Organocatalytic diastereo- and atropo-selective construction of eight-membered bridged (hetero)biaryls via asymmetric intramolecular [3 + 2] cycloaddition.

An unprecedented and straightforward route for the asymmetric construction of privileged atroposelective bridged (hetero)biaryl eight-membered scaffolds has been accomplished through chiral phosphoric acid catalyzed asymmetric intramolecular [3 + 2] cycloaddition of innovative (hetero)biaryl aldehydes with 3-aminooxindole hydrochlorides. A class of eight-membered bridged (hetero)biaryl lactones fused to spiro[pyrrolidine-oxindole] derivatives, possessing both chiral C-C/C-N axes and multiple contiguous stereocenters, were obtained in good yields with excellent enantioselectivities and diastereoselectivities in one step through this direct strategy. In addition, the good scalability and derivatization of the title compounds demonstrated their synthetic utility.

Mix-Key: graph mixup with key structures for molecular property prediction.

Molecular property prediction faces the challenge of limited labeled data as it necessitates a series of specialized experiments to annotate target molecules. Data augmentation techniques can effectively address the issue of data scarcity. In recent years, Mixup has achieved significant success in traditional domains such as image processing. However, its application in molecular property prediction is relatively limited due to the irregular, non-Euclidean nature of graphs and the fact that minor variations in molecular structures can lead to alterations in their properties. To address these challenges, we propose a novel data augmentation method called Mix-Key tailored for molecular property prediction. Mix-Key aims to capture crucial features of molecular graphs, focusing separately on the molecular scaffolds and functional groups. By generating isomers that are relatively invariant to the scaffolds or functional groups, we effectively preserve the core information of molecules. Additionally, to capture interactive information between the scaffolds and functional groups while ensuring correlation between the original and augmented graphs, we introduce molecular fingerprint similarity and node similarity. Through these steps, Mix-Key determines the mixup ratio between the original graph and two isomers, thus generating more informative augmented molecular graphs. We extensively validate our approach on molecular datasets of different scales with several Graph Neural Network architectures. The results demonstrate that Mix-Key consistently outperforms other data augmentation methods in enhancing molecular property prediction on several datasets.

Enantioselective Synthesis of 2,3,3a,8a-Tetrahydrofuro[2,3-b]benzofuran Scaffolds Enabled by Cu(II)/SPDO-Catalyzed [3+2] Cycloaddition of 2,3-Dihydrofuran and Quinone Esters.

An asymmetric [3+2] cycloaddition of quinone esters with 2,3-dihydrofuran has been realized via a newly developed Cu(II)/SPDO complex. It provides straightforward access to 2,3,3a,8a-tetrahydrofuro[2,3-b]benzofurans (TFB) with high enantioselectivity (up to 97.5:2.5 er) and diastereoselectivity (all >20:1 dr). The resulting adducts contain two adjacent stereocenters and a continuously functionalized benzene ring. Additionally, this transformation could be easily performed on a gram scale, allowing for expedient synthesis of natural dihydroaflatoxin D2 and aflatoxin B2.

Enantioselective Nucleophilic Vinylic Substitution (SNV) toward 3-Alkenyl-bisoxindoles Facilitated by C6' Steric Bulk of Cinchona Alkaloid.

A C6' bulky substituted quinine-catalyzed SNV reaction between 3-substituted oxindole and (E)-3-(nitromethylene)-oxindole was developed. This enantioselective C(sp3)-C(sp2) coupling furnished bisoxindole scaffolds featuring a vinyl-substituted all-carbon quaternary stereocenter with high stereoselectivities. In addition, the gram-scale synthesis and synthetic post-transformations were conducted to demonstrate the potential synthetic usefulness.

Discovery of 2,5-disubstituted furan derivatives featuring a benzamide motif for overcoming P-glycoprotein mediated multidrug resistance in MCF-7/ADR cell.

P-glycoprotein (P-gp) is one of the drug efflux transporters that triggers multidrug resistance (MDR) in cells. Herein, by utilizing the strategies of active skeleton splicing and structural optimization on the lead compound 5 m, a total of 50 novel 2,5-disubstituted furan derivatives were designed, synthesized, and screened for P-gp inhibitory activity. The structure-activity relationship analysis enabled the identification of an important pharmacophore N-phenylbenzamide, which resulted in the discovery of a promising drug lead compound Ⅲ-8. Ⅲ-8 possesses broad-spectrum reversal activity and low toxicity in MCF-7/ADR cells. Western blot and Rh123 accumulation assay demonstrated that Ⅲ-8 displayed the reversal activity by inhibiting P-gp efflux. Molecular docking analysis indicated a potent affinity of Ⅲ-8 to P-gp by forming H-bond interactions with residues Asn 721 and Met 986. Ⅲ-8 was determined to be a highly effective and safe P-gp inhibitor in an MCF-7/ADR xenograft mouse model.

