoclonal antibodies conjugated to toxins is gaining space in the treatment of cancer. Here, we report the anti-tumor effect of a new antibody drug conjugate (ADC) delivering a HDAC inhibitor to ErbB2+ solid tumors. Trastuzumab was partially reduced with tris [2-carboxyethyl] phosphine (TCEP) and conjugated to ST7464AA1, the active form of the prodrug HDAC inhibitor ST7612AA1, through a maleimide-thiol linker to obtain the Antibody Drug Conjugate (ADC) ST8176AA1.

New Blue Donor-Acceptor Pechmann Dyes: Synthesis, Spectroscopic, Electrochemical, and Computational Studies.

The design, synthesis, and characterization of a new class of blue-colored thiophene-substituted Pechmann dyes are reported. Due to a distinguishing blue coloration and the capability to absorb light in one of the most photon-dense regions of the solar spectrum, such compounds are of great interest for application as photoactive materials in organic optoelectronics, in particular, in dye-sensitized solar cells. To achieve fine tuning of the optical and electrochemical properties, the electron-poor thiophene-bis-lactone moiety has been decorated with donor (D) and acceptor groups (A), targeting fully conjugated D-A-π-A structures.

Antibody drug conjugates (ADCs) charged with HDAC inhibitor for targeted epigenetic modulation.

We describe here two novel antibody-drug conjugates loaded with the HDAC inhibitor ST7612AA1 (IC equal to 0.07 μM on NCI-H460 cells), a thiol-based molecule with a moderate toxicity . Two payloads were prepared using cleavable and non-cleavable linkers.

Novel smoothened antagonists as anti-neoplastic agents for the treatment of osteosarcoma.

Osteosarcoma (OS) is an ultra-rare highly malignant tumor of the skeletal system affecting mainly children and young adults and it is characterized by an extremely aggressive clinical course. OS patients are currently treated with chemotherapy and complete surgical resection of cancer tissue. However, resistance to chemotherapy and the recurrence of disease, as pulmonary metastasis, remain the two greatest challenges in the management, and treatment of this tumor.

Smoothened-antagonists reverse homogentisic acid-induced alterations of Hedgehog signaling and primary cilium length in alkaptonuria.

Alkaptonuria (AKU) is an ultra-rare genetic disease, in which the accumulation of a toxic metabolite, homogentisic acid (HGA) leads to the systemic development of ochronotic aggregates. These aggregates cause severe complications mainly at the level of joints with extensive degradation of the articular cartilage. Primary cilia have been demonstrated to play an essential role in development and the maintenance of articular cartilage homeostasis, through their involvement in mechanosignaling and Hedgehog signaling pathways.

Benzodiazepine Scaffold as Drug-like Molecular Simplification of FR235222: A Chemical Tool for Exploring HDAC Inhibition.

Background: Synthesis, computational study and biological evaluation of peptidomimetic analogues of FR235222 (3), a natural immunosuppressant and HDAC inhibitor, have been reported. These new compounds, bearing α-hydroxyketone moiety, as more stable zinc binding group (ZBG), were evaluated in vitro as HDAC inhibitors against the human HDACs isoforms 1-9 and in cellular antiproliferative assays on U937 human leukemia cell line. The 1,4-benzodiazepin-2,5-dione (BDZ), capping group and the natural ZBG, (S,R)-2-amino-9-hydroxy-8-oxodecanoic acid (Ahoda), were evaluated in order to probe HDAC inhibition and/or paralogue selectivity.

Design, synthesis and biological characterization of a new class of osteogenic (1H)-quinolone derivatives.

Smoothened (Smo) is the signal transducer of the Hedgehog (Hh) pathway and its stimulation is considered a potential powerful tool in regenerative medicine to treat severe tissue injuries. Starting from GSA-10, a recently reported Hh activator acting on Smo, we have designed and synthesized a new class of quinolone-based compounds. Modification and decoration of three different portions of the original scaffold led to compounds able to induce differentiation of multipotent mesenchymal cells into osteoblasts.

Hedgehog associated to microparticles inhibits adipocyte differentiation via a non-canonical pathway.

Hedgehog (Hh) is a critical regulator of adipogenesis. Extracellular vesicles are natural Hh carriers, as illustrated by activated/apoptotic lymphocytes specifically shedding microparticles (MP) bearing the morphogen (MP(Hh+)). We show that MP(Hh+) inhibit adipocyte differentiation and orientate mesenchymal stem cells towards a pro-osteogenic program.

