Copper(II)-Catalyzed Direct C-H (Hetero)arylation at the C3 Position of Indoles Assisted by a Removable N,N-Bidentate Auxiliary Moiety.

The regioselective arylation of inert C3-H bonds in indoles reacting with arylboronates via effective copper-mediated catalysis with the aid of a facile and removable 2-pyridinylisopropyl (PIP) group without ligand participation is reported. This newly established method features high compatibility with diverse functional groups between coupling partners, including both indole substrates and arylboron reagents, consequentially leading to operational simplicity and providing access to generate the desired arylated products in good to excellent yields of up to 97%. Synthetically, the PIP-derived amide moiety could subsequently be readily removed under mild reaction conditions to produce useful indole carboxylic acids for further transformation.

Copper(II)-catalysed direct C3-H esterification of indoles assisted by an N,N-bidentate auxiliary moiety.

The regioselective direct C3-esterification of indoles with OXA is developed in an efficient reaction with carboxylic acids using the catalyst CuBr2 and oxidants Ag2CO3 and K2S2O8. The simple experimental procedure is proved to be broadly applicable to a range of substrates, including aromatic and aliphatic acids, and the corresponding products were obtained in good yields up to 87%. At the same time, it provides a valuable approach to produce C3-benzyl derivatives of indoles through reaction with benzyl carboxylic acid under the same reaction conditions.

Synthesis of indolo[2,1-α]isoquinoline derivatives via metal-free radical cascade cyclization.

In the present studies, we describe a convenient and efficient protocol for the synthesis of the indolo[2,1-α]isoquinoline core structure through the reaction of 2-aryl-N-acryloyl indoles and aryl or alkyl α-keto acids under air environment in four hours. The developed approach features broad substrate scope and good functional group tolerance under mild reaction conditions without a metal catalyst participation. A series of valuable indolo[2,1-α] isoquinoline derivatives bearing various functional groups were synthesized using this method in good to excellent yields. Based on a series of control experiments, a radical pathway was proposed to explain the experiment.

The nickel-catalyzed C3-acylation of 2H-indazoles with aldehydes.

A direct coupling of 2H-indazoles' C3 position and acyl groups has been achieved to produce 3-acyl-2H-indazoles. The Ni(ii)-catalyzed acylation might proceed through a radical pathway for the reaction of 2H-indazoles with either aryl or alkyl aldehydes in the presence of the free radical initiator TBHP and additive PivOH. This method provided a superior approach to fulfil the direct C3-acylation of 2H-indazoles with yields up to 91%. And various substituted 2H-indazoles were well tolerated with this method, enriching the diversity of 2H-indazole derivatives. In comparison with previously reported approaches for the C3-acylation of 2H-indazoles, the developed reaction represents a more convenient and economical method directly using aldehydes as the acylation agents.

Computational Simulation Studies on the Binding Selectivity of 1-(1H-Benzimidazol-5-yl)-5-aminopyrazoles in Complexes with FGFR1 and FGFR4.

Fibroblast growth factor receptor 1 (FGFR1) has become a potential target for the treatment of cancer. Designing FGFR1-selective inhibitors remains fundamental to the development of anti-cancer drugs because of highly sequential homology among FGFR subtypes. In present work, four inhibitors were examined with intermolecular interaction patterns with FGFR1 and FGFR4, respectively, for the exploration of binding mechanisms by applying a combined approach of computational techniques, including flexible docking, binding site analyses, electronic structure computations, molecular dynamic simulations, and binding free energy predictions. Molecular simulation-predicted binding conformations and pharmacophoric features of these molecules in the active pocket of either FGFR1 or FGFR4. MMPB(GB)SA-calculated binding free energies were accordant with the ordering of their tested potency values. Furthermore, in silico mutations of two residues (FGFR1: Tyr563 and Ser565) were also performed to check their impact on ligand binding by applying MD simulations and binding free energy calculations. The present studies may provide a structural understanding of the FGFR1-selective mechanism. The viewpoints from computational simulations would be valuable guidelines for the development of novel FGFR1-selective inhibitors.

Recent Developments in Medicinal Chemistry and Therapeutic Potential of Anti-Cancer PROTACs-Based Molecules.

