Eunyoung Lim

Synthesis of novel trans-stilbene derivatives and evaluation of their potent antioxidant and neuroprotective effects

A convenient synthesis and the biological properties of new amides, esters and other derivatives of trans-stilbene are described. The key synthetic strategies involve the Wittig-Horner reaction of a phosphonium salt 9 and an aldehyde 10 to generate (E)- or (Z)-olefins and a coupling reaction of an acid 12 and various amines 13a-n to give trans-stilbene derivatives 15a-n in high yields. A amide derivative 15g showed three times more in vitro free radical-scavenging activity than resveratrol, while another 15d exhibited strong inhibitory activity against lipopolysaccharide (LPS)(a)-induced NO generation. Allylamide analogue 15a showed the most potent neuroprotective activity in glutamate-induced primary cortical neuron cells.

Efficient Synthesis and Neuroprotective Effect of Substituted 1,3-Diphenyl-2-propen-1-ones

An efficient synthesis involving a key aldol reaction and biological properties of 1,3-diphenyl-2-propen-1-ones 8- 20 is described. The in vitro activity for 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging of 10 and 11 was 2 times higher than that for resveratrol. Compounds 9 and 11 were the strongest in suppression of in vitro nitric oxide (NO) generation and antiexcitotoxicity. Molecular modeling proposes an electron-donating group at the para position of acetophenones that leads to a dramatic increase in the suppression of NO production.

Simple Synthesis of Modafinil Derivatives and Their Anti-inflammatory Activity

Simple synthesis of modafinil derivatives and their biological activity are described. The key synthetic strategies involve substitution and coupling reactions. We determined the anti-inflammatory effects of modafinil derivatives in cultured BV2 cells by measuring the inhibition of nitrite production and expression of iNOS and COX-2 after LPS stimulation. It was found that for sulfide analogues introduction of aliphatic groups on the amide part (compounds 11a–d) resulted in lower anti-inflammatory activity compared with cyclic or aromatic moieties (compounds 11e–k). However, for the sulfoxide analogues, introduction of aliphatic moieties (compounds 12a–d) showed higher anti-inflammatory activity than cyclic or aromatic fragments (compounds 12e–k) in BV-2 microglia cells.

Practical Synthesis and Biological Evaluation of Bergenin Analogs

Here, we describe the practical synthesis and biological properties of bergenin and its structural analogs. Synthetic bergenin compounds were prepared by acylation of bergenin. These compounds were then evaluated for suppression of lipopolysaccharide‐induced nitric oxide (NO) generation in cultured cells and anti‐narcotic effects on morphine‐dependent mice. We found that bergenin derivatives showed potent anti‐inflammatory activity (suppression of NO generation) at concentrations ranging from 20 to 30 μmin vitro, and bergenin derivatives (10–20 mg/kg) exhibited significant anti‐narcotic effects on morphine dependence in mice. These results suggest the potential utility of bergenin and its analogs as anti‐narcotic agents and the design of more potent anti‐inflammatory compounds.

Synthesis, structural characterization and biological evaluation of novel stilbene derivatives as potential antimalarial agents.

A series of benzamide‐containing stilbene derivatives was synthesized through the incorporation of short basic side‐chains in the B‐ring hydroxy position of resveratrol. Their antiplasmodial activity was evaluated in vitro against the chloroquine resistant Plasmodium falciparum D10 strain, showing IC50 values between 1.5 and 80 μm, while their cytotoxicity was assessed using an human myeloid leukemia (U‐937) cell line. With a selectivity ratio of >51.02, the most selective of these derivatives, 29, also had the most lowest cytotoxic activity of the series.

Total synthesis of flocoumafen via knoevenagel condensation and intramolecular ring cyclization: general access to natural products.