Novel Acylguanidine Derivatives Targeting Smoothened Induce Antiproliferative and Pro-Apoptotic Effects in Chronic Myeloid Leukemia Cells.

The most relevant therapeutic approaches to treat CML rely on the administration of tyrosine kinase inhibitors (TKIs) like Imatinib, which are able to counteract the activity of Bcr-Abl protein increasing patient's life expectancy and survival. Unfortunately, there are some issues TKIs are not able to address; first of all TKIs are not so effective in increasing survival of patients in blast crisis, second they are not able to eradicate leukemic stem cells (LSC) which represent the major cause of disease relapse, and third patients often develop resistance to TKIs due to mutations in the drug binding site. For all these reasons it's of primary interest to find alternative strategies to treat CML.

Domino Hydrogenation-Reductive Amination of Phenols, a Simple Process To Access Substituted Cyclohexylamines.

Phenols can be efficiently reduced by sodium formate and Pd/C as the catalyst in water and in the presence of amines to give the corresponding cyclohexylamines. This reaction works at rt for 12 h or at 60 °C under microwave dielectric heating for 20 min. With the exception of aniline, primary, secondary amines, amino alcohols, and even amino acids can be used as nucleophiles.

Ruthenium-catalyzed synthesis of 5-amino-1,2,3-triazole-4-carboxylates for triazole-based scaffolds: beyond the dimroth rearrangement.

The 5-amino-1,2,3-triazole-4-carboxylic acid is a suitable molecule for the preparation of collections of peptidomimetics or biologically active compounds based on the triazole scaffold. However, its chemistry may be influenced by the possibility of undergoing the Dimroth rearrangement. To overcome this problem, a protocol based on the ruthenium-catalyzed cycloaddition of N-Boc ynamides with azides has been developed to give a protected version of this triazole amino acid.

MRT-92 inhibits Hedgehog signaling by blocking overlapping binding sites in the transmembrane domain of the Smoothened receptor.

The Smoothened (Smo) receptor, a member of class F G protein-coupled receptors, is the main transducer of the Hedgehog (Hh) signaling pathway implicated in a wide range of developmental and adult processes. Smo is the target of anticancer drugs that bind to a long and narrow cavity in the 7-transmembrane (7TM) domain. X-ray structures of human Smo (hSmo) bound to several ligands have revealed 2 types of 7TM-directed antagonists: those binding mostly to extracellular loops (site 1, e.

Organic dyes with intense light absorption especially suitable for application in thin-layer dye-sensitized solar cells.

Three new thiazolo[5,4-d]thiazole-based organic dyes have been designed and synthesized for employment as DSSC sensitizers. Alternation of the electron poor thiazolothiazole unit with two propylenedioxythiophene (ProDOT) groups ensured very intense light absorption in the visible region (ε up to 9.41 × 10(4) M(-1) cm(-1) in THF solution).

Genetic activation of Hedgehog signaling unbalances the rate of neural stem cell renewal by increasing symmetric divisions.

In the adult brain, self-renewal is essential for the persistence of neural stem cells (NSCs) throughout life, but its regulation is still poorly understood. One NSC can give birth to two NSCs or one NSC and one transient progenitor. A correct balance is necessary for the maintenance of germinal areas, and understanding the molecular mechanisms underlying NSC division mode is clearly important.

ST7612AA1, a thioacetate-ω(γ-lactam carboxamide) derivative selected from a novel generation of oral HDAC inhibitors.

A systematic study of medicinal chemistry aimed at identifying a new generation of HDAC inhibitors, through the introduction of a thiol zinc-binding group (ZBG) and of an amide-lactam in the ω-position of the polyethylene chain of the vorinostat scaffold, allowed the selection of a new class of potent pan-HDAC inhibitors (pan-HDACis). Simple, highly versatile, and efficient synthetic approaches were used to synthesize a library of these new derivatives, which were then submitted to a screening for HDAC inhibition as well as to a preliminary in vitro assessment of their antiproliferative activity. Molecular docking into HDAC crystal structures suggested a binding mode for these thiol derivatives consistent with the stereoselectivity observed upon insertion of amide-lactam substituents in the ω-position.