Bingling Luo

Mild Cu(I)-Catalyzed Cascade Reaction of Cyclic Diaryliodoniums, Sodium Azide, and Alkynes: Efficient Synthesis of Triazolophenanthridines

Linear iodoniums are widely used as arylating reagents. However, cyclic diaryl idodoniums are ignored despite their potential to initiate dual arylations, atom and step economically. In our current work, a three-component cascade reaction of cyclic diaryliodoniums, sodium azide, and alkynes has been successfully achieved under mild conditions, catalyzed by cheap copper species. The regioselectivity associated with unsymmetrical iodoniums was enhanced by installing two methyls ortho and para to the I(III) center. The reaction enables a rapid access to a variety of complex molecules, triazolophenanthridine derivatives.

Discovery of novel N-substituted carbazoles as neuroprotective agents with potent anti-oxidative activity

Carbazole moiety is an important scaffold with a variety of biological applications, for example, anti-oxidative stress. Our previous synthesized carbazoles were screened for their neuroprotective properties against two individual oxidative stresses. Some of the new carbazole derivatives were observed with modest to good neuroprotective effects on neuronal cells HT22 against cell injury induced by glutamate or homocysteic acid (HCA). Substituents introduced to the carbazole ring system play crucial roles in their biological activities. In particular, a bulky group favors the neuroprotective activity of the compounds. One of the new compounds, 6, showed the best neuroprotective effects, which might result from its anti-oxidative activity with a GSH-independent mechanism. These findings might provide an alternative strategy for the development of novel carbazole derivatives for the treatment of CNS diseases such as Alzheimers disease.

Three-Component Pd/Cu-Catalyzed Cascade Reactions of Cyclic Iodoniums, Alkynes, and Boronic Acids: An Approach to Methylidenefluorenes

Linear diaryliodonium salts are widely used as arylating reagents for C-C and C-X bond formation. Meanwhile, synthetic applications of cyclic iodoniums are relatively rare although they offer the opportunity to set up reaction cascades. We demonstrate an atom and step economical three-component reaction involving cyclic diphenyleneiodoniums, alkynes, and boronic acids, resulting in the construction of methylidenefluorenes in a single operation. Our route enables facile access to both symmetrical and unsymmetrical methylidenefluorene derivatives, compounds that have attracted interest due to their optical properties.

Synthesis of N -acyl- N, O -acetals mediated by titanium ethoxide

N-Acyl-N,O-acetals are present in a number of bioactive natural products, and this unusual functional group can act as a synthetic precursor to unstable reactive N-acylimines. In this paper, a variety of N-acyl-O-ethyl-N,O-acetals was concisely prepared under mild conditions mediated by titanium ethoxide (Ti(OEt)4). The method also offers a new strategy to make other O-alkyl-N,O-acetals. Furthermore, this strategy was extended to the synthesis of an analogue of the natural product turtschamide.

Relayed Regioselective Alkynylation/Olefination of Unsymmetrical Cyclic Diaryliodonium Species Catalyzed by Cu and Pd: Affording Fluorescent Cytotoxic Benzoxazoles.

Although cyclic diaryliodonium species have the potential to act as valuable synthons for cascade transformations, they still remain largely unexplored. The regioselectivity associated with unsymmetrical cyclic diaryliodonium species has previously been known to pose a challenge. A regioselective relayed alkynylation and olefination of unsymmetrical cyclic diaryliodonium species has been achieved by installation of a directing amido group. These relayed transformations were delayed until an oxazole ring had formed, delivering a series of unique fluorescent benzoxazoles. Moreover, some of these synthetic benzoxazoles showed apparent inhibitory activity against malignant cancer cells. Further confocal visualization revealed that benzoxazoles targeted cell nuclei. These findings might provide a novel structural scaffold to develop desirable anticancer agents.

