Discovery of a potent anticancer agent against pancreatic ductal adenocarcinoma targeting FAK with DFG-out state and JAK/Aurora kinases.

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer because of the difficulty in diagnosis and its resistance to chemotherapy. Focal adhesion kinase (FAK) is found overexpressed in PDAC, and targeting FAK has been proved to impede the progress of PDAC. However, most of FAK inhibitors were reported to bind with FAK in a DFG-in conformation, leading to a limited anti-tumor effect in clinical studies.

Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as novel HIV-1 integrase strand transfer inhibitors.

Integrase plays an important role in the life cycle of HIV-1, and integrase strand transfer inhibitors (INSTIs) can effectively impair the viral replication. However, drug resistance mutations have been confirmed to decrease the efficacy of INSTI during the antiviral therapy. Herein, indole-2-carboxylic acid (1) was found to inhibit the strand transfer of integrase, and the indole nucleus of compound 1 was observed to chelate with two Mg ions within the active site of integrase.

Rh(III)-Catalyzed C7-Alkylation of Isatogens with Malonic Acid Diazoesters.

Rh(III)-catalyzed C7-alkylation of isatogens (indolin-3-one -oxides) with malonic acid diazoesters has been developed. This strategy utilizes oxygen anion on the -oxide group of isatogens as a directing group and successfully achieves the synthesis of a series of C7-alkylated isatogens with moderate to good yields (48-86% yields). Moreover, the -oxides of isatogens can not only serve as the simple directing group for C7-H bond cleavage but also be deoxidized for easy removal.

The Discovery of Indole-2-carboxylic Acid Derivatives as Novel HIV-1 Integrase Strand Transfer Inhibitors.

As an important antiviral target, HIV-1 integrase plays a key role in the viral life cycle, and five integrase strand transfer inhibitors (INSTIs) have been approved for the treatment of HIV-1 infections so far. However, similar to other clinically used antiviral drugs, resistance-causing mutations have appeared, which have impaired the efficacy of INSTIs. In the current study, to identify novel integrase inhibitors, a set of molecular docking-based virtual screenings were performed, and indole-2-carboxylic acid was developed as a potent INSTI scaffold.

Facilitated Drug Repurposing with Artemisinin-Derived PROTACs: Unveiling PCLAF as a Therapeutic Target.

Artemisinin, a prominent anti-malaria drug, is being investigated for its potential as a repurposed cancer treatment. However, its effectiveness in tumor cell lines remains limited, and its mechanism of action is unclear. To make more progress, the PROteolysis-TArgeting chimera (PROTAC) technique has been applied to design and synthesize novel artemisinin derivatives in this study.

Synthesis of diarylmethyl thioethers a DABCO-catalyzed 1,6-conjugate addition reaction of -quinone methides with organosulfur reagents.

A rapid and simple method was developed for the synthesis of diarylmethyl thioethers a DABCO-catalyzed 1,6-conjugate addition reaction of -quinone methides (-QMs) with organosulfur reagents. A series of diarylmethyl thioethers were synthesized at 13-85% yields by this method. After that, the antibacterial activities of synthesized diarylmethyl thioethers and their derivatives were evaluated.

Synthesis and antibiofilm evaluation of N-acyl-2-aminopyrimidine derivatives against Acinetobacter baumannii.

The overuse of antibiotics will led to the increase of drug resistance. Especially, the multidrug-resistant A. baumannii became the leading cause of nosocomial infections with high rates of morbimortality.

Synthesis and antibacterial activity studies of indirubin-3'-monoximes.

Multi-drug-resistant microbial pathogens are a serious global health problem. New compounds with antibacterial activity serve as good candidates for developing novel antibacterial drugs which is very urgent and important. In this work, based on the unique scaffold of indirubin, an active ingredient of traditional Chinese medicine formulation Danggui Luhui Wan, we synthesized 29 indirubin-3'-monoximes and preliminarily evaluated their antibacterial activities.

Design, Synthesis, and Biological Evaluation of N14-Amino Acid-Substituted Tetrandrine Derivatives as Potential Antitumor Agents against Human Colorectal Cancer.

As a typical dibenzylisoquinoline alkaloid, tetrandrine (TET) is clinically used for the treatment of silicosis, inflammatory pulmonary, and cardiovascular diseases in China. Recent investigations have demonstrated the outstanding anticancer activity of this structure, but its poor aqueous solubility severely restricts its further development. Herein, a series of its 14--amino acid-substituted derivatives with improved anticancer effects and aqueous solubility were designed and synthesized.

A solid-supported organocatalyst for asymmetric Mannich reaction to construct C2-quaternary indolin-3-ones.

A simple and novel solid-supported organocatalyst from a 2-chlorotrityl chloride resin-immobilized 4-hydroxyproline was developed, and this organocatalyst has been used for the asymmetric Mannich reaction of 2-aryl-3-indol-3-ones and aldehydes/ketones. A series of C2-quaternary indolin-3-ones were prepared in good yields (up to 83%) and with excellent diastereoselectivities (up to 20 : 1) and enantioselectivities (up to 99% ee). In addition, the organocatalyst can be recovered by simple filtration and also be reused for the asymmetric Mannich reaction without significant loss of catalytic efficiency.

Discovery of β-Carboline Derivatives as a Highly Potent Cardioprotectant against Myocardial Ischemia-Reperfusion Injury.

Timely myocardial reperfusion salvages ischemic myocardium from infarction, whereas reperfusion itself induces cardiomyocyte death, which is called myocardial ischemia/reperfusion (MI/R) injury. Herein, β-carboline derivative was designed and synthesized with obvious myocardial protective activity for the first time. Pretreatment of effectively protected the cardiomyocyte H9c2 cells from HO-induced lactate dehydrogenase leakage and restored the endogenous antioxidants, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px).