Novel Benzo Five-Membered Heterocycle Derivatives as P-Glycoprotein Inhibitors: Design, Synthesis, Molecular Docking, and Anti-Multidrug Resistance Activity.

A proposed strategy to overcome multidrug resistance (MDR) of anticancer drugs in chemotherapy is to disable the efflux function of P-glycoprotein (P-gp). In this study, based on ring-merging and fragment-growing strategies, 105 novel benzo five-membered heterocycle derivatives were designed, synthesized, and screened. Exploration of the structure-activity relationship (SAR) led to the identification of d7 with low cytotoxicity and promising reversal activity to doxorubicin in MCF-7/ADR cells. Furthermore, the mechanism studies revealed that the reversal activity of d7 stemmed from the inhibition of P-gp efflux. Molecular docking further clarified the observed trends in SAR with d7 displaying potent affinity to P-gp. Additionally, coadministration of d7 with doxorubicin achieved stronger antitumor activity in a xenograft model than doxorubicin alone. These results suggest that d7 is a potential MDR reveal agent acting as a P-gp inhibitor and provides guidelines for the future development of new P-gp inhibitors.

Design, synthesis and biological evaluation of novel phenylfuran-bisamide derivatives as P-glycoprotein inhibitors against multidrug resistance in MCF-7/ADR cell.

The co-administration of anticancer drugs and P-glycoprotein (P-gp) inhibitors was a treatment strategy to surmount multidrug resistance (MDR) in anticancer chemotherapy. In this study, novel phenylfuran-bisamide derivatives were designed as P-gp inhibitors based on target-based drug design, and 31 novel compounds were synthesized and screened on MCF-7/ADR cells. The result of bioassay revealed that compound y12d exhibited low cytotoxicity and promising MDR reversal activity (IC50 = 0.0320 µM, reversal fold = 1163.0), 3.64-fold better than third-generation P-gp inhibitor tariquidar (IC50 = 0.1165 µM, reversal fold = 319.3). The results of Western blot and rhodamine 123 accumulation verified that compound y12d exhibited excellent MDR reversal activity by inhibiting the efflux function of P-gp but not expression. Furthermore, molecular docking showed that compound y12d bound to target P-gp by forming the double H-bond interactions with residue Gln 725. These results suggest that compound y12d might be a potential MDR reveal agent acting as a P-gp inhibitor in clinical therapeutics, and provide insight into design strategy and skeleton optimization for the development of P-gp inhibitors.

DBU Promoted Polysubstituted Arene Formation via a Michael Addition/Cyclization/Elimination Cascade Reaction.

The straightforward construction of polysubstituted arenes is essential in both synthetic chemistry and medicinal chemistry. Herein, we reported a DBU promoted Michael addition/cyclization/elimination cascade reaction between vinylogous malononitrile derivatives and chlorinated nitrostyrenes for the synthesis of polysubstituted arenes. The method features mild reaction conditions, wide substrate scope and high yield. Interestingly, preliminary study of the enantioselective version of this cascade was conducted to give chiral biaryl atropisomers with up to 40% ee through center-to-axial chirality transfer strategy.

Recent advances in the applications of pyrazolone derivatives in enantioselective synthesis.

Pyrazolones and pyrazoles, featuring nitrogen-nitrogen bonds, are two of the most important classes of heterocycles, owing to their widespread occurrence in medicinal chemistry and functional materials. The last decade has witnessed a rapid increase in the construction of chiral pyrazolone and pyrazole derivatives, with the application of pyrazolone derivatives as powerful synthons. Since our last review in 2018, a large number of new achievements has emerged in this area, requiring a timely update. Thus, this review summarizes these elegant achievements based on the multiple reactive sites of different pyrazolone synthons. In addition, important mechanisms and interesting biological investigations relating to the corresponding products are also discussed.

Amycolachromones A-F, Isolated from a Streptomycin-Resistant Strain of the Deep-Sea Marine Actinomycete Amycolatopsis sp. WP1.