Inhibition of cancer growth in vitro and in vivo by a novel ROS-modulating agent with ability to eliminate stem-like cancer cells

Reactive oxygen species (ROS) have a crucial role in cell signaling and cellular functions. Mounting evidences suggest that abnormal increase of ROS is often observed in cancer cells and that this biochemical feature can be exploited for selective killing of the malignant cells. A naturally occurring compound phenethyl isothiocyanate (PEITC) has been shown to have promising anticancer activity by modulating intracellular ROS. Here we report a novel synthetic analog of PEITC with superior in vitro and in vivo antitumor effects. Mechanistic study showed that LBL21 induced a rapid depletion of intracellular glutathione (GSH), leading to abnormal ROS accumulation and mitochondrial dysfunction, evident by a decrease in mitochondrial respiration and transmembrane potential. Importantly, LBL21 exhibited the ability to abrogate stem cell-like cancer side population (SP) cells in non-small cell lung cancer A549 cells associated with a downregulation of stem cell markers including OCT4, ABCG2, SOX2 and CD133. Functionally, LBL21 inhibited the ability of cancer cells to form colonies in vitro and develop tumor in vivo. The therapeutic efficacy of LBL21 was further demonstrated in mice bearing A549 lung cancer xenografts. Our study suggests that the novel ROS-modulating agent LBL21 has promising anticancer activity with an advantage of elimination of stem-like cancer cells. This compound merits further study to evaluate its potential for use in cancer treatment.

Pd catalyzed insertion of alkynes into cyclic diaryliodoniums: a direct access to multi-substituted phenanthrenes

Cyclic diaryliodoniums remain unexplored compared to linear iodoniums. In our current work, internal alkynes were for the first time applied to react with cyclic iodoniums, catalyzed by Pd, resulting in a [4 + 2] benzannulation. Our work offers a new strategy to synthesize multi-substituted phenanthrene derivatives which are not easily accessed by conventional methods.

New mild and simple approach to isothiocyanates: A class of potent anticancer agents

In our current work, acetyl chloride-mediated synthesis of phenethyl isothiocyanate (PEITC) derivatives proves to be convenient and provides the expected products at good to excellent yields. Biological evaluation and structure-activity relationship analysis found that the novel compound 7 showed the best anticancer activity against human cancer cell line Panc1 and HGC27 compared with PEITC. Compounds 6 and 7 induced more apoptosis in pancreatic cancer cells but less toxicity in non-cancer cells. Further biological study demonstrated that 7 substantially increased intracellular reactive oxygen species (ROS) and depleted glutathione (GSH), leading to an oxidative stress to kill cancer cell.

L-F001, a Multifunction ROCK Inhibitor Prevents 6-OHDA Induced Cell Death Through Activating Akt/GSK-3beta and Nrf2/HO-1 Signaling Pathway in PC12 Cells and Attenuates MPTP-Induced Dopamine Neuron Toxicity in Mice

Amounting evidences demonstrated that Rho/Rho-associated kinase (ROCK) might be a novel target for the therapy of Parkinson’s disease (PD). Recently, we synthesized L-F001 and revealed it was a potent ROCK inhibitor with multifunctional effects. Here we investigated the effects of L-F001 in PD models. We found that L-F001 potently attenuated 6-OHDA-induced cytotoxicity in PC12 cells and significantly decreased intracellular reactive oxygen species (ROS), prevented the 6-OHDA-induced decline of mitochondrial membrane potential and intracellular GSH levels. In addition, L-F001 increased Akt and GSK-3beta phosphorylation and induced the nuclear Nrf2 and HO-1 expression in a time- and concentration-dependent manner. Moreover, L-F001 restored the levels of p-Akt and p-GSK-3beta (Ser9) as well as HO-1 expression reduced by 6-OHDA. Those effects were blocked by the specific PI3K inhibitor, LY294002, indicating the involvement of Akt/GSK-3beta pathway in the neuroprotective effect of L-F001. In addition, L-F001 significantly attenuated the tyrosinehydroxylase immunoreactive cell loss in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced mice PD model. Together, our findings suggest that L-F001 prevents 6-OHDA-induced cell death through activating Akt/GSK-3beta and Nrf2/HO-1 signaling pathway and attenuates MPTP-induced dopaminergic neuron toxicity in mice. L-F001 might be a promising drug candidate for PD.

Heterocyclic Iodoniums for the Assembly of Oxygen-Bridged Polycyclic Heteroarenes with Water as the Oxygen Source

A diverse set of novel heterocyclic iodoniums was synthesized for the first time. The reactions of these unique iodoniums with environmentally benign water as the oxygen source provided structurally complex oxygen-incorporated heteropolycycles that are essential motifs in natural products and biologically active compounds. The transformation only required low-cost copper acetate. Further derivatization of the obtained polycycles expanded the structural diversity, which is important in the building of chemical libraries for drug discovery.