Synthesis of Indole-Fused Pyrazino[1,2-a]quinazolinones by Copper(I)-Catalyzed Selective Hydroamination-Cyclization of Alkynyl-tethered Quinazolinones.

We described a copper(I)-catalyzed atom economic and selective hydroamination-cyclization of alkynyl-tethered quinazolinones to prepare a variety of indole-fused pyrazino[1,2-a]quinazolinones in good to excellent yields ranging from 39% to 99% under mild reaction conditions. Control experiments revealed that coordination-directed method of quinazolinone moiety with copper(I) was important for the selective hydroamination-cyclization of alkynes at the N1-atom instead of N3-atom of quinazolinone. The reaction could be easily performed at gram scales and some prepared indole-fused pyrazino[1,2-a]quinazolinones with donating groups on the indole moiety showed a distinct fluorescence emission wavelength with blue shift under the acid conditions.

Synthesis of 4-(trichloromethyl)pyrido[2',1':3,4]pyrazino[2,1-b]quinazolinones through a cyclized dearomatization and trichloromethylation cascade strategy.

A variety of 4-(trichloromethyl)pyrido[2',1':3,4]pyrazino[2,1-b]quinazolinones were prepared in moderate to good yields with high regioselectivity through intramolecular 6-endo-dig cyclization and trichloromethylation of N3-alkynyl-2-pyridinyl-tethered quinazolinones in chloroform. Mechanistic studies revealed that chloroform might serve as a trichloromethyl anion precursor. Furthermore, the reaction could be easily performed on gram scales and an estrone-derived 4-(trichloromethyl)pyrido[2',1':3,4]pyrazino[2,1-b]quinazolinone was prepared over five steps. The present method features broad substrate scope, good functional group tolerance, new dearomatization of pyridine rings, and chloroform as the trichloromethylation reagent.

Design and synthesis of luotonin A-derived topoisomerase targeting scaffold with potent antitumor effect and low genotoxicity.

Conventional topoisomerase (Topo) inhibitors typically usually exert their cytotoxicity by damaging the DNAs, which exhibit high toxicity and tend to result in secondary carcinogenesis risk. Molecules that have potent topoisomerase inhibitory activity but involve less DNA damage provide more desirable scaffolds for developing novel chemotherapeutic agents. In this work, we broke the rigid pentacyclic system of luotonin A and synthesized thirty-three compounds as potential Topo inhibitors based on the devised molecular motif. Further investigation disclose that two compounds with the highest antiproliferation activity against cancer cells, 5aA and 5dD, had a distinct Topo I inhibitory mechanism different from those of the classic Topo I inhibitors CPT or luteolin, and were able to obviate the obvious cellular DNA damage typically associated with clinically available Topo inhibitors. The animal model experiments demonstrated that even in mice treated with a high dosage of 50 mg/kg 5aA, there were no obvious signs of toxicity or loss of body weight. The tumor growth inhibition (TGI) rate was 54.3 % when 20 mg/kg 5aA was given to the T24 xenograft mouse model, and 5aA targeted the cancer tissue precisely without causing damage to the liver and other major organs.

Design and synthesis of pseudo-rutaecarpines as potent anti-inflammatory agents via regulating MAPK/NF-κB pathways to relieve inflammation-induced acute liver injury in mice.

Pseudo-natural products (PNPs) design strategy provides a great valuable entrance to effectively identify of novel bioactive scaffolds. In this report, novel pseudo-rutaecarpines were designed via the combination of several privileged structure units and 46 target compounds were synthesized. Most of them display moderate to potent inhibitory effect on LPS-induced NO production and low cytotoxicity in RAW264.7 macrophage. The results of the anti-inflammatory efficacy and action mechanism of compounds 7l and 8c indicated that they significantly reduced the release of IL-6, IL-1ß and TNF-α. Further studies revealed that they can strongly inhibit the activation of NF-κB and MAPK signal pathways. The LPS-induced acute liver injury mice model studies not only confirmed their anti-inflammatory efficacy in vivo but also could effectively relieve the liver injury in mice. The results suggest that compounds 7l and 8c might serve as lead compounds to develop therapeutic drugs for treatment of inflammation.

Advancements in the Biotransformation and Biosynthesis of the Primary Active Flavonoids Derived from Epimedium.