BACKGROUND: PROTACs is an emerging technique that addresses the disease causing proteins by targeting protein degradation. PROTACs molecules are bifunctional small molecules that simultaneously bind to the protein of interest (POIs) and an E3 ligase followed by ubiquitination and degradation of the protein of interest by the proteasome. OBJECTIVE: PROTACs technology offers many advantages over classical inhibition such as PROTACs molecules can target intracellular proteins regardless of their function and have good tissue distribution. They are capable to target mutated and overexpressed proteins, thus potent molecules with the high degradation selectivity can be designed. Moreover, PROTACs molecules can target the undruggable proteome which makes up almost 85% of human proteins. Several PROTACs-based compounds have exhibited high therapeutic potency and some of them are currently under clinical trials. METHODS: Current article gives a comprehensive overview of the current development of PROTACs-based anticancer compounds along with the structure-activity relationship of the reported molecules. RESULTS: The development of PROTACs-based compounds and related research regarding medicinal chemistry is one of the most active and hot topics for research. CONCLUSION: It is believed that the current review article can be helpful to understand the logical design of more efficacious PROTACs-based molecules with less toxicity and more selectivity.

The synthesis of anticancer sulfonated indolo[2,1-a]isoquinoline and benzimidazo[2,1-a]isoquinolin-6(5H)-ones derivatives via a free radical cascade pathway.

A facile CuBr2 induced radical relay addition/cyclization of activated alkenes with substituted-thiosulfonates has been achieved, leading to a broad range of sulfonated indolo[2,1-a]isoquinolines and benzimidazo[2,1-a]isoquinolin-6(5H)-ones in moderate to good yields. In particular, some compounds exhibit bioactivity against cancer cell lines. This protocol shows advantages of low-cost, base-free, simple operation, and broad functional group tolerance.

The progress of small-molecules and degraders against BCR-ABL for the treatment of CML.

Chronic myeloid leukemia (CML) is a malignant disease of the hematopoietic system with crucial pathogenic protein named BCR-ABL, which endangers the life of patients severely. As a milestone of targeted drug, Imatinib has achieved great success in the treatment of CML. Nevertheless, inevitable drug resistance of Imatinib has occurred frequently in clinical due to the several mutations in the BCR-ABL kinase. Subsequently, the second-generation of tyrosine kinase inhibitors (TKIs) against BCR-ABL was developed to address the mutants of Imatinib resistance, except T315I. To date, the third-generation of TKIs targeting T315I has been developed for improving the selectivity and safety. Notably, the first allosteric inhibitor has been in market which could overcome the mutations in ATP binding site effectively. Meanwhile, some advanced technology, such as proteolysis-targeting chimeras (PROTAC) based on different E3 ligand, are highly expected to overcome the drug resistance by selectively degrading the targeted proteins. In this review, we summarized the current research progress of inhibitors and degraders targeting BCR-ABL for the treatment of CML.

Direct Acyloxylation of C(sp2)-H and C(sp2)-X (X = Cl, Br) Bonds in Aromatic Amides Using Copper Bromide and 2-(4,5-Dihydro-oxazol-2-yl)-phenylamine.

Here we reported a method for Cu2+-catalyzed ortho-acyloxylation of either the C(sp2)-H or C(sp2)-X (X = Cl, Br) bond of aromatic amides with carboxylic acid, especially olefine acids, to obtain corresponding products in good yields up to 91%. The catalyst CuBr2 is cheap and stable to conserve in comparison with other metals, like Rh, Pd, Ru, and Cu+. This simple procedure is applicable for wide substrate scope and various functional groups to produce carboxylic esters without any additives or ligands.

Design, Synthesis, and SAR Studies of Heteroarylpyrimidines and Heteroaryltriazines as CB2 R Ligands.

Herein we describe the design and synthesis of a new series of heteroarylpyrimidine/heteroaryltriazine derivatives on the basis of quinazoline-2,4(1H,3H)-diones as CB2 R-selective ligands using a bioisosterism strategy. An acetamide group was explored to displace the enamine linker of the lead compound for the purpose of stereoisomerism elimination and hydrophilicity increase. As a result, some of the synthesized compounds showed high bioactivity and selectivity for CB2 R in calcium mobilization assays, and four displayed CB2 R agonist activity, with EC50 values below 30 nm. The compound exhibiting the highest agonist activity toward CB2 R (EC50 =7.53±3.15 nm) had a selectivity over CB1 R of more than 1328-fold. Moreover, structure-activity relationship (SAR) studies indicated that the substituents on the nucleus play key roles in the functionality of a ligand, with one such example demonstrating CB2 R antagonist activity. Additionally, molecular docking simulations were conducted with the aim of better understanding of these new derivatives in relation to the structural requirements for agonists/antagonists binding to CB2 R.

Development of Quinazoline/Pyrimidine-2,4(1H,3H)-diones as Agonists of Cannabinoid Receptor Type 2.

