Substrate-Controlled Divergent Synthesis of Benzimidazole-Fused Quinolines and Spirocyclic Benzimidazole-Fused Isoindoles.

A Rh(III)-catalyzed annulation of 2-arylbenzimidazoles with α-diazo carbonyl compounds via C-H activation/carbene insertion/intramolecular cyclization is explored. The switchable product selectivity is achieved by the use of distinct α-diazo carbonyl compounds. Benzimidazole-fused quinolines are obtained through [4 + 2] annulation exclusively when 2-diazocyclohexane-1,3-diones are used, where they act as a C2 synthon. Alternatively, diazonaphthalen-1(2H)-ones merely function as a one-carbon unit synthon to generate a quaternary center through [4 + 1] cyclization to afford spirocyclic benzimidazole-fused isoindole naphthalen-2-ones. A thorough mechanistic study reveals the course of the reaction.

Parallel Synthesis of Pyrazolone-Fused Cinnolines by the Palladium-Catalyzed [4 + 2] Annulation of Pyrazol-3-ones with Substituted Allenoates.

The synthesis of pyrazolone-fused cinnolines from pyrazol-3-ones and α,γ-substituted allenoates via a palladium-catalyzed C-H activation/annulation cascade was developed. Mechanistic studies revealed the course of the reaction. Initially, N-acyl-valine ligand-assisted ortho-C-H activation gives ortho-alkenylated intermediate. Subsequent cyclopalladation and migratory insertion of allenoate give a seven-membered palladacycle. Reductive elimination finally furnishes pyrazolone-fused cinnolines.

Pd(II)-Catalyzed [5 + 2] Cyclization of N-Triflyl Aryl Indoles and α,γ-Substituted Allenoates: A Route to Indole-Fused Benzodiazepines.

A Pd(II)-catalyzed [5 + 2] annulation between N-triflyl aryl indoles and α,γ-substituted allenoates for the synthesis of indole-fused benzodiazepines is reported. This protocol is highly efficient when N-acetylated valine amino acid and DMSO have been used as ligand and cosolvent, respectively. The substrate scope can be further extended to disubstituted allenoates. A reaction mechanism has been proposed based on the mechanistic studies. Mechanistically, the N-acetylated valine amino acid ligand accelerates C-H activation of the C(sp2)-H bond. Consequent cyclopalladation leads to the formation of a six-membered palladacycle. Subsequent coordination and migratory insertion of an allenoate forms the possible eight-membered intermediate. Reductive elimination followed by a [1,3]-H shift results in the indole-fused benzodiazepines.

Rapid Synthesis of Benzimidazole-Fused Isoindoles by Rh(III)/Ru(II)-Catalyzed [4 + 1] Cascade C-H/N-H Annulation of 2-Arylbenzimidazoles with Alkynoates and Alkynamide.

A Rh(III)-catalyzed [4 + 1] cyclization of 2-arylbenzimidazoles with alkynoates through C-H activation/ortho-alkenylation/intramolecular annulation cascade to obtain benzimidazole-fused isoindoles is reported. The reaction of the Rh catalyst and internal alkyne ester provides benzo[4,5]imidazo[2,1-a]isoindole acetate exclusively. Conversely, internal alkyne amide participates in the annulation process in the presence of a Ru catalyst to provide benzo[4,5]imidazo[2,1-a]isoindole acetamide. The alkyne acts as a C1 synthon and undergoes [4 + 1] cyclization rather than traditional [4 + 2] annulation.

Rh(III)-Catalyzed Switchable [4 + 1] and [4 + 2] Annulation of N-Aryl Pyrazolones with Maleimides: An Access to Spiro Pyrazolo[1,2-a]indazole-pyrrolidine and Fused Pyrazolopyrrolo Cinnolines.

A rhodium(III)-catalyzed controllable [4 + 1] and [4 + 2] annulation of N-aryl pyrazolones with maleimides as C1 and C2 synthon has been explored for the synthesis of spiro[pyrazolo[1,2-a]indazole-pyrrolidines] and fused pyrazolopyrrolo cinnolines. The product selectivity was achieved through time-dependent annulation. The [4 + 1] annulation reaction involves sequential Rh(III)-catalyzed C-H alkenylation of N-aryl pyrazolone, followed by an intramolecular spirocyclization via aza-Michael-type addition to afford spiro[pyrazolo[1,2-a]indazole-pyrrolidine]. However, prolonged reaction time converts in situ formed spiro[pyrazolo[1,2-a]indazole-pyrrolidine] into fused pyrazolopyrrolocinnoline. This unique product formation switch proceeds via strain-driven ring expansion through a 1,2-shift of the C-C bond.

