Hyeryoung Jung

Polyphenols bearing cinnamaldehyde scaffold showing cell growth inhibitory effects on the cisplatin-resistant A2780/Cis ovarian cancer cells.

Ovarian carcinoma remains the most lethal among gynecological cancers. Chemoresistance is a clinical problem that severely limits treatment success. To identify potent anticancer agents against the cisplatin-resistant human ovarian cancer cell line A2780/Cis, 26 polyphenols bearing a cinnamaldehyde scaffold were synthesized. Structural differences in their inhibitory effect on clonogenicity of A2780/Cis cells were elucidated using comparative molecular field analysis and comparative molecular similarity indices analysis. Structural conditions required for increased inhibitory activity can be derived based on the analysis of their contour maps. The two most active compounds (16 and 19) were selected and further characterized their biological activities. We found that compounds 16 and 19 trigger cell cycle arrest at the G2/M phase and apoptotic cell death in cisplatin-resistant A2780/Cis human ovarian cancer cells. The molecular mechanism of compound 16 was elucidated using in vitro aurora A kinase assay, and the binding mode between the compound 16 and aurora A kinase was interpreted using in silico docking experiments. The findings obtained here may help us develop novel plant-derived polyphenols used for potent chemotherapeutic agents. In conclusion, compounds 16 and 19 could be used as promising lead compounds for the development of novel anticancer therapies in the treatment of cisplatin-resistant ovarian cancers.

Targeting Cancer Cells via the Reactive Oxygen Species-Mediated Unfolded Protein Response with a Novel Synthetic Polyphenol Conjugate

Purpose: The selective killing of tumor cells is an important strategy for cancer therapeutics. The aim of this study was to develop a novel antitumor agent that is safe for normal cells with the ability to selectively target cancer cells. Experimental Design: On the basis of quantitative structure–activity relationship, we synthesized a novel polyphenol conjugate (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (DPP-23). We evaluated the effect of DPP-23 on proliferation, cell cycle, and apoptosis in various tumor cells. We also assessed molecular targets of DPP-23 using genome-wide expression profiling by DNA microarray and real-time PCR array systems. Results: DPP-23 effectively inhibited the growth of cancer cells in vitro and in vivo (xenografts in Balb/c nude mice). At a molecular level, DPP-23 targeted the unfolded protein response (UPR) in the endoplasmic reticulum (ER) through the production of reactive oxygen species (ROS) in cancer cells, but not in normal cells, resulting in selective killing of tumor cells via caspase-dependent apoptosis. Conclusions: The selective generation of ROS in cancer cells could be an attractive strategy for the selective killing of cancer cells, while maintaining negligible cytotoxicity to normal cells. DPP-23 represents a promising novel therapeutic agent for the selective production of ROS in cancer cells. Clin Cancer Res; 20(16); 4302–13. ©2014 AACR.

Synthesis and biological evaluation of phenyl-1H-1,2,3-triazole derivatives as anti-inflammatory agents

Rapid and efficient synthesis of a phenyl-1H-1,2,3-triazole library enabled cost-effective biological testing of a range of novel non-steroidal anti-inflammatory drugs with potential for improved drug efficacy and toxicity profiles. Anti-inflammatory activities of the phenyl-1H-1,2,3-triazole analogs synthesized in this report were assessed using the xylene-induced ear edema model in mice. At least four analogs, 2a, 2b, 2c, and 4a, showed more potent effects than the reference anti-inflammatory drug diclofenac at the same dose of 25 mg/kg. To explore relationships between the structural properties of phenyl-1H-1,2,3-triazole analogs and their anti-inflammatory activities in xylene-induced ear edema, comparative molecular field analysis was performed, and pharmacophores showing good anti-inflammatory activities were identified based on an analysis of contour maps obtained from comparative molecular field analysis. The anti-inflammatory effect on the molecular level was tested by the expression of tumor necrosis factor-alpha induced COX-2 using Western blots. Because the addition of the analog 2c caused the expression change of TNF-α induced COX-2, the molecular binding mode between 2c and COX-2 was elucidated using in silico docking.

