Xuejian Wang

Development of tetrahydroisoquinoline-based hydroxamic acid derivatives: potent histone deacetylase inhibitors with marked in vitro and in vivo antitumor activities.

Inhibition of histone deacetylase (HDAC) results in growth arrest, differentiation, and apoptosis in nearly all tumor cell lines, promoting HDACs as promising targets for antitumor therapy. In our previous study we developed a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as HDAC inhibitors (HDACi), among which compound 7d exhibited promising HDAC8 inhibitory and antiproliferative activities. Herein, we report the design and development of a new class of tetrahydroisoquinoline-bearing hydroxamic acid analogues as potential HDACi and anticancer agents. In vitro biological evaluation of these compounds showed improved HDAC8 inhibition (compounds 31a and 31b exhibited mid-nM IC(50) values against HDAC8) and potent growth inhibition in multiple tumor cell lines. Most importantly, compounds 25e, 34a, and 34b exhibited excellent in vivo anticancer activities in a human breast carcinoma (MDA-MB-231) xenograft model compared with suberoylanilide hydroxamic acid (SAHA), an approved HDACi. Collectively, our results indicate that tetrahydroisoquinoline bearing a hydroxamic acid is an excellent template to develop novel HDACi as potential anticancer agents.

Discovery of a tetrahydroisoquinoline-based hydroxamic acid derivative (ZYJ-34c) as histone deacetylase inhibitor with potent oral antitumor activities.

Histone deacetylase (HDAC) has emerged as an attractive target for the development of antitumor agents during the past decade. Previously tetrahydroisoquinoline-bearing hydroxamic acid analogue, ZYJ-25e (1), was identified and validated as a potent histone deacetylase inhibitor (HDACi) with marked in vitro and in vivo antitumor potency. In the present study, further modification of 1 led to another more potent, orally active HDACi, ZYJ-34c (4). Compared to FDA-approved drug suberoylanilide hydroxamic acid (SAHA), compound 4 exhibited higher in vivo antitumor potency in a human breast carcinoma (MDA-MB-231) xenograft model and in a mouse hepatoma-22 (H22) pulmonary metastasis model and similar in vivo antitumor potency in a human colon tumor (HCT116) xenograft model.

Agonistic anti-4-1BB antibody promotes the expansion of natural regulatory T cells while maintaining Foxp3 expression.

The engagement of the 4‐1BB (CD137) co‐stimulatory pathway promotes the activation and proliferation of conventional CD4+ T and CD8+ T cells, but the role of 4‐1BB co‐stimulation in CD4+ CD25+ regulatory T cells (Treg) is less clear. In particular, whether 4‐1BB stimulation affects the expression of Foxp3, a master gene for Treg, is unknown. This study demonstrates that co‐stimulation of 4‐1BB engaged by an agonistic antibody promotes the proliferation of Treg in a dependent manner of low‐concentration interleukin‐2 in vitro. The 4‐1BB‐expanded Treg maintain Foxp3 expression and their ability to suppress conventional CD4+ T cells and their feature to produce no interleukin‐2. However, the 4‐1BB‐expanded Treg produce increased levels of interferon‐γ, whose significance is unknown. Thus, 4‐1BB co‐stimulation plays a role in the expansion of functional CD4+ CD25+ Treg cells without adversely affecting their suppressive activity.

Design, synthesis and primary activity evaluation of l-arginine derivatives as amino-peptidase N/CD13 inhibitors

Abstract A series of l-arginine derivatives were designed, synthesized and assayed for their activities against amino-peptidase N (APN)/CD13 and metalloproteinase-2 (MMP-2). The results showed that most compounds exhibited high inhibitory activities against APN and low activities against MMP-2. Within this series, two compounds 5q and 5s (IC50 =5.3 and 5.1μM) showed similar inhibitory activities compared with bestatin (IC50 =3.8μM), which could be used as novel lead compounds for the future APN inhibitors development as anticancer agents.

The Expression and Significance of TIPE2 in Peripheral Blood Mononuclear Cells from Asthmatic Children

Tumour necrosis factor‐α‐induced protein‐8 like‐2 (TIPE2) is a newly identified immune negative regulator. The abnormal expression of TIPE2 has been found in several human inflammatory diseases. However, the expression level and clinical significance of TIPE2 in childhood asthma remain unclear. In this study, we detected TIPE2 expression in peripheral blood mononuclear cells (PBMC) from 42 children with asthma and 39 healthy controls by RT‐PCR, qRT‐PCR and Western blot. We also detected the levels of serum total immunoglobulin E (IgE), eosinophil (EO), interleukin‐4 (IL‐4) and interferon‐γ (IFN‐γ) and analysed the correlations of TIPE2 expression with IgE, EO, IL‐4 and IFN‐γ. The results showed that TIPE2 mRNA and protein expression were decreased in children with asthma compared with healthy controls. The levels of IgE, EO and IL‐4 in the children with asthma were obviously higher than those in normal controls, while the level of IFN‐γ in patients with asthma was significantly lower than that in healthy subjects. Furthermore, the expression level of TIPE2 mRNA was negatively correlated with IgE, EO and IL‐4. However, no statistically significant correlation was found between TIPE2 mRNA expression and serum IFN‐γ level. In conclusion, our data suggest that reduced TIPE2 expression may contribute to the pathogenesis of childhood asthma.