Epimedium is a classical Chinese herbal medicine, which has been used extensively to treat various diseases, such as sexual dysfunction, osteoporosis, cancer, rheumatoid arthritis, and brain diseases. Flavonoids, such as icariin, baohuoside I, icaritin, and epimedin C, are the main active ingredients with diverse pharmacological activities. Currently, most Epimedium flavonoids are extracted from Epimedium plants, but this method cannot meet the increasing market demand. Biotransformation strategies promised huge potential for increasing the contents of high-value Epimedium flavonoids, which would promote the full use of the Epimedium herb. Complete biosynthesis of major Epimedium flavonoids by microbial cell factories would enable industrial-scale production of Epimedium flavonoids. This review summarizes the structures, pharmacological activities, and biosynthesis pathways in the Epimedium plant, as well as the extraction methods of major Epimedium flavonoids, and advancements in the biotransformation and complete microbial synthesis of Epimedium flavonoids, which would provide valuable insights for future studies on Epimedium herb usage and the production of Epimedium flavonoids.

Recent advances in the synthesis of 2,3-fused quinazolinones.

As one of the most important structural units in pharmaceuticals and medicinal chemistry, quinazolinone and its derivatives exhibit a wide range of biological and pharmacological activities, including anti-inflammatory, antitubercular, antiviral, and anticancer activities, etc. In particular, 2,3-fused quinazolinones have attracted much attention because the rings fused to the 2,3-positions of quinazolinones improve their rigidity and planarity. Their synthetic strategies have made great advances in recent years. Therefore, this review focuses on novel strategies for the synthesis of 2,3-fused quinazolinone derivatives from 2017 to 2022, such as the difunctionalization of alkenes, the ring-opening of easily available small rings, dehydrogenative cross-coupling reactions, transition-metal catalyzed cyclizations, cycloadditions, and other cascade reactions.

Synthesis of spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinones through gold(I)-catalyzed dearomative cyclization of N-alkynyl quinazolinone-tethered indoles.

A variety of functionalized spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinones were prepared in good to excellent yields through a gold(I)-catalyzed dearomative cyclization of N-alkynyl quinazolinone-tethered C2-substituted indoles. This reaction features a broad substrate scope, good functional group tolerance, and easy gram-scale preparation and transformations. Furthermore, biological activity studies showed that most of the obtained spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinone scaffolds showed potential as good anti-inflammatory agents.

Copper(I)-catalyzed [4 + 2] cycloaddition of aza-ortho-quinone methides with bicyclic alkenes.

A variety of tetrahydroquinoline-fused bicycles bearing multiple stereocenters are prepared in good yields with high diastereoselectivity through Cu2O-catalyzed [4 + 2] cycloaddition of aza-ortho-quinone methides (ao-QMs) with bicyclic alkenes. Mechanistic studies reveal that the Cu(i) catalyst not only promotes the formation of ao-QMs through a radical process by single electron transfer but also accelerates [4 + 2] cycloaddition. The reaction was easily performed on gram scale and the obtained tetrahydroquinoline-fused bicycles can be converted to diverse tetrahydroquinoline scaffolds.

3-Arylamino-quinoxaline-2-carboxamides inhibit the PI3K/Akt/mTOR signaling pathways to activate P53 and induce apoptosis.

Thirty-eight new 3-arylaminoquinoxaline-2-carboxamide derivatives were in silico designed, synthesized and their cytotoxicity against five human cancer cell lines and one normal cells WI-38 were evaluated. Molecular mechanism studies indicated that N-(3-Aminopropyl)-3-(4-chlorophenyl) amino-quinoxaline-2-carboxamide (6be), the compound with the most potent anti-proliferation can inhibit the PI3K-Akt-mTOR pathway via down regulating the levels of PI3K, Akt, p-Akt, p-mTOR and simultaneously inhibit the phosphorylation of Thr308 and Ser473 residues in Akt kinase to servers as a dual inhibitor. Further investigation revealed that 6be activate the P53 signal pathway, modulated the downstream target gene of Akt kinase such p21, p27, Bax and Bcl-2, caused the fluctuation of intracellular ROS, Ca2+ and mitochondrial membrane potential to induce cell cycle arrest and apoptosis in MGC-803 cells. 6be also display moderate anti-tumor activity in vivo while displaying no obvious adverse signs during the drug administration. The results suggest that 3-arylaminoquinoxaline-2-carboxamide derivatives might server as new scaffold for development of PI3K-Akt-mTOR inhibitor.

