A Regioselective [3 + 2] Cycloaddition of Alkynols and Ketones To Access Diverse 1,3-Dioxolane Scaffolds.

This study presents a stepwise exoselective [3 + 2] cycloaddition reaction of alkynols with ketones, leading to the synthesis of 4-methylene-1,3-dioxolane derivatives. Remarkably, without any Thorpe-Ingold induced effect, the cyclization reaction was demonstrated with complete regio- and chemoselectivity, which was solely promoted by cesium carbonate. A wide range of unactivated ketones are viable under these mild reaction conditions, and both primary and tertiary alkynols are compatible with these cyclization reactions. We have prepared a diverse array of highly dense exomethylene 1,3-dioxolane rings demonstrating a remarkable tolerance for various functional groups.

Time and Atom Economical Regio- and Chemoselective Radical Cyclization of Unactivated 1,6-Enynes Under Metal- and Oxidant-Free Conditions.

We developed time-atom economic regio- and chemoselective sulfonyl radical triggered 5-exo-dig cyclization of unactivated 1,6-enynes with sulfonyl halides under metal, additive-free reaction conditions to achieve highly substituted five-membered heterocyclic compounds. This transformation creates three new bonds, such as C-SO2 , C-C, and active C-I/Br bonds. Importantly, one-pot protocols produce desired products directly from sodium sulfinates and have an additional advantage such as minimising chemical waste, saving time, and simplifying practical aspects compared to existing protocols.

A metal-free strategy for the cross-dehydrogenative coupling of 1,3-dicarbonyl compounds with 2-methoxyethanol.

Here, we report a metal-free approach for the construction of methylene-bridged bis-1,3-dicarbonyl compounds via cross-dehydrogenative coupling of 1,3-dicarbonyl compounds with 2-methoxyethanol. In addition, we have extended this methodology to synthesize tetra-substituted pyridine derivatives using 1,3-dicarbonyl, 2-methoxyethanol and NH4OAc in one step. The key advantages include accepting a wide range of substrates, utilizing O2 as the sole oxidant, and synthesizing biologically active compounds such as 1,4-dihydropyridine and pyrazole.

Sensitive Assay for the Lactonase Activity of Serum Paraoxonase 1 (PON1) by Harnessing the Fluorescence Turn-On Characteristics of Bioorthogonally Synthesized and Geometrically Controlled Chemical Probes.

The lactonase activity of paraoxonase 1 (PON1) has a crucial antiatherogenic function, and also serves as an important biochemical marker in human blood because the aberrant lactonase activity of PON1 is a key indicator for a number of diverse human diseases. However, no sensitive fluorescence assays that detect PON1 lactonase activity are available. We report the synthesis of two fluorescence turn-on chemical probes 16a and 16b (16) able to quantify PON1 lactonase activity. The chemical probes were constructed utilizing a disulfide-containing bicyclononyne, derivatives of rhodamine B and carboxyfluorescein, and reactions including copper-free azide-alkyne cycloaddition. Fluorescence quenching in 16 was characterized by spectroscopic studies and was mainly attributed to the effect of contact quenching. Kinetic analysis of 16b confirmed the outstanding reactivity and specificity of 16b with thiols in the presence of general base catalysts. The 16b-based assay was employed to determine PON1 lactonase activity, with a linear range of 10.8-232.1 U L-1 and detection limit (LOD) of 10.8 U L-1, to quantify serum PON1 activity in human sera, and to determine the Ki of 20.9 µM for the 2-hydroxyquinoline inhibition of PON1 lactonase. We are employing 16b to develop high-throughput assays for PON1 lactonase activity.

Unusual C3-acetylation of quinoxalin-2(1H)-one via oxidative C-C and C-O bond cleavages of PEG-400.

Aerobic oxidative tandem conversion of PEG-400 to acetyl radical via C-C and C-O bond cleavages followed by silver-catalyzed menisci-type addition to the C3 position of quinoxalin-2(1H)-one is described. This reaction involves the in situ formation of the acetyl radical from PEG-400 via a sequence of acetaldehyde, 2-oxopropanal and, 2-oxopropanoic acid formation and successive oxidative cleavage to form the acetyl radical. This protocol uses cheap, readily available and environmentally-friendly PEG-400 as the acetyl source and solvent. The in situ generated acetyl radicals from PEG-400 have been coupled to a broad range of electron-deficient quinoxalin-2(1H)-one compounds in a menisci-type reaction.