In this study, a detailed chemical investigation of a streptomycin-resistant strain of the deep-sea marine, actinomycete Amycolatopsis sp. WP1, yielded six novel amycolachromones A-F (1-6), together with five known analogues (7-11). Amycolachromones A-B (1-2) possessed unique dimer skeletons. The structures and relative configurations of compounds 1-11 were elucidated by extensive spectroscopic data analyses combined with X-ray crystal diffraction analysis. Plausible biogenetic pathways of amycolachromones A-F were also proposed.

Construction of a spiro[pyrazolone-4,2'-pyridoindole] scaffold via a [3 + 3] cycloaddition of 2-indolylmethanol with a 4-aminopyrazolone-derived azomethine ylide.

This work reports a facile [3 + 3] cycloaddition sequence of two important heterocyclic pharmacophores, pyrazolone and 2-indolylmethanol, integrated into a polycyclic hybrid scaffold. In this process, an in situ generated azomethine ylide obtained from 4-aminopyrazolone and benzaldehyde reacts with 2-indolylmethanols to offer spiro[pyrazolone-pyridoindole] scaffolds in high yields with excellent diastereoselectivities. Remarkably, the reaction is carried out at room temperature without any catalyst and base.

Advances of α-activated cyclic isothiocyanate for the enantioselective construction of spirocycles.

The efficient and enantioselective synthesis of pharmaceutically important spirocycles has attracted the focus of organic and medicinal chemists. In this context, with the excellent reactivity of α-activated isothiocyanate as formal 1,3-dipoles in the (3 + 2) cyclization process, the cyclic isothiocyanates featuring important pharmacophores, such as oxindole, pyrazolone, and indanone moieties, have emerged as powerful precursors to access a variety of spirocycles with highly structural diversities. In addition, the facile transformations of these spirocycles have shown potential applications in drug design. This review will cover the recent advances of α-activated cyclic isothiocyanates in the enantioselective construction of spirocycles since 2015, and the applications of corresponding products in organic and medicinal chemistry.

Discovery of pyrazolones as novel carboxylesterase 2 inhibitors that potently inhibit the adipogenesis in cells.

Carboxylesterase 2 (CES2) is one of the most important Phase I drug metabolizing enzymes in the carboxylesterase family. It plays crucial roles in the bioavailability of oral ester prodrugs and the therapeutic effect of some anticancer drugs such as irinotecan (CPT11) and capecitabine. In addition to the well-known roles of CES2 in xenobiotic metabolism, the enzyme also participates in endogenous metabolism and the production of lipids. In this study, we synthesized a series of pyrazolones and assayed their inhibitory effects against CES2 in vitro. Structure-activity relationship analysis of these pyrazolones reveals that the introduction of 4-methylphenyl unit (R1), 4-methylbenzyl (R2) and cyclohexyl (R3) moieties are beneficial for CES2 inhibition. Guided by these SARs results, 1-cyclohexyl-4-(4-methylbenzyl)-3-p-tolyl-1H- pyrazol-5(4H)-one (27) was designed and synthesized. Further investigations demonstrated that the compound 27 exhibited stronger CES2 inhibition activity with a lower IC50 value (0.13 µM). The inhibition kinetic study demonstrated that compound 27 inhibited the hydrolysis of CES2-fluorescein diacetate (FD) through non-competitive inhibition. In addition, the molecular docking showed that the core of pyrazolone, the cyclohexane moiety, 4-methylbenzyl and 4-methylphenyl groups in compound 27 all played important roles with the amino acid residues of CSE2. Also, compound 27 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. In brief, we designed and synthesized a novel pyrazolone compound with a strong inhibitory ability on CES2 and could inhibit the adipogenesis induced by mouse preadipocytes, which can be served as a promising lead compound for the development of more potent pyrazolone-type CES2 inhibitors, and also used as a potential tool for exploring the biological functions of CES2 in human being.

Design, synthesis and bioactivity study on 5-phenylfuran derivatives as potent reversal agents against P-glycoprotein-mediated multidrug resistance in MCF-7/ADR cell.

