•Cobalt(II) phthalocyanine covalently immobilized on cellulose as a heterogeneous catalyst was synthesized.•Cobalt(II) phthalocyanine oxidized alkyl arenes and alcohols.•Oxidation was proceeded under ...mild reaction conditions.•Catalyst recycled for several times without significant decrease in catalytic activity.
Cobalt(II) phthalocyanine covalently immobilized on cellulose as a heterogeneous catalyst was synthesized and characterized. The catalyst showed good catalytic activity for the aerobic oxidation of alkyl arenes and alcohols under relatively mild reaction conditions. The catalyst can readily be recovered from the reaction mixture and reused for several runs without significant decrease in catalytic activity.
Blockade of the immunoinhibitory PD‐1/PD‐L1 pathway using monoclonal antibodies has shown impressive results with durable clinical antitumor responses. Anti‐PD‐1 and anti‐PD‐L1 antibodies have now ...been approved for the treatment of a number of tumor types, whereas the development of small molecules targeting immune checkpoints lags far behind. We characterized two classes of macrocyclic‐peptide inhibitors directed at the PD‐1/PD‐L1 pathway. We show that these macrocyclic compounds act by directly binding to PD‐L1 and that they are capable of antagonizing PD‐L1 signaling and, similarly to antibodies, can restore the function of T‐cells. We also provide the crystal structures of two of these small‐molecule inhibitors bound to PD‐L1. The structures provide a rationale for the checkpoint inhibition by these small molecules, and a description of their small molecule/PD‐L1 interfaces provides a blueprint for the design of small‐molecule inhibitors of the PD‐1/PD‐L1 pathway.
Circle of life: Macrocyclic peptide inhibitors can block the PD‐1/PD‐L1 pathway by directly binding to PD‐L1 and, similarly to anti‐PD‐L1 antibodies, they can restore the function of T‐cells. Structures of the macrocycle/PD‐L1 interfaces provide a foundation for the design of small‐molecule inhibitors with antitumor properties.
Introduction: The protein-protein interaction PD1/PD-L1 is an important immune checkpoint and several recently approved monoclonal antibodies show promising anti cancer activities in the clinical ...practice. However, only a small percentage of cancer patients benefit from PD1/PD-L1 directed mAbs. Moreover, some patients experience immune related side effects upon treatment with these mAbs. Recently, several atomic-resolution structures of human PD1/PD-L1, and small molecules, peptides and mAbs with PD-L1 and PD1 open the field for structure based drug design. Small molecules and peptides targeting PD1/PD-L1 promise to enhance tumor activity while showing less immune related side effects.
Areas covered: We reviewed the small molecules classes and peptides targeting PD1/PD-L1.
Expert opinion: Currently approved PD1/PD-L1 directed therapeutics show room for improvement. Three classes of non mAb small molecule classes have been discovered so far: (cyclic) peptides as direct competitive PD1/PD-L1 antagonists; small molecules disrupting PD1/PD-L1 and inducing a PD-L1 dimerization; and a small molecule class of unknown mode-of-action. An example of the later group CA-170 is currently investigated in a Phase 1 trial in patients with advanced solid tumors and lymphomas. Potential advantages of small molecules over mAbs include high distribution and better tumor penetration, improved PK/PD, less side effects and oral bioavailability.
Thalidomide and its analogs are molecular glues (MGs) that lead to targeted ubiquitination and degradation of key cancer proteins via the cereblon (CRBN) E3 ligase. Here, we develop a ...direct-to-biology (D2B) approach for accelerated discovery of MGs. In this platform, automated, high throughput, and nano scale synthesis of hundreds of pomalidomide-based MGs was combined with rapid phenotypic screening, enabling an unprecedented fast identification of potent CRBN-acting MGs. The small molecules were further validated by degradation profiling and anti-cancer activity. This revealed E14 as a potent MG degrader targeting IKZF1/3, GSPT1 and 2 with profound effects on a panel of cancer cells. In a more generalized view, integration of automated, nanoscale synthesis with phenotypic assays has the potential to accelerate MGs discovery.
A novel, efficient and environmentally friendly approach has been developed for the synthesis of biologically important
bis
-heterocyclic oxazepine-quinazolinone derivatives. The structurally ...interesting compounds of high purity were synthesized by a one-pot three-component reaction of 2-(2-formylphenoxy) acetic acid and 2-aminobenzamide as bifunctional reagents and an isocyanide without using any catalyst, with excellent overall yields.
DNA‐encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, ...or “hot spot”, regions of protein–protein interactions. A DNA‐encoded combinatorial peptoid library was designed based on the Ugi four‐component reaction by employing tryptophan‐mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide “hexT”, encoded by DNA sequences, and substituted by azide‐alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor‐relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD‐YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.
A focused approach: A DNA‐encoded peptoid library was designed by the Ugi multicomponent reaction around indole structures that mimic the side chain of tryptophan. Applying this focused library to the challenging cancer targets MDM2 and hTEAD4 yielded compounds for inhibitor development. Compounds binding to hTEAD4 disrupted the hTEAD4–YAP interaction, and reduced expression of a gene under control of the TEAD–YAP transcription factor complex.
Cobalt was successfully immobilized on natural hydroxyapatite nanocrystals which were obtained from cow bones (Co–NHAp). The chemical, structural, and electronic properties of this nanobiocatalyst ...were investigated using flame atomic absorption spectroscopy (FAAS), Fourier transform infrared (FT-IR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS) analysis. Natural hydroxyapatite (NHAp) as the support enhanced both catalytic activity and selectivity in the liquid phase aerobic oxidation of alkyl arenes and alcohols to their corresponding carbonyl compounds. The use of air as an inexpensive oxidant, the recyclability of the Co–NHAp nanobiocatalyst without significant decrease in its catalytic activity and easy workup are some advantages of this work.
The direct nonpeptidic macrocycle synthesis of α-isocyano-ω-amines via the classical Ugi four-component reaction (U-4CR) is introduced. Herein an efficient and flexible two-step procedure to complex ...macrocycles is reported. In the first step, the reaction between unprotected diamines and isocyanocarboxylic acids gives high diversity of unprecedented building blocks in high yield. In the next step, the α-isocyano-ω-amines undergo a U-4CR with high diversity of aldehydes and carboxylic acids in a one-pot procedure. This synthetic approach is short and efficient and leads to a wide range of macrocycles with different ring sizes.
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