A simple and efficient method for constructing azepino[4,5-b]indole derivatives via acid catalysis.

A new synthetic methodology has been developed to prepare the biologically important azepino[4,5-b]indole derivatives under Brønsted acid catalysis. The notable features of this protocol include its operational simplicity, high reaction yields and environmentally benign and mild reaction conditions.

A Palladium- and Copper-Catalyzed Synthesis of Dihydro[1,2-b]indenoindole-9-ol and Benzofuro[3,2-b]indolines: Metal-Controlled Intramolecular C-C and C-O Bond-Forming Reactions.

A palladium- and copper-catalyzed synthesis of dihydro[1,2-b]indenoindole-9-ol and benzofuro[3,2-b]indolines has been developed, whereby the same starting material is employed for the synthesis of both heterocyclic scaffolds and the selectivity of the product is controlled by switching the choice of metal. Salient features of these cascade reactions include wide-ranging functional group tolerance, simple reaction conditions, and moderate to high yields.

Palladium(0)-catalyzed single and double isonitrile insertion: a facile synthesis of benzofurans, indoles, and isatins.

A palladium(0)-catalyzed cascade process consisting of isonitrile insertion and α-Csp(3)-H cross-coupling can be achieved for the synthesis of benzofurans and indoles. The construction of isatins by a Pd-catalyzed cascade reaction incorporating double isonitrile insertion, amination, and hydrolysis has also been achieved. The key features of this work include diverse heterocycle synthesis, phosphine-ligand-free reaction conditions, a one-pot procedure, simple and commercially available starting materials, broad functional-group compatibility, and moderate to good reaction yields.

An iron-catalyzed cascade approach to benzo[b]carbazole synthesis followed by 1,4-sulfonyl migration.

A simple and straightforward approach was developed to construct 5H-benzo[b]carbazole derivatives by iron catalysis in a cascade sequence. The notable features of this work include an atom-economical cascade sequence, unprecedented 1,4-sulfonyl migration, tolerance of a variety of functional groups, good yields, and an economical catalytic system.

Metal-free cycloaddition to synthesize naphtho[2,3-d][1,2,3]triazole-4,9-diones.

A metal-free domino [3 + 2] cycloaddition is reported to construct naphtho[2,3-d][1,2,3]triazole-4,9-dione derivatives and provide an alternative approach to the azide-alkyne cycloadditions. The key features are easily available starting materials, mild reaction conditions, a good atom economy, eco-friendly characteristics and a broad substrate scope with high yields.

Apoptosis induced by 2-aryl benzothiazoles-mediated photodynamic therapy in melanomas via mitochondrial dysfunction.

A mild and efficient synthetic development of 2-arylbenzothiazoles 5 mediated by ceric ammonium nitrate (CAN) via intramolecular cyclization of N-phenyl-thiobenzamides 4 was achieved. Further compounds 5 were reduced to corresponding amines 6, and their photodynamic therapy (PDT) effect was evaluated on malignant human melanoma A375 cells. Amine 6l plus ultraviolet A (UVA) induced caspase-3 activity, poly(ADP-ribose)polymerase cleavage, M30 positive CytoDeath staining, and subsequent apoptotic cell death. Our data disclosed that treatment of A375 cells with 6l plus UVA resulted in a decrease in mitochondrial membrane potential (ΔΨmt), oxidative phosphorylation system (OXPHOS) subunits, and adenosine triphosphate (ATP) but an increase in mitochondrial DNA 4977-bp deletion via reactive oxygen species (ROS) generation. Transmission electron microscopy (TEM) observations also showed major ultrastructural alterations of mitochondria. Additionally, 6l plus UVA was also shown to reduce murine melanoma size in a mouse model. The present study supports the hypothesis that 6l-PDT may serve as a potential ancillary modality for the treatment of melanoma.

Copper-catalyzed oxidative coupling of formamides with salicylaldehydes: synthesis of carbamates in the presence of a sensitive aldehyde group.