Rh(III)-Catalyzed (4 + 1) Annulation of Pyrazol-3-ones with Alkynoates via Ortho-Alkenylation/Cyclization Cascade: Synthesis of Indazole-Fused Pyrazoles.

A facile synthesis of novel indazole-fused pyrazoles from pyrazol-3-ones and alkynoate esters/amides via Rh(III)-catalyzed sequential C-H activation/ortho-alkenylation/intramolecular cyclization cascade is reported. The important characteristic of this method is that the resulting scaffold bearing quaternary carbon has been obtained through unusual [4 + 1] rather than expected [4 + 2] addition where alkynoate acts as a one-carbon unit.

Substrate-controlled Rh(III)-catalyzed regiodivergent annulation towards fused and spiro benzimidazoles.

A Rh(III)-catalyzed cascade C-H activation and cyclization of 2-aryl benzimidazoles with maleimides for the synthesis of benzimidazole-fused isoquinolines and benzimidazole-spiro isoindoles is reported. Switchable selectivity towards the formation of these two distinct products can be achieved using unsubstituted and substituted benzimidazoles at the ortho-position of the phenyl ring. Mechanistically, C-H activation followed by migratory insertion of maleimide forms a Heck-type intermediate. Unsubstituted benzimidazole undergoes aza-Michael addition to form a (4 + 2) fused product, whereas ortho-substituted phenyl benzimidazole causes steric clash to deliver a (4 + 1) spiro-adduct favorably via acid-catalyzed intramolecular annulation.

The Anti-Cancer Activity of Pentamidine and Its Derivatives (WLC-4059) Is through Blocking the Interaction between S100A1 and RAGE V Domain.

The S100A1 protein in humans is a calcium-binding protein. Upon Ca2+ binding to S100A1 EF-hand motifs, the conformation of S100A1 changes and promotes interactions with target proteins. RAGE consists of three domains: the cytoplasmic, transmembrane, and extracellular domains. The extracellular domain consists of C1, C2, and V domains. V domains are the primary receptors for the S100 protein. It was reported several years ago that S100A1 and RAGE V domains interact in a pathway involving S100A1-RAGE signaling, whereby S100A1 binds to the V domain, resulting in RAGE dimerization. The autophosphorylation of the cytoplasmic domain initiates a signaling cascade that regulates cell proliferation, cell growth, and tumor formation. In this study, we used pentamidine and a newly synthesized pentamidine analog (WLC-4059) to inhibit the S100A1-RAGE V interaction. 1H-15N HSQC NMR titration was carried out to characterize the interaction between mS100A1 (mutant S100A1, C86S) and pentamidine analogs. We found that pentamidine analogs interact with S100A1 via 1H-15N HSQC NMR spectroscopy. Based on the results, we utilized the HADDOCK program to generate structures of the mS100A1-WLC-4059 binary complex. Interestingly, the binary complex overlapped with the complex crystal structure of the mS100A1-RAGE-V domain, proving that WLC-4059 blocks interaction sites between S100A1 and RAGE-V. A WST-1 cell proliferation assay also supported these results. We conclude that pentamidine analogs could potentially enhance therapeutic approaches against cancers.

Synthesis of Novel Suramin Analogs With Anti-Proliferative Activity via FGF1 and FGFRD2 Blockade.

A promising approach in cancer therapy is the inhibition of cell proliferation using small molecules. In this study, we report the synthesis of suramin derivatives and their applications. We used NMR spectroscopy and docking simulations to confirm binding sites and three-dimensional models of the ligand-protein complex. The WST-1 assay was used to assess cell viability and cell proliferation in vitro to evaluate the inhibition of protein-protein interactions and to investigate the anti-proliferative activities in a breast cancer cell line. All the suramin derivatives showed anti-proliferative activity by blocking FGF1 binding to its receptor FGFRD2. The dissociation constant was measured by fluorescence spectroscopy. The suramin compound derivatives synthesized herein show potential as novel therapeutic agents for their anti-proliferative activity via the inhibition of protein-protein interactions. The cytotoxicity of these suramin derivatives was lower than that of the parent suramin compound, which may be considered a significant advancement in this field. Thus, these novel suramin derivatives may be considered superior anti-metastasis molecules than those of suramin.

Suramin derivatives play an important role in blocking the interaction between FGF1 and FGFRD2 to inhibit cell proliferation.