Design, synthesis and preliminary biological evaluation of N-hydroxy-4-(3-phenylpropanamido)benzamide (HPPB) derivatives as novel histone deacetylase inhibitors

A novel series of N-hydroxy-4-(3-phenylpropanamido)benzamide (HPPB) derivatives comprising N-hydroxybenzamide group as zinc-chelating moiety were designed, synthesized and evaluated for their ability to inhibit histone deacetylases. These compounds possessed inhibitory activity against the enzymes with IC(50) values as low as 4.0 microM. Among them, the thiophene substituted derivative 5j (IC(50)=0.3 microM) and benzo[d][1,3]dioxole derivative 5t (IC(50)=0.4 microM) exhibited good antiproliferative activity against the growth of human colon carcinoma cell line HCT116 and non-small cell lung cancer cell (NSCLC) line A549. In addition, they were found to potently induce cell-cycle arrest at G2 phase.

Novel 3-phenylpropane-1,2 -diamine derivates as inhibitors of aminopeptidase N (APN)

Aminopeptidase N (APN) is an essential peptidase involved in the process of tumor invasion and metastasis. Here we describe a novel class of inhibitor with 3-phenylpropane-1,2-diamine as scaffold to APN. Preliminary activity evaluation with enzyme inhibition studies showed that compound 12i exhibited potent and selective inhibitory activity towards APN with the IC(50) value 15.5+/-1.2microM.

Novel cyclic-imide peptidomimetics as aminopeptidase N inhibitors. Structure-based design, chemistry and activity evaluation. II.

A novel class of potent aminopeptidase N inhibitors with 3-amino-cyclic-imide scaffold is described. The preliminary biological test revealed that all the compounds displayed high specific inhibitory activity against aminopeptidase N compared with previous work because of the existence of free amino group. Compounds containing hydroxamate group are more potent than carboxyl and ester derivatives. Compound 13f potentially inhibited APN activity with IC(50) value of 1.8 microM and displayed specific activity profiles in cells assay and in vivo anti-metastasis assay.

Histone Deacetylase Inhibitors with Enhanced Enzymatic Inhibition Effects and Potent in vitro and in vivo Antitumor Activities

In the present work, a series of small molecules were designed and synthesized based on structural optimization. A significant improvement in the enzyme inhibitory activity of these compounds was discovered. Moreover, the tested compounds have moderate preference for class I HDACs over HDAC6, as demonstrated by enzyme selectivity assays. In vitro antiproliferation assay results show that representative compounds can selectively inhibit the growth of non‐solid lymphoma and leukemic cells such as U937, K562, and HL60. In the in vivo antitumor assay, (S)‐4‐(2‐(5‐(dimethylamino)naphthalene‐1‐sulfonamido)‐2‐phenylacetamido)‐N‐hydroxybenzamide (D17) showed better performance than SAHA in blocking U937 tumor growth. Western blot analysis revealed that representative molecules can block the function of both class I HDACs and HDAC6. More importantly, our western blot results reveal that the levels of some oncogenic proteins (p‐Akt in the PI3K/AKT/mTOR signal pathway, c‐Raf and p‐Erk in the MAPK signal pathway) were dramatically down‐regulated by our compounds in the U937 cell line rather than MDA‐MB‐231 cells. This distinction in cellular mechanism might be an important reason why the U937 cell line was found to more sensitive to our HDAC inhibitors than the MDA‐MB‐231 cell line.

Synthesis and biological evaluation of N-(4-hydroxy-3-mercaptonaphthalen-1-yl)amides as inhibitors of angiogenesis and tumor growth.

A series of N-(4-hydroxy-3-mercaptonaphthalen-1-yl)amides were synthesized and investigated for their in vitro antiangiogenic activity. Among these compounds, 6d, which possesses an ortho-nitro group at the benzene ring, exhibited potent inhibitory effect on the proliferation of HUVECs, A549, K562, PC-3, HCT116, MDA-MB-231 and MCF-7 cells (IC50 = 5.34, 40.53, 10.81, 52.52, 10.19, 21.37 and 2.81 μM, respectively). Meanwhile, compound 6d inhibited in vitro angiogenesis markedly in both HUVECs tube formation assay and the rat thoracic aorta rings test. Further kinase assay study showed that compound 6d had good VEGFR2, ALK, AKT1 and ABL inhibitory activities and moderate EGFR and PDGFR-β inhibitory activities. The data supports the further investigation of this class of compounds as potential antiangiogenic and anticancer agents.