Yuou Teng

Synthesis and anti-cancer activity evaluation of 5-(2-carboxyethenyl)-isatin derivatives

A series of novel di- or trisubstituted isatin derivatives were designed and synthesized in 5-6 steps in 25-45% overall yields. Their structures were confirmed by 1H NMR and 13C NMR as well as LC-MS. The anticancer activity of the fourty-three new isatin derivatives against human T lymphocyte cells Jurkat was evaluated by MTT assay in vitro. SAR study suggested that the combination of 1-benzyl and 5-[trans-2-(methoxycarbonyl)ethen-1-yl] substitution greatly enhanced their cytotoxic activity. Among them, compound 2h was shown to have a significant cytotoxic activity with an IC50 value of 0.03 μM, more than 330-fold higher than that of its mother molecule isatin. Investigation of the cell morphology changes and annexin-V/PI staining study demonstrated that compound 2h inhibited the proliferation of Jurkat cells by inducing apoptosis. Since compound 2h induced the dissipation of mitochondrial membrane potential and the activation of caspase-3, it was obvious that compound 2h inhibited the proliferation of Jurkat cells through the mitochondrial apoptotic pathway. Other than this, compound 2h exerted inhibition effect to many other tumor cells and only showed weak cytotoxic to human normal cells suggesting that compound 2h possessed a broad range of anticancer spectrum and high safety to normal cells.

Synthesis and antitumor activity evaluation of a novel series of camptothecin analogs

A series of novel 10-substituted camptothecin analogs (3–10) with a carbamate linker were synthesized, and their biological activities were evaluated. The amino acid-linked carbamate derivatives (8–10) of the camptothecin-type natural product not only possessed good to excellent inhibitory activity against three human tumor cell lines K562, HepG2, and HT-29, but also showed significantly less cytotoxicity against normal human cell HEK293 (half maximal inhibiting concentration >10 μM). The selectivity of compound 9 toward tumor cells relative to normal cells is at least 250 times better than that of camptothecin. The preliminary testing result indicated that the solubility of these compounds was also improved compared to that of 10-hydroxy camptothecin.

Paris saponin I inhibits proliferation and promotes apoptosis through down-regulating AKT activity in human non-small-cell lung cancer cells and inhibiting ERK expression in human small-cell lung cancer cells

Paris Saponin I (PSI), a steroidal saponin derivative extracted from a traditional Chinese herbal Paris polyphylla, has shown cytotoxic effects on several tumor cell lines. However, the mechanisms of its antitumor activity especially for lung cancers remain to be elucidated. In this present investigation, we continue to explore the efficacy and mechanisms underlying the cytotoxic effects of PSI in lung cancer cell lines. Three non-small cell lung cancer (NSCLC) cells (H1299, H520, H460) and one small cell lung cancer (SCLC) cell (H446) were treated with PSI for the first time. PSI significantly induced cell cycle arrest at the G2/M phase and mitochondrial-related apoptosis NSCLC cells but not SCLC cells. Additionally, PSI reduced phosphorylation of AKT in NSCLC and ERK in SCLC in general. Interestingly, we observed that PSI influenced different signaling pathways among the four kinds of lung cancer cells. After PSI treatment, p38 MAPK and ERK activation were observed in H1299, while p38 MAPK increased and JNK decreased in H520. On the contrary, we found JNK activation in H460 cells with PSI. However, PSI upregulated the AKT activity and inhibited the JNK expression in H446 cells. The results indicate that PSI exhibits the cytotoxicity in different pathways depending on the cancer types.

Synthesis and antitumor activity evaluation of a novel series of xanthone derivatives

A natural xanthone, 1,3,6-trihydroxy-5-methoxyxanthone, was totally synthesized for the first time by six steps in 31% overall yield. The xanthone skeleton was formed by a one-step synthesis in 80% yield, and five of its novel derivatives were also obtained by this approach. This synthetic strategy and all the derivatives could be further used for the preparation of other natural xanthones. All the xanthones were characterized by NMR and ESI-MS, and the cytotoxicity of these xanthones was evaluated against HepG2 and HT-29 cells, and the preliminary structure–activity relationship was evaluated from the results. It was proved that the presence of 3-OH group in the molecule is crucial for its biological activity, while the presence of substituents at C-5 and C-6 may also be beneficial.

Synthesis and Biological Evaluation of Novel Water-Soluble Poly-(ethylene glycol)-10-hydroxycamptothecin Conjugates

In order to improve the antitumor activity and water solubility of 10-hydroxycamptothecin (HCPT), a series of novel HCPT conjugates were designed and synthesized by conjugating polyethylene glycol (PEG) to the 10-hydroxyl group of HCPT via a valine spacer. The in vitro stability of these synthesized compounds was determined in pH 7.4 buffer at 37 °C, and the results showed that they released HCPT at different rates. All the compounds demonstrated significant antitumor activity in vitro against K562, HepG2 and HT-29 cells. Among them, compounds, 4a, 4d, 4e and 4f, exhibited 2–5 times higher potency than HCPT. The stability and antitumor activity of these conjugates were found to be closely related to the length of PEG and the linker type, conjugates with a relatively short PEG chain and carbamate linkages (compounds 4a and 4f) exhibited controlled release of HCPT and excellent antitumor in vitro activity.