The inhibition of protein function by small compounds plays a critical role in controlling cell proliferation. We report on a new class of small molecule (NCTU-Alan-2026) inhibitors for cell proliferation. NCTU-Alan-2026 blocks the interaction between FGF1 and its receptor FGF1R2D2. Extensive NMR studies combined with fluorescence experiments provided the specific mechanism of how NCTU-Alan-2026 could inhibit cell proliferation. We describe an innovative therapeutic approach for anti-proliferation and demonstrate an example of inhibition of small molecules by blocking the protein-protein interaction. We found that the compound NCTU-Alan-2026 blocked the interaction between the two proteins FGF1 and FGF1R2D2 and inhibited cell proliferation. The toxicity of NCTU-Alan-2026 is lower than that of suramin. Thus, NCTU-Alan-2026 could be a better drug than suramin in the treatment of cancer.

A site-moiety map and virtual screening approach for discovery of novel 5-LOX inhibitors.

The immune system works in conjunction with inflammation. Excessive inflammation underlies various human diseases, such as asthma, diabetes and heart disease. Previous studies found that 5-lipoxygenase (5-LOX) plays a crucial role in metabolizing arachidonic acid into inflammatory mediators and is a potential therapeutic target. In this study, we performed an in silico approach to establish a site-moiety map (SiMMap) to screen for new 5-LOX inhibitors. The map is composed of several anchors that contain key residues, moiety preferences, and their interaction types (i.e., electrostatic (E), hydrogen-bonding (H), and van der Waals (V) interactions) within the catalytic site. In total, we identified one EH, one H, and five V anchors, within the 5-LOX catalytic site. Based on the SiMMap, three 5-LOX inhibitors (YS1, YS2, and YS3) were identified. An enzyme-based assay validated inhibitory activity of YS1, YS2, and YS3 against 5-LOX with an IC50 value of 2.7, 4.2, and 5.3 µM, respectively. All three inhibitors significantly decrease LPS-induced TNF-α and IL-6 production, which suggests its potential use an anti-inflammatory agent. In addition, the identified 5-LOX inhibitors contain a novel scaffold. The discovery of these inhibitors presents an opportunity for designing specific anti-inflammatory drugs.

Molecular Iodine-Promoted [3 + 2] Oxidative Cyclization for the Synthesis of Heteroarene-Fused [1,2,4] Thiadiazoles/Selenadiazoles.

Two new classes of heteroarene-fused [1,2,4]thiadiazole and [1,2,4]selenadiazole are synthesized through the iodine-mediated [3 + 2] oxidative cyclization of 2-aminoheteroarenes and isothiocyanates/isoselenocyanates. This oxidative [3 + 2] annulation strategy is highly regiospecific to proceed a selective C-N bond formation at the endo-nitrogen of 2-aminoheteroarenes followed by an intramolecular oxidative N-S/N-Se bond formation. It is the first example of an I2-mediated oxidative nitrogen-selenium (N-Se) bond formation.

Catalyst-Controlled Regioselective Synthesis of Benzotriazlolodiazepin-7-ones and Benzotriazolodiazocin-8-ones.

A catalyst-controlled highly chemoselective and regioselective intramolecular cycloamidation of triazol-1-ylbenzamides toward the synthesis of scarcely known heterocycles is reported. In the presence of a palladium catalyst, this cycloisomerization reaction afforded substituted benzotriazlolodiazepin-7-ones via intramolecular insertion of a palladium into C-C triple bond in a 7-exo-dig way. Alternatively, the use of a silver catalyst in the reaction produced substituted benzotriazolodiazocin-8-ones in a highly regioselective manner through 8-endo-dig intramolecular ring closure.

One-Pot Synthesis of Unsymmetrical Bis-Heterocycles: Benzimidazole-, Benzoxazole-, and Benzothiazole-Linked Thiazolidines.

A one-pot, three-component synthesis of benzimidazole-linked thiazolidines from 2-cyanomethyl benzimidazole, iso-, isothio-, or isoselenocyanates and 1,2-dichloroethane is reported. Isolation of the key intermediate formed during the course of the reaction validates its mechanistic pathway. Under the same reaction conditions, benzimidazole-linked/fused thiazinanes were obtained when 1,3-dichloropropane or diiodomethane was used.

Enantioselective Synthesis of Hydantoin and Diketopiperazine-Fused Tetrahydroisoquinolines via Pictet-Spengler Reaction.

An enantioselective synthesis of iso-, isothio-, and isoselenohydantoin and diketopiperazine-fused tetrahydroisoquinolines from l-Dopa was reported. The route consists of an Pictet-Spengler reaction of ( S)-2-amino-3-(3,4-dimethoxyphenyl)propanoates with various aldehydes to afford diastereomeric tetrahydroisoquinolines. Next step, the tetrahydroisoquinolines were further reacted with iso-, isothio-, or isoselenocyanates to construct hydantoin. Similarly, the diketopiperazine moiety was constructed by subjecting tetrahydroisoquinolines to a condensation reaction with chloroacetyl chloride followed by nucleophilic addition with various primary amines.

