Huazhou Ying

MSFTZ, a Flavanone Derivative, Induces Human Hepatoma Cell Apoptosis via a Reactive Oxygen Species- and Caspase-Dependent Mitochondrial Pathway

Hepatocellular carcinoma (HCC) is the most common malignancy of the liver. It is unfortunate that HCCs are highly refractory to conventional chemotherapy, radiation therapy, and even immunotherapy. Thus, novel therapeutic targets need to be sought for the successful treatment of HCCs. We now report that (±)-(3aRS,4SR)-2-(2-chloro-4-methylsulfonylphenyl)-4′-chloro-3α,4-diethoxy-flavane[4,3-d]-D1,9b-1,2,3-thiadiazoline (MSFTZ), a synthesized flavanone derivative, induced growth arrest and apoptosis of HCCs both in vitro and in vivo. MSFTZ induced a time- and dose-dependent increase in HCC apoptosis through caspase-3 activation and poly(ADP-ribose) polymerase-1 cleavage. Activation of caspase-9 induced by MSFTZ suggested that MSFTZ-induced signaling was mediated through a mitochondrial death pathway. In addition, we observed an elevation of reactive oxygen species (ROS) and a consequent loss of mitochondrial membrane potential, further suggesting that MSFTZ-induced death signaling was mediated through a mitochondrial oxygen stress pathway. These events were associated with a decrease and increase in Bcl-2 and Bax expression, respectively, as well as phosphorylation of mitogen-activated protein kinase (MAPK) and activation of p53-MDM2 pathway. However, the antioxidant N-acetylcysteine opposed MSFTZ-mediated mitochondrial dysfunction, caspase activation, Bcl-2/Bax modulation, and apoptosis, supporting the role of ROS in the apoptotic process. We were surprised that we failed to observe the protective effect of N-acetylcysteine against MSFTZ-induced MAPK activation. Furthermore, MSFTZ had an antitumor effect in vivo by 34.8 to 78.7% reduction of tumor size in SMMC-7721-xenografted nude mice. We conclude that MSFTZ induces HCC cell apoptosis both in vivo and in vitro via caspase- and ROS-dependent mitochondrial pathway. In addition, MSFTZ has potential as a novel therapeutic agent for the treatment of HCC.

Microwave-Assisted Mannich Reaction of 2-Hydroxy-chalcones

Abstract A series of Mannich base derivatives of 2-hydroxy-chalcones were obtained expediently in good to excellent yields by microwave-assisted Mannich reaction. The regioselectivity of the reaction occurred preferentially at the C-3 position of the 2-hydroxy-chalcone backbone. In comparison with conventional results, results from microwave possesses give better yields in shorter times. Further vasorelaxation assay showed that 2-hydroxy-3-((4-methylpiperazin-1-yl)methyl)-4,6-dimethoxymethoxy-3′-bromo-chalcone 8 significantly decreased maximal PE-induced contraction (Emax = 100 ± 5.97%, EC50 = 10.2 ± 0.51 µM).

Design, synthesis and biological evaluation of novel 4-alkynyl-quinoline derivatives as PI3K/mTOR dual inhibitors.

A novel series of 4-alkynyl-quinoline derivatives were designed, synthesized and biologically evaluated for their PI3Kα inhibitory activities and anti-proliferative effects against two cancer cell lines PC-3 and HCT-116. Most of them showed potent PI3Kα inhibitory activities with IC50 values at low nanomolar level and good to excellent anti-proliferative effects against both cell lines. Among them, compound 15d, the most potent one, was selected for further biological evaluation. As a result, 15d displayed strong inhibitory activity against other class I PI3K isoforms (PI3Kβ, PI3Kγ and PI3Kδ) and mTOR with an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that the phosphorylation of Akt, another downstream effector of PI3K, can be remarkably suppressed by 15d at cellular level. All these experimental results suggested that 15d is a potent PI3K/mTOR dual inhibitor and could serve as a promising lead compound for the development of anticancer agents.

Discovery of Novel Succinate Dehydrogenase Inhibitors by the Integration of in Silico Library Design and Pharmacophore Mapping

Succinate dehydrogenase (SDH) has been demonstrated as a promising target for fungicide discovery. Crystal structure data have indicated that the carboxyl core of current SDH inhibitors contributed largely to their binding affinity. Thus, identifying novel carboxyl core SDH inhibitors would remarkably improve the biological potency of current SDHI fungicides. Herein, we report the discovery and optimization of novel carboxyl scaffold SDH inhibitor via the integration of in silico library design and a highly specific amide feature-based pharmacophore model. To our delight, a promising SDH inhibitor, A16c (IC50 = 1.07 μM), with a novel pyrazol-benzoic scaffold was identified, which displayed excellent activity against Rhizoctonia solani (EC50 = 11.0 μM) and improved potency against Sclerotinia sclerotiorum (EC50 = 5.5 μM) and Phyricularia grisea (EC50 = 12.0 μM) in comparison with the positive control thifluzamide, with EC50 values of 0.09, 33.2, and 33.4 μM, respectively. The results showed that our virtual screening strategy could serve as a powerful tool to accelerate the discovery of novel SDH inhibitors.