Design, Synthesis and Biological Evaluation of the Novel Antitumor Agent 5-Bromobenzofuran-3(2H)-One and its Derivatives

Aurones and auronols are naturally occurring 2-benzylidenebenzofuranone-3(2H)-one derivatives. Aurones have a limited occurrence in fruits, vegetables, and bright yellow color to flowers such as cosmos and coreopsis. Aurones possess a wide range of biological activities, such as antitumor, antifungal, phytoalexin, and so on. Some aurone derivatives have been studied as antitumor drug molecules, but 2-benzylidene-5-bromobenzofuranone-3(2H)-one series have not been reported yet. In this paper, we’d like to report the design, synthesis, and biological evaluation of the novel aurone derivatives. All the newly synthesized compounds were characterized by 1H NMR and their antitumor activities were evaluated by using MTT method in HT-29, K562, and HepG2 cell lines. 5-bromo-2-(4-nitrobenzylidene) benzofuran-3(2H)-one demonstrated good antitumor activity against K562 cells with an IC50 of 0.37 μM.

Study the Role of E-selectin and Its Ligand sLeX in the Adhesion Between THP-1 Cells and HUVEC Cells

E-selectin (CD62E), a transmembrane glycoprotein, is a C-type lectin that binds to the tetrasaccharide sialyl Lewis X (sLex) structure. E-selectin plays an important role in inflammation and in the adhesion of leukemia cells to endothelial cells. E-selectin can induce the interaction of specific cell–cell adhesion on the cells’ surface that can reduce the flow rate of leukocytes in the blood vessel to make inflammation worse or mediate the growth and metastasis of cancer. Actually, normal endothelial cells do not express E-selectin. However, the expression of E-selectin will be increased when endothelial cells are stimulated by inflammatory factors such as tumor necrosis factor (TNF-α), interleukin-1 (IL-β) and bacterial lipopolysaccharide (LPS). In this study, we optimized the model of THP-1 adhesion to human umbilical vein endothelial (HUVEC) includes plating density and the time required that E-selectin can express when inflammatory factors stimulate to endothelial cells. This paper intends to optimize the model of an adhesion between HUVEC and THP-1 through the stimulation of inflammatory factors. Meanwhile, we determined the condition for the expression of E-selectin. The results showed that the expression of E-selectin reached the peak when HUVEC was stimulated by TNF-α (20 ng/mL) for 6 h.

The Prokaryotic Expression of Cyclin-Dependent Kinase 2, and the Establish of Its Inhibitor Screening System

Cyclin dependent kinases 2 (CDK2), a kind of serine/threonine protein kinase, can form a complex with Cyclin A, which is indispensible ingredient in co-regulating the cell cycle of the DNA synthesis phase (S phase). The disorder of CDK2 gives rise to abnormal cell cycle regulation and thus results in tumor progression. In recent years, the development of highly effective CDK2 inhibitors has become one of the most talked about topics in the field of antitumor drug research. Firstly, the recombinant plasmids of CDK2 and Cyclin A were constructed in this paper. Then the soluble expression protein of CDK2 and Cyclin A were induced in E. coli BL21 (DE3) Plyss cells. The proteins were purified by Ni-beads and eluted by imidazole to obtain recombinant CDK2 and Cyclin A respectively. Next, the in vitro CDK2 kinase activity test platform was constructed with purified CDK2 and Cyclin A. Roscovitine, a well-known CDK inhibitor, was used as a positive control in our screening system. The half of the inhibition concentration (IC50) of Roscovitine in the system was 1.87 μM, which is in agreement with the previous reported. In summary, we established a rapid and stable CDK2 expression system, which could be used for the inhibitor screening and lay a good foundation for the study of new CDK inhibitors in the future.

Design, Synthesis and Biological Evaluation of the Novel Antitumor Agent 2-benzyl-3, 4-dihydroisoquinolin-1(2H)-one and Its Derivatives

Tetrahydroisoquinoline and its derivatives have a wide range of biological activities, such as antitumor, antimicrobial, and analgesic properties and so on. Some tetrahydroisoquinoline alkaloid derivatives have been studied as antitumor drug molecules, but 2-benzyl-7-substituted-ethoxy]-3, 4-dihydro-1(2H)-isoquinolinone series have not been reported yet. In this paper, we would like to report the design, synthesis, and biological evaluation of the novel tetrahydroisoquinoline derivatives. Among those compounds, four new tetrahydroisoquinoline derivatives have not been reported before. All the newly synthesized compounds were characterized by 1H NMR and their antitumor activities were evaluated by using HT-29, K562 and HepG2 cell line. 2-Benzyl-7-[2-(tert-butyl-4-piperazinecarboxylate) ethoxy]-3, 4-dihydro-1(2H)-isoquinolinone demonstrated good antitumor activity against K562 cancer cell with an IC50 of 1.58 μM.

Design, Synthesis and Primary Biological Evaluation of the Novel Antitumor Agent Indoline-3-One and Its Derivatives

Indolinone displays promising antitumor properties by inhibiting various kinase families. In this paper, we’d like to report the design, synthesis, and primary biological evaluation of the novel indoline-3-one and its derivatives. All the newly synthesized compounds including the novel compound 2-(4-(trifluoromethyl)benzylidene)indolin-3-one (5f) were characterized by 1H NMR and their antitumor activities were evaluated by using MTT method in HT-29, K562, and HepG2 cell lines. 2-(2-nitrobenzylidene)indolin-3-one (5d) demonstrated good antitumor activity against HT-29, K562, and HepG2 with an IC50 of 2.04 μM, 2.33 μM, 2.24 μM, respectively. 2-(4-(trifluoromethyl)benzylidene)indolin-3-one(5f) demonstrated good antitumor activity against K562 and HepG2 with an IC50 of 2.27 μM, 3.47 μM.