A multicomponent reaction for modular assembly of indole-fused heterocycles.

Indoles are privileged chemical entities in natural products and drug discovery. Indole-fused heterocycles, particularly seven-membered ones, have received increasing attention due to their distinctive chemical characteristics and wide spectrum of bioactivities. However, the synthetic access to these compounds is highly limited. Herein, we report a unique multicomponent reaction (MCR) for modular assembly of indole-fused seven-membered heterocycles. In this process, indole, formaldehyde and amino hydrochloride could assemble rapidly to yield indole-fused oxadiazepines, and another addition of sodium thiosulphate would furnish indole-fused thiadiazepines. The biological evaluation disclosed the promising anticancer activity of these compounds. Furthermore, this MCR could be applicable in the late-stage and selective modifications of peptides. Therefore, this work provides a powerful strategy for indole functionalization and valuable tool for construction of seven-membered heterocycles.

Chemical Evolution and Biological Evaluation of Natural Products for Efficient Therapy of Acute Lung Injury.

Acute lung injury (ALI) is one of the most common complications in COVID-19 and also a syndrome of acute respiratory failure with high mortality rates, but lacks effective therapeutic drugs. Natural products provide inspiration and have proven to be the most valuable source for bioactive molecule discovery. In this study, the chemical evolution of the natural product Tanshinone IIA (Tan-IIA) to achieve a piperidine-fused scaffold through a synthetic route of pre-activation, multi-component reaction, and post-modification is presented. Through biological evaluation, it is pinpointed that compound 8b is a standout candidate with remarkable anti-inflammation and anti-oxidative stress properties, coupled with low toxicity. The mechanistic study unveils a multifaceted biological profile of 8b and shows that 8b is highly efficient in vivo for the treatment of ALI. Therefore, this work not only provides an effective strategy for the treatment of ALI, but also offers a distinctive natural product-inspired drug discovery.

Modular assembly of indole alkaloids enabled by multicomponent reaction.

Indole alkaloids are one of the largest alkaloid classes, proving valuable structural moiety in pharmaceuticals. Although methods for the synthesis of indole alkaloids are constantly explored, the direct single-step synthesis of these chemical entities with broad structural diversity remains a formidable challenge. Herein, we report a modular assembly of tetrahydrocarboline type of indole alkaloids from simple building blocks in a single step while showing broad compatibility with medicinally relevant functionality. In this protocol, the 2-alkylated or 3-alkylated indoles, formaldehyde, and amine hydrochlorides could undergo a one-pot reaction to deliver γ-tetrahydrocarbolines or ß-tetrahydrocarbolines directly. A wide scope of these readily available starting materials is applicable in this process, and numerous structural divergent tetrahydrocarbolines could be achieved rapidly. The control reaction and deuterium-labelling reaction are conducted to probe the mechanism. And mechanistically, this multicomponent reaction relies on a multiple alkylamination cascade wherein an unusual C(sp3)-C(sp3) connection was involved in this process. This method could render rapid access to pharmaceutically interesting compounds, greatly enlarge the indole alkaloid library and accelerate the lead compound optimization thus facilitating drug discovery.

Discovery of Novel 1,2,3,4-Tetrahydrobenzofuro[2,3-c]pyridine Histone Deacetylase Inhibitors for Efficient Treatment of Hepatocellular Carcinoma.

The development of histone deacetylase (HDAC) inhibitors for treating hematologic malignancies has been widely investigated, while their role in hepatocellular carcinoma (HCC) remains unexplored. In this study, we employed a scaffold-hopping design and a multicomponent synthesis approach to develop a novel series of 1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridines as HDAC inhibitors. There were a total of 29 compounds achieved with flexible linkers and zinc-binding groups, wherein compound 12k was identified as a promising candidate with good HDAC inhibitory activity, pharmacokinetic profiles, and potency. It exhibited significant therapeutic efficacy in HCC cell lines (IC50 = 30 nM for Bel-7402) and xenograft models (76% inhibition for Bel-7402 xenografts, P.O. at 20 mg/kg, QOD, for 14 days) and was found to upregulate the acetylation of histone H3 and α-tubulin, leading to apoptosis and autophagy in HCC models. Molecular docking studies indicated a unique T-shaped conformation of 12k with the catalytic domain of HDAC1. Therefore, this work provides a new structure design for HDAC inhibitors and also offers a promising treatment for HCC.

Scaffold Hybrid of the Natural Product Tanshinone I with Piperidine for the Discovery of a Potent NLRP3 Inflammasome Inhibitor.

Natural products provide inspiration and have proven to be the most valuable source for drug discovery. Herein, we report a scaffold hybrid strategy of Tanshinone I for the discovery of NLRP3 inflammasome inhibitors. 36 compounds were designed and synthesized, and the cheminformatic analyses showed that these compounds occupy a unique chemical space. The biological evaluation identified compounds 5j, 12a, and 12d as NLRP3 inflammasome inhibitors with significant potency, selectivity, and drug-likeness. Mechanistic studies revealed that these Tanshinone I derivatives could inhibit the degradation of the protein NLRP3 and block the oligomerization of NLRP3-induced apoptosis-associated speck-like proteins, thus inhibiting NLRP3 inflammasome activation. In addition, the water solubility, in vitro metabolic stability, and oral bioavailability of these compounds were also greatly improved compared to Tanshinone I. Therefore, this protocol provides a new structural evolution of Tanshinone I and a new class of potent NLRP3 inflammasome inhibitors.