Design, Synthesis and Evaluation of Indene Derivatives as Retinoic Acid Receptor α Agonists

A series of novel indene-derived retinoic acid receptor α (RARα) agonists have been designed and synthesized. The use of receptor binding, cell proliferation and cell differentiation assays demonstrated that most of these compounds exhibited moderate RARα binding activity and potent antiproliferative activity. In particular, 4-((3-isopropoxy-2,3-dihydro-1H-inden-5-yl)-carbamoyl)benzoic acid (36d), which showed a moderate binding affinity, exhibited a great potential to induce the differentiation of NB4 cells (68.88% at 5 μM). Importantly, our work established indene as a promising skeleton for the development of novel RARα agonists.

Design, synthesis and biological evaluation of novel podophyllotoxin derivatives bearing 4β-disulfide/trisulfide bond as cytotoxic agents

A novel series of C-4β-disulfide/trisulfide-containing podophyllotoxin derivatives were designed, synthesized, and biologically evaluated for their cytotoxic activities against human cancer cell lines, including KB (Mouth Epidermal Carcinoma Cells) and KB/VCR (Vincristine-resistant Mouth Epidermal Carcinoma Cells). Most of these compounds exhibited promising moderate to good cytotoxic activities. In particular, some of them displayed even superior activities to that of etoposide, especially for KB/VCR cell lines, indicating that introduction of the disulfide/trisulfide moiety would be beneficial for overcoming the multi-drug resistant limitation of etoposide. Moreover, the metabolic evaluation of the most promising compound was further performed to reveal that disulfide bond can be stable in human plasma over 8 hours, indicating good potential of these compounds for in vivo anti-cancer activities.

Discovery and optimization of phthalazinone derivatives as a new class of potent dengue virus inhibitors

Using a dengue replicon cell line-based screening, we identified 3-(dimethylamino)propyl(3-((4-(4-fluorophenyl)-1-oxophthalazin-2(1H)-yl)methyl)phenyl)carbamate (10a) as a potent DENV-2 inhibitor, with an IC50 value of 0.64u202fμM. A series of novel phthalazinone derivatives based on hit 10a were synthesized and evaluated for their inxa0vitro anti-DENV activity and cytotoxicity. The subsequent SAR study and optimization led to the discovery of the most promising compound 14l, which displayed potent anti-DENV-2 activity, with low IC50 value against DENV-2 RNA replication of 0.13u202fμM and high selectivity (SIu202f=u202f89.2) with acceptable pharmacokinetics profiles.

Design, synthesis, and molecular docking study of 3H-imidazole[4,5-c]pyridine derivatives as CDK2 inhibitors

A novel series of imidazo[4,5‐c]pyridine‐based CDK2 inhibitors were designed from the structure of CYC202 via scaffold hopping strategy. These compounds were synthesized and biologically evaluated for their CDK2 inhibitory and in vitro anti‐proliferation potential against cancer cell lines. Several compounds exhibited potent CDK2 inhibition with IC50 values of less than 1u2009µM. The most potent compound 5b showed excellent CDK2 inhibitory (IC50u2009=u200921u2009nM) and in vitro anti‐proliferation activity against three different cell lines (HL60, A549, and HCT116). The molecular docking and dynamic studies portrayed the potential binding mechanism between 5b and CDK2, and several key interactions between them were observed, which would be the reason for its potent CDK2 inhibitory and anti‐proliferation activities. Therefore, the pyridin‐3‐ylmethyl moiety would serve as an excellent pharmacophore for the development of novel CDK2 inhibitors for targeted anti‐cancer therapy.

Discriminatory analysis based molecular docking study for in silico identification of epigallocatechin-3-gallate (EGCG) derivatives as B-RafV600E inhibitors

Virtual screening and biological testing were utilized to identify novel B-RafV600E inhibitors. The employed LigandFit program was evaluated by examining the accuracy of the binding conformation prediction and binding affinity estimation (scoring function) via discriminative analysis training. Ten novel compound hits from the database screening were selected and subjected to in vitro biological tests. The natural product EGCG (A8) was discovered to have promising B-RafV600E inhibitory, and then we evaluated six structurally similar compounds (B1, B2, B3, C1, C2, and C3) for their B-RafV600E inhibitory activities in order to establish a structure–activity relationship. One of these compounds, B2, demonstrated a promising B-RafV600E inhibitory activity with an IC50 value of 9.1 μM, providing a theoretical basis for the development of novel agents as B-RafV600E inhibitors.