Design, synthesis, and biological evaluation of 2,4-diamino pyrimidine derivatives as potent FAK inhibitors with anti-cancer and anti-angiogenesis activities.

A series of 2,4-diamino pyrimidine (DAPY) derivatives were designed, synthesized, and evaluated as inhibitors of focal adhesion kinase (FAK) with antitumor and anti-angiogenesis activities. Most compounds effectively suppressed the enzymatic activities of FAK, and the ICs of 11b and 12f were 2.75 and 1.

Enantioselective amination of 4-alkylisoquinoline-1,3(2,4)-dione derivatives.

A mild and efficient enantioselective amination of 4-alkylisoquinoline-1,3(2,4)-dione derivatives was established, which is compatible with a broad range of substrates and delivers the final products in excellent yields (up to 99%) and ee values (up to 99%) with low catalyst loading (down to 1 mol%). The synthetic potential of this methodology was also demonstrated in the gram scale level.

Discovery of tetrandrine derivatives as tumor migration, invasion and angiogenesis inhibitors.

Metastatic progression of cancer is a complex and clinically daunting process, with migration, invasion and angiogenesis being the key features. Tetrandrine (TET) is a typical dibenzylisoquinoline alkaloid with promising anti-tumor activity. In our previous work, a number of TET derivatives were designed and synthesized with obvious anti-proliferation activities against cancer cells, however, the anti-metastatic effects of these compounds were not evaluated.

Design, synthesis, and biological evaluation of 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)sulfonyl)benzamide derivatives as potent HIV-1 Vif inhibitors.

Viral infectivity factor (Vif) is one of the accessory protein of human immunodeficiency virus type I (HIV-1) that inhibits host defense factor, APOBEC3G (A3G), mediated viral cDNA hypermutations. Previous work developed a novel Vif inhibitor 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide (1) with strong antiviral activity. Through optimizations on the two side branches, a series of compound 1 derivatives (2-18) were designed, synthesized and tested in vitro for their antiviral activities.

Organocatalytic Asymmetric α-Sulfenylation of 2-Substituted Indolin-3-ones: A Strategy for the Synthesis of Chiral 2,2-Disubstituted Indole-3-ones with S- and N-Containing Heteroquaternary Carbon Stereocenter.

An organocatalytic asymmetric α-sulfenylation of 2-substituted indolin-3-ones with N-(alkylthio or arylthio)succinimides has been developed for the first time using Cinchona-derived squaramide as the catalyst. Various chiral 2,2-disubstituted indole-3-ones with S- and N-containing heteroquaternary carbon stereocenters were obtained with up to 98% yield and 99% ee.

Catalyst-free Cleavage of Amide and C-O Double Bond for the Diastereoselective Synthesis of Trifluoromethyl-Containing Dihydrooxazole Derivatives.

A novel and efficient cascade method has been developed for the diastereoselective preparation of trifluoromethyl-containing dihydrooxazoles in high yields. The reaction was applicable to electron-deficient, electron-rich arenes, heteroarenes, and alkyl groups. Control experiments were conducted to explore the reaction mechanism and reveal that the byproduct formed in situ is the catalyst for this reaction and a tether derived from trifluoropyruvate is a key intermediate for this reaction.

Palladium-catalyzed direct C(sp)-H arylation of indole-3-ones with aryl halides: a novel and efficient method for the synthesis of nucleophilic 2-monoarylated indole-3-ones.

A novel and efficient method for the synthesis of nucleophilic 2-monoarylated indole-3-ones palladium-catalyzed direct C(sp)-H arylation of indole-3-ones with aryl halides has been developed. Various 2-monoarylated indole-3-ones were readily obtained with yields up to 95%. As a class of important nucleophilic intermediates, 2-monoarylated indole-3-ones can be used for the construction of C2-quaternary indolin-3-one skeletons.

Design, synthesis, and cytotoxic activity of novel 7-substituted camptothecin derivatives incorporating piperazinyl-sulfonylamidine moieties.

In our continuing search for camptothecin (CPT)-derived antitumor drugs, novel 7-substituted CPT derivatives incorporating piperazinyl-sulfonylamidine moieties were designed, synthesized and evaluated for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB, and KB-VIN). All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, and were more potent than irinotecan. Remarkably, most of the compounds exhibited comparable cytotoxicity against the multidrug-resistant (MDR) KB-VIN and parental KB tumor cell lines, while irinotecan lost activity completely against KB-VIN.

Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives.

In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3).

Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents.

Twelve novel 20-sulfonylamidine derivatives (9a-9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3.

Organocatalytic asymmetric Michael-Michael cascade for the construction of highly functionalized N-fused piperidinoindoline derivatives.

Application of indolin-3-one derivatives in a cascade reaction for efficient assembly of complex molecules is a much less explored research area. It is demonstrated that structurally interesting polysubstituted piperidino[1,2-a]indoline compounds containing four contiguous stereocenters including one tetrasubstituted carbon center can be readily obtained with good yields (up to 94% yield) and excellent enantioselectivities (up to >99% ee) by employing indolin-3-one derivatives as substrates via bifunctional catalysis.

Merging organocatalysis with transition metal catalysis and using O2 as the oxidant for enantioselective C-H functionalization of aldehydes.

A new catalytic Saegusa oxidation-Michael addition cascade reaction has been developed for the enantioselective β-functionalization of aldehydes. The feature of this research is the combination of organocatalysis and transition-metal catalysis for the asymmetric C-H functionalization which remains an underdeveloped research topic.