The total synthesis and structure determination of cis- and trans-flocoumafen was described. The key synthetic steps involve Knoevenagel condensation with p-methoxybenzaldehyde, in situ decarboxylation and intramolecular ring cyclization to construct the tetralone skeleton. Stereospecific reduction of the O-alkylated ketone 13 afforded good yield of precusor alcohol 5. Final coupling of alcohol 5 with 4-hydroxy-coumarin yielded flocoumafen (1). Separation and structure determination of cis- and trans-flocoumafen through 2D NMR analyses-assisted computer simulation techniques for the evaluation of anticoagulant activities are reported for the first time. This method is useful for generating the core tetralone skeleton of 4-hydroxycoumarin derivatives and provides a generalized access to various warfarin type anticoagulants.

Convenient Synthesis and Biological Evaluation of Modafinil Derivatives: Benzhydrylsulfanyl and Benzhydrylsulfinyl [1,2,3]triazol-4-yl-methyl Esters

Simple synthesis and biological activities of modafinil derivatives are described. The key reactions include condensation of acid and propargyl alcohol, subsequent 1,3-dipolar cycloaddition reaction of alkynes and (3-azido-propyl)cyclohexane or (4-azido-butyl)benzene in the presence of sodium ascorbate and CuSO4·5H2O in excellent yield. They were then evaluated for the suppression of LPS-induced NO generation in vitro. It was found that all compounds showed moderate effects for suppression of LPS-induced NO generation.

Nonmuscle myosin heavy chain and histone H3 are intracellular binding partners of lithospermic acid B and mediate its antiproliferative effect on VSMCs.

Lithospermic acid B (LAB), an active component of danshen, is known to inhibit the proliferation of vascular smooth muscle cells (VSMCs) and has pharmacological activity scavenging free radicals in VSMCs. However, the precise mechanism through which LAB exerts its antiproliferative effect is unclear. Therefore, we investigated how LAB regulates cellular proliferation in primary cultured rat VSMCs. Using fluorescein isothiocyanate (FITC)-conjugated LAB to track its cellular localization, we show that LAB localizes to the nucleus, specifically to the nucleolus, where it binds to histone H3, leading to the inhibition of the platelet-derived growth factor (PDGF)- induced phosphorylation of histone H3. LAB also only moves into the nucleus during the normal expression of nonmuscle myosin heavy chain (NMHC-IIA), which is associated with LAB in VSMCs. Notably, LAB suppressed the PDGF-induced phosphorylation of Akt and the expression of cyclin D2 in the presence of NMHC-IIA expression. Knockdown of NMHC-IIA expression impeded the function of LAB, which was then unable to inhibit the PDGF-induced proliferation of VSMCs. We conclude that LAB modulates the PDGF-induced proliferation of VSMCs by interacting with NMHC-IIA, which allows LAB to localize in the nucleus and to suppress the PDGF-induced proliferation of VSMCs.

Quantitative Structure-Activity Relationship Study of Aromatic Inhibitors Against Rat Lens Aldose Reductase Activity Using Variable Selections

A quantitative structure-activity relationship (QSAR) study of aromatic inhibitors against aldose reductase (AR) activity was performed using variable selection from stepwise multiple linear regression (MLR) and genetic algorithm (GA)-MLR. As a result of variable selection, stepwise MLR and GA-MLR gave the same results with one, two, three and five descriptors and different results with four and six descriptors. GA-MLR produced higher values and was better in explanatory and predictive power than stepwise MLR in four variables. AR activity (pIC50) of aromatic derivatives was expressed with acceptable explanatory (74.6-81.2%) and predictive power (68.8-74.4%) in models 3 and 4. The resulting models with the given descriptors illustrate that hydrophobic and electrostatic interactions play a significant role in inhibition of AR activity. This study suggests that the QSAR models can be used as guidelines to predict improved aldose reductase inhibitory activity and to obtain reliable predictions in structurally diverse compounds.

Synthesis of a dual-labeled probe of dimethyl lithospermate B with photochemical and fluorescent properties.

Dimethyl lithosermate B (DLB) is a highly potent natural antioxidant and antidiabetic polyphenol with unknown mode of action. To determine its cellular targets, a photochemical and fluorescent dimethyl lithopermate B probe was designed and efficiently synthesized. The dual-labeled chemical probe for biological application was evaluated by UV and fluorescence to determine its electrochemical absorption and emission properties. This probe could be valuable for investigating ligand-protein interactions and subcellular localization.