Metal-Free Reductive Coupling of para-Quinone Methides with 4-Cyanopyridines Enabled by Pyridine-Boryl Radicals: Access to Pyridylated Diarylmethanes with Anti-Cancer Activity.

Reported herein is a streamlined protocol to produce pyridylated diarylmethanes through pyridine-boryl radical induced reductive coupling between para-quinone methides (p-QMs) and 4-cyanopyridines using bis(pinacolato)diboron (B2 pin2 ) as a templated reagent. The metal-free process is characterized by an operationally simple approach, excellent chemoselectivity (1,2- vs. 1,6-selectivity), and a broad substrate scope with good functional group compatibility. The mechanistic studies provided important insights into the reductive cross-coupling process between diarylmethyl radical and pyridine-boryl radical. Moreover, part of the obtained pyridylated diarylmethane products were screened against a panel of cancer cell lines, and 3 v was confirmed to significantly inhibit the proliferation of head and neck squamous cell carcinoma (HNSCC) cells. This method offers a platform for the preparation of new lead compounds with antitumor activity.

Antiproliferative Evaluation of Novel 4-Imidazolidinone Derivatives as Anticancer Agent Which Triggers ROS-Dependent Apoptosis in Colorectal Cancer Cell.

Colorectal cancer (CRC) is one of the most common causes of cancer-related death worldwide, and more therapies are needed to treat CRC. To discover novel CRC chemotherapeutic molecules, we used a series of previously synthesized novel imidazolidin-4-one derivatives to study their anticancer role in several cancer cell lines. Among these compounds, compound 9r exhibited the best anticancer activity in CRC cell lines HCT116 and SW620. We further investigated the anticancer molecular mechanism of compound 9r. We found that compound 9r induced mitochondrial pathway apoptosis in HCT116 and SW620 cells by inducing reactive oxygen species (ROS) production. Moreover, the elevated ROS generation activated the c-Jun N-terminal kinase (JNK) pathway, which further accelerated apoptosis. N-acetylcysteine (NAC), an antioxidant reagent, suppressed compound 9r-induced ROS production, JNK pathway activation, and apoptosis. Collectively, this research synthesized a series of imidazolidin-4-one derivatives, evaluated their anticancer activity, and explored the molecular mechanism of compound 9r-induced apoptosis in CRC cells. The present results suggest that compound 9r has a potential therapeutic role in CRC. Hence, it deserves further exploration as a lead compound for CRC treatment.

Selective sulfonylation and isonitrilation of para-quinone methides employing TosMIC as a source of sulfonyl group or isonitrile group.

Chemoselective sulfonylation and isonitrilation reactions for the divergent synthesis of valuable diarylmethyl sulfones and isonitrile diarylmethanes starting from easy-to-synthesize para-quinone methides (p-QMs) and commercially abundant p-toluenesulfonylmethyl isocyanide (TosMIC) by using respectively zinc iodide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalysts were developed. The distinguishing feature of this method is that TosMIC plays a dual role from the same substrates in the reaction: as a sulfonyl source or as an isonitrile source. The synthetic utility of this protocol was also demonstrated in the synthesis of difluoroalkylated diarylmethane 5 and diarylmethane ketone derivatives 6 and 7, which are important core structures in natural products and medicines.

Microwave-Assisted Copper Catalysis of α-Difluorinated gem-Diol toward Difluoroalkyl Radical for Hydrodifluoroalkylation of para-Quinone Methides.

Reported herein is a unified strategy to generate difluoroalkyl radicals from readily prepared α-difluorinated gem-diols by single electron oxidation. Under microwave irradiation, a catalytic amount of oxidant Cu(OAc)2 succeeds in the formation of transient difluoroalkyl radicals in situ, for the first time. The reaction features a simple protocol, short reaction time, scalability, and high yield. The synthetic utility of this new methodology was also explored for the synthesis of difluoroalkylated spiro-cyclohexadienones, which is an important core structure in natural products and pharmaceuticals.

Synthesis of monofluorooxazoles with quaternary C-F centers through photoredox-catalyzed radical addition of methylene-2-oxazolines.

A novel photoredox-catalyzed radical addition of methylene-2-oxazolines has been developed under visible light irradiation to synthesize monofluorooxazoles with a quaternary carbon center using 2-bromo-2-fluoro-3-oxo-3-phenylpropionates as radical source. This method with a simple protocol, scalability and high yield offers a facile path to get diverse monofluorinated oxazoles with quaternary C-F centers, which are a class of highly valuable motifs and synthons.

Diversity-Oriented Synthesis of Imidazo-Dipyridines with Anticancer Activity via the Groebke-Blackburn-Bienaymé and TBAB-Mediated Cascade Reaction in One Pot.