A diverse library of novel carbamates was synthesized utilizing copper-catalyzed oxidative C-O coupling of formamides and salicylaldehydes. Sensitive aldehyde groups remained intact in the presence of an oxidant and a transition-metal salt. Salicylaldehydes bearing electron-donating, electron-withdrawing, and halogen groups as well as 1-hydroxy-2-naphthaldehydes provided the desired carbamates in good to excellent yields.

Photochemical Radical Bicyclization of 1,5-Enynes: Divergent Synthesis of Fluorenes and Azepinones.

A dual nickel- and iridium-photocatalyzed radical cascade bicyclization reaction for the synthesis of highly complex molecular structures in an atom- and step-economic manner has been described. A series of radical precursors are utilized for the divergent synthesis of diversely substituted fluorenes and indenoazepinones bearing quaternary carbons by using cascade cyclization reactions of 1,5-enynes. This reaction is characterized by its mild conditions, broad substrate scope, excellent selectivity, and satisfactory yield including facile scale-up synthesis.

Synthesis, DNA-binding abilities and anticancer activities of triazole-pyrrolo[2,1-c][1,4]benzodiazepines hybrid scaffolds.

We synthesized a new series of PBD-hybrid derivatives having tethered triazoles and investigated for their cytotoxicity. The studies indicated that cis-olefin compounds induce higher cytotoxicity with increase in the G1 cell cycle phase compared with the trans-compounds. Quantitative RT-PCR assay indicated that compounds (16a-d) induced G1 phase arrest through down-regulation of cyclin D1 and up-regulation of p21, p27, and p53 mRNA expressions. Compounds 16a-d induced A375 early apoptosis as detected by flow cytometry after double-staining with annexin V and propidium iodide. Moreover, the Western blot analysis showed that A375 treated by compounds (16a-d) resulted in decreased levels of Bcl-2 and Bcl-xL, increased levels of Bax and Bad, and caspase/PARP degradation to identify apoptotic cells.

A convenient method to construct (Z)-oxazines via 6-exo-dig iodocyclization and synthesis of indolin-3-one.

An efficient regio-, stereo- and chemo-specific synthesis of 1,3-benzoxazines via 6-exo-dig cyclization to afford the Z-isomer is reported. The structure and connectivity were confirmed unambiguously on the basis of (1)H NMR, NOESY, and ORTEP. Furthermore, DFT studies revealed that the Z-isomer was more stable than the E-isomer. Iodine substituted 1,3-benzoxazines were very useful precursors for cross coupling reactions. Suzuki reaction was carried out successfully and the resulting product was transformed to 1-(4-nitrobenzoyl)-2,2-diphenylindolin-3-one in the presence of a Lewis acid.

DC-81-enediyne induces apoptosis of human melanoma A375 cells: involvement of the ROS, p38 MAPK, and AP-1 signaling pathways.

Melanoma is one of the most chemoresistant cancers in patient care. The remission rate of current therapy remains low. DC-81, an antitumor antibiotic produced by Streptomyces species, belongs to pyrrolo[2,1-c][1,4]benzodiazepine (PBD), which is a potent inhibitor of nucleic acid synthesis. An enediyne contains either DNA intercalating groups or DNA minor groove binding functions and these are potent DNA-damaging agents due to their ability to generate benzenoid diradicals. We have previously reported an efficient synthesis and antitumor activity of a series of novel PBD hybrids linked with enediyne. The purpose of this study was to examine the mechanism of the antiproliferative effect of DC-81-enediyne agent on human melanoma A375 cells. DC-81-enediyne induced an increase in Ca(2+) level and reactive oxygen species (ROS) generation as detected by flow cytometric assay. Western blot analysis showed that DC-81-enediyne induced the phosphorylation of p38 and activating transcription factor 2 (ATF-2). By using the luciferase reporter assay, activating protein-1 (AP-1) activity was further enhanced after A375 cells were treated with graded concentrations of DC-81-enediyne. DC-81-enediyne treatment-induced A375 cell apoptosis was significantly abrogated by the addition of Ca(2+), ROS, and p38 inhibitors. Collectively, our studies indicate that DC-81-enediyne induces A375 cell apoptosis through an increased Ca(2+) and ROS generation, which involves p38 phosphorylation and enhanced ATF-2/AP-1 expressions, leading to caspase-3 activity, poly(ADP-ribose)polymerase cleavage, M30 CytoDeath staining, and subsequent apoptotic cell death.