Multicomponent double Mannich alkylamination involving C(sp2)-H and benzylic C(sp3)-H bonds.

Alkylamines are ubiquitous in pharmaceuticals, materials and agrochemicals. The Mannich reaction is a well-known three-component reaction for preparing alkylamines and has been widely used in academic research and industry. However, the nucleophilic components in this process rely on C(sp2)-H and activated C(sp3)-H bonds while the unactivated C(sp3)-H bonds involved Mannich alkylamination is a long-standing challenge. Here, we report an unprecedented multicomponent double Mannich alkylamination for both C(sp2)-H and unactivated benzylic C(sp3)-H bonds. In this process, various 3-alkylbenzofurans, formaldehyde and alkylamine hydrochlorides assemble efficiently to furnish benzofuran-fused piperidines. Mechanistic studies and density functional theory (DFT) calculations revealed a distinctive pathway that a multiple Mannich reaction and retro-Mannich reaction of benzofuran and dehydrogenation of benzylic C(sp3)-H bonds were key steps to constitute the alkylamination. This protocol furnishes a Mannich alkylamine synthesis from unusual C-H inputs to access benzofuran-fused piperidines with exceptional structural diversity, molecular complexity and drug-likeness. Therefore, this work opens a distinctive vision for the alkylamination of unactivated C(sp3)-H bonds, and provides a powerful tool in diversity-oriented synthesis (DOS) and drug discovery.

Tanshinones: An Update in the Medicinal Chemistry in Recent 5 Years.

Tanshinones are an important type of natural products isolated from Salvia miltiorrhiza Bunge with various bioactivities. Tanshinone IIa, cryptotanshinone and tanshinone I are three kinds of tanshinones which have been widely investigated. Particularly, sodium tanshinone IIa sulfonate is a water-soluble derivative of tanshinone IIa and it is used in clinical in China for treating cardiovascular diseases. In recent years, there are increasing interests in the investigation of tanshinones derivatives in various diseases. This article presents a review of the anti-atherosclerotic effects, cardioprotective effects, anticancer activities, antibacterial activities and antiviral activities of tanshinones and structural modification work in recent years.

Triazenyl Alkynes as Versatile Building Blocks in Multicomponent Reactions: Diastereoselective Synthesis of ß-Amino Amides.

Multicomponent reactions (MCRs) are powerful tool for the construction of polyfunctional molecules in an operationally simple and atom-economic manner, and the discovery of novel MCRs requests various building blocks. Herein, triazenyl alkynes were disclosed as versatile building blocks in a multicomponent reaction with carboxylic acids, aldehydes and anilines to furnish ß-amino amides with the achievement of high diastereoselectivity and structural diversity. In this process, triazenyl alkynes were bifunctional so that the alkyne moiety acts as C2 fragment and triazene serves as directing group to modulate the transition state thus achieving high diastereoselectivity, in consistence with DFT calculations. Furthermore, the triazenyl group also enables diverse late-stage transformation. This protocol opens a new vision for the discovery of building block and rational design of MCRs.

Directing-Group-Enabled Cycloaddition of Azides and Alkynes toward Functionalized Triazoles.

Herein, we report a directing-group-enabled Huisgen cycloaddition of azides and alkynes for the synthesis of functionalized triazoles in which the triazene group could act as a directing group to enable this regioselective [3 + 2] cycloaddition and further replacement by diverse groups, including amino, amide, halogen, and heterocycle substituents. This method represents a general and practical synthesis of triazoles under mild reaction conditions and broad substrate scope.

Redox Cyclization of Amides and Sulfonamides with Nitrous Oxide for Direct Synthesis of Heterocycles.

Herein we report a redox cyclization of amides and sulfonamides with nitrous oxide (N2O) for the direct synthesis of heterocycles. Various amides and sulfonamides could undergo directed ortho metalation (DoM) by treatment with BuLi, and the lithium intermediate could be trapped by N2O gas to achieve redox cyclization. N2O serves as a N-atom donor to mediate the intramolecular coupling of lithium species toward heterocycle formation with free external oxidant. This protocol offers a direct synthesis of heterocycles with features of readily available starting materials, simple operation, and a broad substrate scope.

One-Pot Reaction of Carboxylic Acids and Ynol Ethers for The Synthesis of ß-Keto Esters.

An one-pot reaction of carboxylic acids and ynol ethers for the synthesis of ß-keto esters has been developed. Under promotion of Ag2O, various carboxylic acids and ynol ethers could transform to α-acyloxy enol esters, which undergo a following DMAP-catalyzed rearrangement to deliver ß-keto esters rapidly. This method provides a direct approach to ß-keto esters from carboxylic acids without any preactivation. The protocol features mild reaction conditions, broad substrate scope, and the products could be transformed to an array of compounds.