Quantitative Relationships Between the Cytotoxicity of Flavonoids on the Human Breast Cancer Stem-Like Cells MCF7-SC and Their Structural Properties

As some breast cancer‐related deaths can be attributed to the metastasis of cancer stem cells, chemotherapeutic agents targeting breast cancer stem cells are of interest as a potential treatment. Flavonoids that exhibit cytotoxicity on breast cancer stem cells have rarely been observed. Thus, the objective of this study was to measure potential cytotoxic effects of 42 different flavonoids on the human breast cancer stem‐like cell line, MCF7‐SC. The relationship between flavonoid structural properties and cytotoxicity has not been reported previously; therefore, we determined quantitative structure–activity relationships using both comparative molecular field analysis and comparative molecular similarity analysis. Further biological experiments including Western blot analysis, flow cytometry, and immunofluorescence microscopy were also conducted on the most cytotoxic 8‐chloroflavanone.

1H and 13C NMR spectral assignments of novel flavonoids bearing benzothiazepine

Benzothiazepine is a heterocyclic compound containing nitrogen and sulfur. A variety of derivatives can be designed by modifying the positions of the double bond and benzene ring. 2,3-Dihydro1,5-benzothiazepine (also known as 2,3-dihydro[b][1,4]thiazepine) derivatives show diverse biological activities, including inhibitory effects on alpha-glucosidase, urease, cholinesterase, and butyrylcholinesterase, and agonistic activity toward the transient receptor potential ankyrin 1 (TRPA1) receptor (Fig. 1(A)). When two benzene rings are attached at the C-2 and C-4 positions, 2,4-diphenyl2,3-dihydro-1,5-benzothiazepine containing a C6-C3-C6 skeleton can be derived (Fig. 1(B)). Flavonoids are found in various plants as their secondary metabolites and are composed of C6-C3-C6 skeletons (Fig. 1(C)). Because methoxylation and naphthalenyl groups can increase cellular compartmentation and cell permeability, we designed and synthesized methoxylated 4-(1-hydroxy-naphthalen-2-yl)-2-phenyl-2,3-dihydro-1,5-benzothiazepine derivatives (Fig. 1(D)). However, flavonoids bearing a benzothiazepine skeleton have rarely been reported, even though their design and synthesis are of interest because of their biological diversity. Furthermore, because the 1H and 13C NMR, and high resolution mass spectrometric (HR/MS) data can be used as references for further study, herein, we report the NMR and MS data of 27 novel flavonoids bearing benzothiazepine skeletons.

Colorectal anticancer activities of polymethoxylated 3-naphthyl-5-phenylpyrazoline-carbothioamides.

To develop potent chemotherapeutic agents for treating colorectal cancers, polymethoxylated 3-naphthyl-5-phenylpyrazoline-carbothioamide derivatives were designed. Twenty-two novel derivatives were synthesized and their cytotoxicities were measured using a clonogenic long-term survival assay. Of these derivatives, 3-(1-hydroxynaphthalen-2-yl)-N-(3-methoxyphenyl)-5-(4-methoxyphenyl)-pyrazoline-1-carbothioamide (NPC 15) exhibited the best half-maximal cell growth inhibitory concentrations (196.35nM). To explain its cytotoxicity, further biological experiments were performed. Treatment with NPC 15 inhibited cell cycle progression and triggered apoptosis through the caspase-mediated pathway. Its inhibitory effects on several kinases participating in the cell cycle were investigated using an in vitro kinase assay. Its half-maximal inhibitory concentrations for aurora kinases A and B were 105.03μM and 8.53μM, respectively. Further analysis showed that NPC 15 decreased phosphorylation of aurora kinases A, B, and C and phosphorylation of histone H3, a substrate of aurora kinases A and B. Its molecular binding mode for aurora kinase B was elucidated using in silico docking. In summary, polymethoxylated 3-naphthyl-5-phenylpyrazoline-carbothioamides could be potent chemotherapeutic agents.

1H and 13C NMR spectral assignments of 18 novel polymethoxylated hydroxynaphthopyrazolylchalconoids

Among plant-derived polyphenols produced via phenylpropanoids pathway, chalcones are biosynthesized by a combination of 4-coumaroyl-CoA with malonyl-CoA. Chalcones are known as chalconoids (Figure 1A). They consist of two benzene rings connected via the α,β-unsaturated carbonyl group, which may close to form another ring, to give flavonoids with three rings. It was known that chalconoids act as potassium channel blockers and aromatase inhibitors. As reported previously, some chalconoids can be converted to flavonoids easily (Fig. 1B). Therefore, their stabilities remained to be solved to develop as biological active compounds. A substitution of α,β-unsaturated carbonyl group with pyrazoline group (pyrazolylchalconoids) can prevent the conversion of chalconoids to flavonoids (Fig. 1C). Methoxylation increases the cell permeability and stability of many plant-derived polyphenols. We designed hydroxynaphthopyrazolylchalconoids with hydroxynaphthyl A-ring and trimethoxylated B-ring (Fig. 1D), and synthesized 18 derivatives. Their NMR data and mass spectrometric (MS) data can help us to identify plant-derived polyphenols newly synthesized or isolated from natural sources in the future, thus, we report here the complete H and C NMR data and high-resolution MS data.