Visible-light-induced oxidant/additive-free atom-economic synthesis of multifunctionalized cyclopropanes via energy transfer.

Herein we describe intramolecular cascade reactions enabling the synthesis of bridged cyclopropanes, via the photoinduced energy-transfer catalysis of tethered conjugated dienes. Photocatalysis affords the efficient synthesis of complex tricyclic compounds that exhibit multiple stereocenters from readily accessible starting materials that would otherwise be difficult to obtain. This single-step reaction is characterized by its broad substrate scope, atom-economy, excellent selectivity, and satisfactory yield, which includes a facile scale-up synthesis and synthetic transformation. An in-depth mechanistic study reveals that the reaction proceeds via an energy-transfer pathway.

Light-mediated sulfonyl-iodination of ynamides and internal alkynes.

We synthesized tetrasubstituted olefins regioselectively and stereoselectively from ynamides and internal alkynes with sulfonyl iodides under blue LEDs in few minutes. The key features are being metal-free, easy to handle, simple, broad in scope, and environmentally friendly. Furthermore, a gram-scale experiment was conducted, and the synthesized corresponding sulfonyl-iodinated products were smoothly altered into various other products.

Manipulating Diastereomeric Bicyclononynes to Sensitively Determine Enzyme Activity and Facilitate Macromolecule Conjugations.

Bicyclo[6.1.0]nonyne (BCN) is one of the most commonly used cycloalkynes in strain-promoted azide-alkyne cycloaddition (SPAAC). The synthesis of BCN produces two diastereomers, exo-BCN and endo-BCN. The potential significance of the different steric structures of the tricyclic fused rings in SPAAC products synthesized from the BCN diastereomers has not been previously studied. We first demonstrated that only endo-BCN could reduce the level of fluorescence quenching in SPAAC reaction products. The reduction was likely due to the presence of extended tricyclic fused ring systems. This hypothesis was supported by the synthesis of a fluorescence always-on construct by substituting endo-BCN for exo-BCN in a previously reported chemical probe that was characterized with good contact fluorescence quenching. We also synthesized bis-BCN derivatives to enhance the steric structural differences in the corresponding SPAAC products. A constitutional isomer of the azido-derivatized 5(6)-carboxyfluorescein [5(6)-FAM] was reacted with both bis-exo-BCN and bis-endo-BCN compounds. However, one form of the bis-exo-BCN-based product did not augment contact fluorescence quenching, while a second bis-exo-BCN product could not further reduce contact fluorescence quenching. Nevertheless, a new fluorescence turn-on chemical probe was employed to determine the activities of two serum biomarkers, butyrylcholinesterase and paraoxonase 1. Moreover, bis-endo-BCN was exploited to successfully conjugate BSA with a 5-FAM derivative compound.

Photoinduced ynamide structural reshuffling and functionalization.

The radical chemistry of ynamides has recently drawn the attention of synthetic organic chemists to the construction of various N-heterocyclic compounds. Nevertheless, the ynamide-radical chemistry remains a long-standing challenge for chemists due to its high reactivity, undesirable byproducts, severe inherent regio- and chemoselective problems. Importantly, the ynamide C(sp)-N bond fission remains an unsolved challenge. In this paper, we observe Photoinduced radical trigger regio- and chemoselective ynamide bond fission, structural reshuffling and functionalization of 2-alkynyl-ynamides to prepare synthetically inaccessible/challenging chalcogen-substituted indole derivatives with excellent step/atom economy. The key breakthroughs of this work includes, ynamide bond cleavage, divergent radical precursors, broad scope, easy to handle, larger-scale reactions, generation of multiple bonds (N-C(sp2), C(sp2)-C(sp2), C(sp2)-SO2R/C-SR, and C-I/C-Se/C-H) in a few minutes without photocatalysts, metals, oxidants, additives. Control experiments and 13C-labeling experiments supporting the conclusion that sulfone radicals contribute to ynamide structural reshuffling processes via a radical pathway.