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a phenomenon in which cells become resistant to structurally and mechanistically unrelated drugs resulting in low intracellular drug concentrations. It is one of the noteworthy problems in malignant tumor clinical therapeutics. So P-gp protein is one of the ideal targets to solve MDR. Based on the lead compound 5m obtained from our previous work, a series of furan derivatives featuring alkyl-substituted phenols and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline were designed and synthesized as reversal agents against P-gp in this paper. Compound 16 containing isopropoxy possessed good potency against P-gp mediated MDR in MCF-7/ADR (IC50 (doxorubicin) = 0.73 µM, RF = 69.6 with 5 µM 16 treated). Western blot results and Rh123 accumulation assays showed that 16 effectively inhibited P-gp efflux function but not its expression. The preliminary structure-activity relationship and docking studies demonstrated that compound 16 would be a potential P-gp inhibitor. Most worthy of mention is that compound 16 has achieved satisfactory results in combination with a variety of anti-tumor drugs, such as doxorubicin, paclitaxel, and vincristine. This study forwards a hopeful P-gp inhibitor for withstanding malignant tumor cell with multidrug resistance setting the basis for further studies.

Design, Synthesis, and Structure-Activity Relationship Study of Pyrazolones as Potent Inhibitors of Pancreatic Lipase.

Pancreatic lipase (PL), a key target for the prevention and treatment of obesity, plays crucial roles in the hydrolysis and absorption of in dietary fat. In this study, a series of pyrazolones was synthesized, and their inhibitory effects against PL were assayed by using 4-methylumbelliferyl oleate (4-MUO) as optical substrate for PL. Comprehensive structure-activity relationship analysis of these pyrazolones led us to design and synthesize a novel compound P32 (5-(naphthalen-2-yl)-2-phenyl-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-pyrazol-3-one) as a potent mixed-competitive inhibitor of PL (IC50 =0.30 µM). In addition, P32 displayed some selectivity over other known serine hydrolases. A molecular docking study for P32 demonstrated that the inhibitory activity of P32 towards PL could be attributed to the π-π interactions of 2-naphthyl unit (R1 ) and hydrophobic interactions of phenyl moiety (R3 ) with the active site of PL. Thus, P32 could serve as promising lead compound for the development of more efficacious and selective pyrazolones-type PL inhibitors for biomedical applications.

Enantioselective [3 + 2] annulation of 4-isothiocyanato pyrazolones and alkynyl ketones under organocatalysis.

An asymmetric [3 + 2] annulation reaction of 4-isothiocyanato pyrazolones with alkynyl ketones in the presence of an organic catalyst derived from a cinchona alkaloid under mild conditions is realized. This protocol provides unprecedented expeditious access to a wide range of optically active spiro[pyrroline-pyrazolones] with various electronic properties in high yields with good to excellent enantioselectivities.

Asymmetric sequential annulation/aldol process of 4-isothiocyanato pyrazolones and allenones: access to novel spiro[pyrrole-pyrazolones] and spiro[thiopyranopyrrole-pyrazolones].

A catalytic asymmetric sequential annulation/aldol reaction of 4-isothiocyanato pyrazolones and allenyl ketones has been developed, which furnished a series of spiro[pyrrole-pyrazolone] heterocycles and structurally novel spiro[thiopyranopyrrole-pyrazolone] derivatives in good yields with high to excellent enantioselectivities. Notably, parallel resolution of racemic spiro[pyrrole-pyrazolones] was achieved by a catalyst-controlled asymmetric intramolecular vinylogous aldol process. Structure diversity of the product was further enhanced by ready transformations.

2-Activated 1,3-enynes in enantioselective synthesis.

The rapid enantioselective synthesis of valuable building blocks and pharmaceutically important compounds from easily accessible precursors is one of the major areas of focus in organic chemistry. In this context, 2-activated 1,3-enyne has emerged as a powerful synthon in recent years for the efficient synthesis of enantioenriched furans, allenes, 4-H-pyrans, and 4-isoxazolines, which are privileged scaffolds in bioactive compounds and natural products. This review will cover the history of the development of 2-activated 1,3-enyne in enantioselective synthesis along with the corresponding mechanisms, which may motivate further development in this area to forge more complex and valuable molecules.

Simultaneous Control of Central and Helical Chiralities: Expedient Helicoselective Synthesis of Dioxa[6]helicenes.

An expedient synthesis of a new family of configurationally stable dioxa[6]helicenes was established using a sequential helicoselective organocatalyzed heteroannulation/eliminative aromatization via enantioenriched fused 2-nitro dihydrofurans featuring both central and helical chiralities. Starting from simple achiral precursors, a broad range of these previously unknown chiral heterocyclic scaffolds were obtained with good efficiency, and their aromatization proceeded with very high enantiopurity retention in most cases.