Luteolin combined with low-dose paclitaxel synergistically inhibits epithelial-mesenchymal transition and induces cell apoptosis on esophageal carcinoma in vitro and in vivo.

Although paclitaxel is a promising frontline chemotherapy agent for various malignancies, the clinical applications have been restricted by side effects, drug resistance, and cancer metastasis. The combination of paclitaxel and other agents could be the promising strategies against malignant tumor, which enhances the antitumor effect through synergistic effects, reduces required drug concentrations, and also suppresses tumorigenesis in multiple ways. In this study, we found that luteolin, a natural flavonoid compound, combined with low-dose paclitaxel synergistically regulated the proliferation, migration, epithelial-mesenchymal transition (EMT), and apoptosis of esophageal cancer cells in vitro, as well as synergistically inhibited tumor growth without obvious toxicity in vivo. The molecular mechanism of inhibiting cell migration and EMT processes may be related to the inhibition of SIRT1, and the mechanism of apoptosis induction is associated with the reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK) pathway-mediated activation of mitochondrial apoptotic pathway.

Nickel(II)-Catalyzed [5 + 1] Annulation of 2-Carbonyl-1-propargylindoles with Hydroxylamine To Synthesize Pyrazino[1,2-a]indole-2-oxides in Water.

An atom-economical and practical method for the efficient synthesis of various pyrazino[1,2-a]indole-2-oxides was developed through a nickel(II)-catalyzed [5 + 1] annulation of 2-carbonyl-1-propargylindoles with hydroxylamine in water without using an organic solvent. The reaction involved an initial condensation of 2-carbonyl-1-propargylindoles with hydroxylamine to afford oxime intermediates, which then underwent a nickel(II)-catalyzed 6-exo-dig cyclization. Preliminary studies showed that (n-Bu)4NI served as a phase transfer catalyst and promoted the formation of active nickel(II) species. More importantly, the nickel(II) salt and phase transfer catalyst-in-water could be recycled seven times, and a gram scalable product was easily obtained in good yields through a filtration and washing protocol.

Gold(III)-Catalyzed Selective Cyclization of Alkynyl Quinazolinone-Tethered Pyrroles: Synthesis of Fused Quinazolinone Scaffolds.

A series of 1,2- and 2,3-fused quinazolinones have been synthesized in good to excellent yields through gold-catalyzed selective hydroarylations of alkynyl quinazolinone-tethered pyrroles. The studies revealed that 1,2-fused quinazolinones were obtained through a 1,3-rearrangement and sequential 6- exo-trig cyclization of N1-alkynyl quinazolinone-tethered pyrroles, while N3-alkynyl quinazolinone-tethered pyrroles went through 6- exo-dig or 7- endo-dig cyclizations directly to afford 2,3-fused quinazolinones. The fused quinazolinones could be prepared at gram scale in three steps from commercial ortho-aminobenzamide.

Gold-Catalyzed Selective 6-exo-dig and 7-endo-dig Cyclizations of Alkyn-Tethered Indoles To Prepare Rutaecarpine Derivatives.

An efficient method to synthesize rutaecarpine derivatives via the gold-catalyzed selective cyclization of alkyn-tethered indoles under mild conditions is described. The alkyn-tethered indole can undergo 6-exo-dig cyclization by oxidation and sequential gold catalysis, while it goes through 7-endo-dig cyclization by gold catalysis and sequential oxidation. Substrate scope studies reveal that the selectivity of cyclization was controlled by the substrates with sp3 and sp2 hybridization of carbon at the 2 position in quinazolinone. Furthermore, the rutaecarpine scaffold was prepared in 67% yield at gram scale easily in four steps from isatoic anhydride.

Copper-Catalyzed Selective N-Vinylation of 3-(Hydroxyimino)indolin-2-ones with Alkenyl Boronic Acids: Synthesis of N-Vinyl Nitrones and Spirooxindoles.

A copper-catalyzed selective cross-coupling reaction of 3-(hydroxyimino)indolin-2-ones with alkenyl boronic acids to access (E)-N-vinyl oxindole nitrones has been achieved under mild conditions. The studies showed that catalytic copper salt selectively gave mono N-vinylation products, while 2.0 equiv of copper salt provided double N-vinylation products. The control experiments revealed that the carbonyl group in 3-(hydroxyimino)indolin-2-one played important roles on N-vinylation. Furthermore, the prepared N-vinyl oxindole nitrones could be converted to spirooxindoles in good yields under thermal conditions.