Andrographolide and its potent derivative exhibit anticancer effects against imatinib-resistant chronic myeloid leukemia cells by downregulating the Bcr-Abl oncoprotein.

Chronic myelogenous leukemia (CML) is clinically treated with imatinib, which inhibits the kinase activity of the Bcr-Abl oncoprotein. However, imatinib resistance remains a common clinical issue. Andrographolide, the major compound of the medicinal plant Andrographis paniculata, was reported to exhibit anticancer activity. In this study, we explored the therapeutic potential of andrographolide and its derivative, NCTU-322, against both imatinib-sensitive and imatinib-resistant human CML cell lines. Both andrographolide and NCTU-322 downregulated the Bcr-Abl oncoprotein in imatinib-resistant CML cells through an Hsp90-dependent mechanism similar to that observed in imatinib-sensitive CML cells. In addition, NCTU-322 had stronger effects than andrographolide on downregulation of Bcr-Abl oncoprotein, induction of Hsp90 cleavage and cytotoxicity of CML cells. Notably, andrographolide and NCTU-322 could induce differentiation, mitotic arrest and apoptosis of both imatinib-sensitive and imatinib-resistant CML cells. Finally, the anticancer activity of NCTU-322 against imatinib-resistant CML cells was demonstrated in vivo. In summary, our data demonstrated that andrographolide and NCTU-322 inhibit Bcr-abl function via a mechanism different from that of imatinib, and they induced multiple anticancer effects in both imatinib-sensitive and resistant CML cells. Our findings demonstrate that andrographolide and NCTU-322 are potential therapeutic agents again CML.

One-pot synthesis of 4-arylidene imidazolin-5-ones by reaction of amino acid esters with isocyanates and α-bromoketones.

A simple and new multicomponent reaction for the one-pot synthesis of substituted 4-arylidene imidazolin-5-ones from l-amino acid methyl esters, iso-, isothio- or isoselenocyanates, and α-bromoketones is demonstrated. Isolation of thiohydantoin and 5-benzylidene 2-thioxoimidazolidin-4-one intermediates revealed a possible reaction mechanism. The strategy was further extended to the synthesis of 2-iminothiazolines and 2-thioxoimidazolin-4-ones.

Base Controlled Three-Component Regioselective Synthesis of 2-Imino Thiazolines and 2-Thioxoimidazolin-4-ones.

Base-controlled regioselective synthesis of 2-imino thiazolines and 2-thioxoimidazolin-4-ones was achieved to use a one-pot reaction between chiral amino esters, isothiocyanates, and α-bromoketones/alkyl halides. This three-component coupling reaction in acetonitrile provides 2-imino thiazolines, whereas the formation of 2-thioxoimidazolin-4-ones was observed under basic conditions at ambient temperature. The corresponding products were obtained in good to excellent yield with broad substrate scope. Isolation of thiourea and thiohydantoin intermediates disclosed the course of the reaction mechanism.

Regioselective Synthesis of Pyranone-Fused Indazoles via Reductive Cyclization and Alkyne Insertion.

A novel and efficient method for the one-pot synthesis of 2 H-indazole from readily available building blocks is reported. The reaction of 2-nitrobenzylamines with zinc and ammonium formate underwent partial reduction to nitroso-benzylamine followed by an intramolecular cyclization to afford 2 H-indazole via N-N bond formation. The carboxylic acid moiety of indazole was proceeded to regioselective alkyne insertion under ruthenium catalysis to form pyranone-fused indazoles. The regioselectivity is influenced by the weak coordination of indazole ring nitrogen to the metal center.

Cascade Synthesis of Benzimidazole-Linked Pyrroles via Copper Catalyzed Oxidative Cyclization and Ketonization.

A three-component cascade reaction of 2-aminobenzimidazole, aldehyde, and terminal alkyne has been explored for an efficient synthesis of benzimidazole-linked tetrasubstituted pyrroles. The reaction sequence involves the formation of propargylamine, insertion of a terminal alkyne, and a ring opening reaction followed by an intramolecular carbonylative cyclization under aerobic conditions. It represents a novel strategy to the construction of C═N, C═C, C═O bonds and a new five-membered 2-ketopyrrole ring. In this process, the reaction conditions are crucial and an attempt to elucidate the novel reaction pathway is well supported by X-ray crystallography.