A facile and metal-free one-pot protocol for the synthesis of fused imidazopyridine scaffolds has been developed. This novel protocol combines the Groebke-Blackburn-Bienaymé reaction (GBBR) with a sequential TBAB-mediated cyclization cascade. Biological evaluation demonstrated that compound 6a inhibits human prostate cancer cell DU-145 proliferation with an IC50 of 1.6 µM. The molecular mechanism study indicates that 6a significantly suppresses the oncogenic Erk kinase phosphorylation at 3 µM.

Microwave-assisted facile construction of quinoxalinone and benzimidazopyrazinone derivatives via two paths of post-Ugi cascade reaction.

A facile and efficient route to synthesize quinoxalinone and benzimidazopyrazinone was developed via two paths of a post-Ugi cascade reaction. By simply alternating the order of nucleophilic substitution reactions, both heterocycles could be accessed selectively from the same Ugi adduct. Microwave-assisted synthesis protocol provided these compounds with one purification procedure for three steps. These two scaffolds with more possible spaces for further modifications provide great benefit toward combinatorial and medicinal chemistry campaigns.

Facile microwave-assisted synthesis of benzimidazole scaffolds via Ugi-type three-component condensation (3CC) reactions.

Two series of fused benzimidazoles were synthesized via a facile, one-pot procedure under microwave irradiation. This procedure generated the desired products in high yields and could provide a useful synthetic platform with potential applications in medicinal chemistry.

Acid-Promoted Direct C-H Carbamoylation at the C-3 Position of Quinoxalin-2(1H)-ones with Isocyanide in Water.

Described herein is a concise and practical direct amidation at the C-3 position of quinoxalin-2(1H)-ones through an acid-promoted carbamoylation with isocyanide in water. In this conversion, environmentally friendly water and commercial inexpensive isocyanide were used as a solvent and carbamoylation reagent, respectively. This study not only provides a green and efficient strategy for the construction of 3-carbamoylquinoxalin-2(1H)-one derivatives that can be applied to the synthesis of druglike structures but also expands the application of isocyanide in organic chemistry.

A Novel Imidazopyridine Derivative Exerts Anticancer Activity by Inducing Mitochondrial Pathway-Mediated Apoptosis.

BACKGROUND: Cancer remains a major clinical challenge because of the lack of effective drug for its treatment. To find out novel cancer chemotherapeutic molecules, we explored the anticancer effect of novel imidazopyridine compound 9i and also investigated the underlying molecular mechanism. METHODS: Human cervical cancer cell (HeLa) viability was measured by an MTT assay after treatment with compound 9i. Clonogenicity of HeLa cells was investigated by an in vitro colony formation assay. Cell death was visualized by propidium iodide (PI) staining. Fluorescence-activated cell sorting (FACS) was used to determine apoptosis and mitochondrial membrane potential in HeLa cells. The expression level of apoptosis-related proteins was also determined by western blot. RESULTS: Compound 9i suppressed HeLa cell viability in a time- and dose-dependent manner. Compound 9i induced mitochondrial outer membrane permeabilization (MOMP), activated caspase cascade, and finally resulted in apoptosis. CONCLUSION: Compound 9i induces mitochondrial pathway-mediated apoptosis in human cervical cancer cells, suggesting that 9i could be a potential lead compound to be developed as a cancer therapeutic molecule.

Correction: One-pot construction of functionalized aziridines and maleimides via a novel pseudo-Knoevenagel cascade reaction.

Correction for 'One-pot construction of functionalized aziridines and maleimides via a novel pseudo-Knoevenagel cascade reaction' by Jie Lei et al., Chem. Commun., 2020, DOI: .

One-pot construction of functionalized aziridines and maleimides via a novel pseudo-Knoevenagel cascade reaction.

An Ugi, novel pseudo-Knoevenagel, ring expansion cascade reaction was discovered and utilized for the synthesis of aziridinyl succinimides in one-pot. Subsequently, densely functionalized aziridines and maleimides have been designed and synthesized through similar cascade reactions. The target compounds were prepared by means of a mild reaction and a simple operation procedure, which could be applicable to a broad scope of starting materials. This series of novel cascade reactions generates opportunities for the tailored synthesis of a wide range of biologically active scaffolds through tuneable Ugi inputs. Discovery of compound 8i with comparable potency to sorafenib in liver cancer cell lines could provide a new avenue for liver cancer drug discovery.

Merging Visible Light with Cross-Coupling: The Photochemical Direct C-H Difluoroalkylation of Imidazopyridines.

A transition-metal-free protocol for the difluoroalkylation of imidazopyridines with bromodifluoroaryl ketones promoted by visible light irradiation is presented. This protocol is distinguished by simple, mild, and catalyst-free reaction conditions with a wide reaction scope, which is complementary to existing difluoroalkylation strategies by photoredox scenarios. Additionally, this protocol potentially offers a new way for streamlining the synthesis of compounds containing the difluoro moiety.