Tandem C-N Bond Formation through Condensation and Metal-Free N-Arylation: Protocol for Synthesizing Diverse Functionalized Quinoxalines.

Diverse functionalized quinoxalines were synthesized in good yields from arylamines and readily available ß-keto oximes through condensation and metal-free N-arylation. The reaction was compatible with various functional groups, such as halides, cyano, and esters. A mechanism was proposed based on the experimental results. These quinoxalines were easily obtained on a gram scale and converted to various useful scaffolds. Compound LASSBio-1022 was prepared in 83% yield in two steps.

Synthesis and antitumor evaluation of 2,3-diarylbenzofuran derivatives on HeLa cells.

2,2-Dihydroxyarylethanones, readily prepared from the commercially available aromatic ethyl ketones, were reacted with resorcinol, 3-methoxyphenol or 2-methoxyphenol in multi steps one-pot manner promoted by trifluoroacetic acid to furnish the 2,3-diarylbenzofuran derivatives in 22-95% yield. Sixteen targeted compounds were synthesized and characterized by 1H NMR, 13C NMR and HRMS. MTT assay indicated that most compounds possessed effectively inhibitory activities against the proliferation of HeLa cell. Among them, 4f had the highest inhibitory activities, with the IC50 being 13.40±2.04µmol/L. Cell cycle analysis, Annexin V-FITC/propidium iodide dual staining assay and western blotting analysis revealed that 4f inhibited the proliferation of Hela cell through apoptosis induction in a dose-dependent manner via obviously up-regulated the levels of Bak and Bim, while striking down-regulated the level of Bcl-2 and Bcl-xL protein.

Synthesis of ß-acetoxy alcohols by PhI(OAc)2-mediated metal-free diastereoselective ß-acetoxylation of alcohols.

ß-Acetoxy alcohols can be synthesized in good yields with excellent diastereoselectivity from tertiary alcohols through PhI(OAc)2-mediated metal-free ß-acetoxylation. Mechanistic studies showed that the ß-acetoxylation process might undergo dehydration and sequential highly regioselective and diastereoseletive dioxygenation. Gram scale and diverse useful scaffolds could be prepared via this ß-acetoxylation process.

Tandem C-O and C-N Bonds Formation Through O-Arylation and [3,3]-Rearrangement by Diaryliodonium Salts: Synthesis of N-Aryl Benzo[1,2,3]triazin-4(1H)-one Derivatives.

Metal-free O-arylation and [3, 3]-rearrangement have been shown as an efficient strategy to construct new C-O and C-N bonds in one-pot reactions. The method was used to prepare N-aryl benzo[1,2,3]triazin-4(1H)-one derivatives in good yields from N-hydroxy benzo[1,2,3]triazin-4(3H)-one and diaryliodonium salts. The reaction was tolerated a variety of sensitive functional groups such as iodine, nitro, ester, and aldehyde groups. A rational mechanism was proposed based on the experimental results, and the reaction was easily up to gram scale.

(Diacetoxyiodo)benzene-Mediated Reaction of Ethynylcarbinols: Entry to α,α'-Diacetoxy Ketones and Glycerol Derivatives.

Efficient access to α,α'-diacetoxy ketones has been developed from ethynylcarbinols and PhI(OAc)2. A plausible mechanism for this was proposed on the basis of experimental studies. The usefulness of α,α'-diacetoxy ketone products has been documented, and glycerol derivatives can be easily synthesized in good yields via a one-pot reaction.

Synthesis of α,ß-Unsaturated N-Aryl Ketonitrones from Oximes and Diaryliodonium Salts: Observation of a Metal-Free N-Arylation Process.

An efficient transition-metal-free method for the preparation of α,ß-unsaturated N-aryl ketonitrones under mild conditions has been developed. This reaction shows good functional group tolerance for both electron-rich and electron-deficient substituents on both oximes and diaryliodonium salts. Two examples of gram-scale preparations have been realized in good yields. Further transformations of these nitrones to different N-heterocycles have been demonstrated. DFT calculations suggest that N-arylation products are formed by [1,3]-phenyl migration of an O-coordinated oximate complex via a four-centered transition state, while the O-arylation products are formed by [1,3]-phenyl migration of a N-coordinated oximate complex.