Starting from a prototypical structure 1, we describe our efforts to design and obtain novel quinazoline/pyrimidine-2,4(1H,3H)-diones with high CB2 agonist potency and selectivity as well as improved physicochemical characteristics, mainly hydrophilicity. The most potent and selective CB2 agonists, 8 and 36, in this series were also endowed with lower logP values than that of GW842166X and lead compound 1. These derivatives appear to be promising lead compounds for the development of future CB2 agonists.

Developing pyridazine-3-carboxamides to be CB2 agonists: The design, synthesis, structure-activity relationships and docking studies.

Herein, we described the design and synthesis of a series of pyridazine-3-carboxamides to be CB2-selective agonists via a combination of scaffold hopping and bioisosterism strategies. The compounds were subjected to assessment of their potential activities through calcium mobilization assays. Among the tested derivatives, more than half of these compounds exhibited moderate to potent CB2 agonist activity. Six compounds showed EC50 values below 35 nM, and several derivatives also exhibited significantly enhanced potency and high selectivity at the CB2 receptor over the CB1 receptor. Specifically, compound 26 showed the highest CB2 agonist activity (EC50 = 3.665 ± 0.553 nM) and remarkable selectivity (Selectivity Index > 2729) against CB1. In addition, logPs of some representative compounds were measured to display significantly decreased values in comparison with GW842166X. Furthermore, docking simulations were conducted to explain the interaction mode of this series.

Molecular simulation studies on the binding selectivity of 2-anilino-4-(thiazol-5-yl)-pyrimidines in complexes with CDK2 and CDK7.

Cyclin dependent kinase 2 (CDK2) was regarded as a potentially therapeutic target for cancer therapy. Since the CDK family includes couples of high homology members, designing CDK2-selective inhibitors would provide valuable opportunities for the development of anticancer drugs with optimal efficacy. In this study, three thiazo-5-yl-pyrimidines as CDK2 inhibitors with different selectivity over cyclin dependent kinase 7 (CDK7) were examined to study the selectivity mechanism using a combined approach of computational techniques of flexible docking, EasyMIFs, molecular electrostatic potential (MESP), natural bond orbital (NBO), molecular dynamics (MD) simulations, and binding free energy calculations. Molecular simulations elicited new chemical insights into steric and electronic complementarities of these molecules to the binding sites of CDK2 and CDK7. The computed binding free energies were consistent with the ranking of their experimental binding affinities on CDK2 and CDK7. We also conducted in silico mutations of three key amino acids (CDK2: Gln85, Lys89, Asp145) to examine their impact on ligand binding with MD simulations and binding free energy calculations. The results indicated that these residues exhibited a strong tendency to mediate ligand-protein interactions through the H-bond and vdW interaction with CDK2-selective inhibitor. The present work may provide a better structural understanding of the molecular mechanism of CDK2 selective inhibition. The new computational insights presented in this study are expected to be valuable for the guidelines and development of new potent CDK2 inhibitors.

Molecular modeling studies to characterize N-phenylpyrimidin-2-amine selectivity for CDK2 and CDK4 through 3D-QSAR and molecular dynamics simulations.

CDK2 is a promising target for the development of anti-cancer agents. It is not an easy task to design CDK2-selective inhibitors which do not exhibit activity for other CDK family members, particularly CDK4, due to a high degree of structural homology among CDK family members. In this study, 4-substituted N-phenylpyrimidin-2-amine derivatives as CDK2 inhibitors were examined to understand the selectivity mechanism against CDK4 using a combined approach of 3D-QSAR, molecular docking, MESP, MD simulations, and binding free energy calculations. 3D-QSAR models were developed to propose structural determinants for CDK2 and CDK4 inhibition. High q(2) and r(2) values for CoMFA and CoMSIA models based on both internal and external validations suggested that the generated 3D-QSAR models may exhibit good capability to predict bioactivities of inhibitors against CDK2 or CDK4. Electrostatic potentials on the molecular surface have been discussed in detail for determining the binding affinity of studied inhibitors by combining molecular docking with MESP and Mulliken charge analyses. Binding free energy calculations suggested that the residues Gln85, Asp86, and Lys89 of CDK2 would play a critical role in selective CDK2 inhibition. The electrostatic interactions of an inhibitor with Glu144 and Asn145 of CDK4 may predominately drive CDK4 inhibition. These findings may provide a better structural understanding of the mechanism of CDK2 selective inhibition. The results obtained in the current study may provide valuable guidelines for developing novel potent and selective CDK2 inhibitors.