Investigation of 2-hydroxy-4-methoxy-2′,3′-benzochalcone binding to tubulin by using NMR and in silico docking

Hydroxychalcones act as autophagy inducers and methoxy chalcones induce apoptosis. Additionally, benzoflavones inhibit the hepatitis C virus. Based on these findings, a chalcone derivative, 2-hydroxy-4-methoxy-2′,3′-benzochalcone, was prepared. It showed antimitotic activity through its inhibitory effect on tubulin polymerization. Its molecular binding mode with tubulin was elucidated using in silico docking and nuclear magnetic resonance spectroscopy. In addition, the three-dimensional structure of 2-hydroxy-4-methoxy-2′,3′-benzochalcone was determined by X-ray crystallography.

1) H and (13) C NMR spectral assignments of novel naphthalenylphenylpyrazolines.

Compounds containing pyrazolinyl-1-carbothioamide scaffolds (Fig. 1A) can act as anticancer agents, antimicrobial agents, and monoamine oxidase inhibitors. When ethyl 2-bromoacetate is added to pyrazolinyl-1-carbothioamide, 2-pyrazolin-1-ylthiazol4(5H)-one (Fig. 1B) is produced. Compounds containing thiazolone scaffolds show hepatitis C virus inhibitory effects, antitubercular, antibacterial, and antimicrobial activities. We designed naphthalenylphenylpyrazolinyl-1-carbothioamides (Fig. 1C) and naphthalenylphenyl-2-pyrazolin-1-ylthiazol-4(5H)-ones (Fig. 1D). Five thousand compounds containing pyrazolinyl-1-carbothioamide scaffolds and three thousand compounds containing 2-pyrazolin-1ylthiazol-4(5H)-one scaffolds have been reported. Similar to chalcones (Fig. 1E), naphthalenylphenylpyrazolinyl-1-carbothioamides and naphthalenylphenyl-2-pyrazolin-1-ylthiazol-4(5H)-ones contain a C6C3-C6 skeleton. Chalcones are a group of plant-derived polyphenols. Because of their diverse biological activities, chalcones are still being derivatized. Therefore, the NMR and mass spectrometric (MS) data of the compounds we have designed and synthesized could help us identify newly synthesized derivatives or derivatives isolated from natural sources in the future. We report herein the complete H and C NMR data and high resolution MS data of 13 novel naphthalenylphenylpyrazolinyl-1-carbothioamides and five novel naphthalenylphenylpyrazolinyl-1-thiazol-4(5H)-ones.

1) H and (13) C NMR spectral assignments of 19 novel polymethoxylated diphenylnaphthylpyrazolinylcarbothioamides.

Chalcones are secondary metabolites in plants produced via the phenylpropanoid pathway. Because 2-hydroxychalcones (Fig. 1A) are known to show various biological activities including anticancer and antioxidative effects, their derivatives have been investigated and reported. However, cyclization of 2hydroxychalcones results in the formation of flavanones. As such, the α,β-unsaturated carbonyl group was replaced with a pyrazoline group (Fig. 1B). Diphenylpyrazolines contain a C6-C3-C6 skeleton similar to chalcones, and they show more biological activities including tyrosinase inhibition, antimicrobial effects, and monoamine oxidase inhibition. Diphenylpyrazolinyl-1-carbothioamdes (Fig. 1C) show dual inhibitory effects on monoamine oxidase and cholinesterase. Therefore, we designed phenyl-N-phenyl-naphthalenylpyrazolinyl-1-carbothioamide (Fig. 1D) and synthesized 19 derivatives. Pyrazolinyl-1-carbothioamdes are important because of their diverse biological activities, and their NMR and mass spectrometric (MS) data can aid in the identification of newly synthesized or isolated derivatives in the future. Therefore, we report herein the complete H and C NMR and highresolution MS data of 19 novel polymethoxylated diphenylnaphthylpyrazolinyl-1-carbothioamides.