[Show abstract][Hide abstract] ABSTRACT: Pharmacological inhibition of histone deacetylases (HDACs) has been successfully applied in the treatment of a wide range of disorders, including Parkinson's disease, infection, cardiac diseases, inflammation, and especially cancer. HDAC inhibitors (HDACIs) have been proved to be effective antitumor agents by various stages of investigation. At present, there are two opposite focuses of HDACI design in the cancer therapy, highly selective inhibitor strategy and dual- or multitargeted inhibitors. The former method, which is supposed to elucidate the function of individual HDAC and provide candidate inhibitors with fewer side effects, has been widely accepted by the inhibitor developer. The latter approach, though less practiced, has promising potential for the antitumor therapy based on HDACIs. Effective HDACIs, some of which are in clinic anticancer research, have been developed by both methods. In order to gain insight into HDACI design, the strategies and achievements of the two diverse methods are reviewed.
Preview · Article · Jan 2015 · Medicinal Research Reviews
[Show abstract][Hide abstract] ABSTRACT: A novel series of N-(3-((7H-purin-6-yl)thio)-4-hydroxynaphthalen-1-yl)-sulfonamides were designed and synthesized. Biological characterization revealed that several compounds exerted enhanced anti-proliferative activity against human umbilical vein endothelial cells (HUVECs) and several cancer cell lines and high specific protein kinase and angiogenesis inhibitory activities. Compared with our previously synthesized compounds, the substitution of sulfonamide structure for amide fragment played an essential role for the advance of inhibitory activities. In addition, the replacement of 1H-1,2,4-triazole ring by 7H-purine did not result in obvious decrease of inhibition efficacy, indicating that the sulfonamide structure contributes even more to the inhibition efficacy than the 1H-1,2,4-triazole ring. Among these compounds, compound 9n demonstrated comparable in vitro antiangiogenic activities to pazopanib in both HUVEC tube formation assay and the rat thoracic aorta rings (TARs) test. Meanwhile, compound 9n was identified to inhibit Akt1 (IC50=1.73μM) and Abl tyrosine kinase (IC50=1.53μM) effectively.
No preview · Article · Dec 2013 · Bioorganic & medicinal chemistry
[Show abstract][Hide abstract] ABSTRACT: A novel series of pazopanib derivatives were designed, synthesized and evaluated their inhibitory activity against a series of kinases including VEGFR-2, EGFR, AKT1, ALK1 and ABL1. The anti-angiogenic activities ex vivo of some compounds were also investigated. Compounds P2d and P2e demonstrated outstanding inhibitory activity against VEGFR-2 and ABL1 and higher anti-angiogenic activity compared with Pazopanib, the reference standard. These two compounds (P2d and P2e) could be used as novel lead compounds for further development of anticancer agents. This article is protected by copyright. All rights reserved.
No preview · Article · Oct 2013 · Chemical Biology & Drug Design
[Show abstract][Hide abstract] ABSTRACT: Among the numerous endogenous promoters of angiogenesis, vascular endothelia growth factor (VEGF) plays a leading role in angiogenesis, which has huge impact on proliferation, survival, migration and permeability of tumor cells. VEGF signal system also becomes remarkable anticancer targets, including VEGF, vascular endothelia growth factor receptor (VEGFR), and VEGF downstream signal pathways. So far, there has been many clinical or approved anticancer drugs that directly or indireactly interfere with VEGF signal system applied in the treatment of various tumors and other diseases associated with pathological angiogenesis. Various kinds of antiangiogenic agents which inhibit VEGF and VEGFR have been developed and discovered gradually, including antibodies, ribozymes and small molecule inhibitors. Meanwhile, the investigation into antiangiogenic agents which block certain signal proteins of VEGF downstream signal pathways attracts the attention of medicinal chemists and enriches the application of antiangiogenic agents. This review will interpret the mysterious VEGF signal system from its molecular structure and probe to the mechanism of the combination of VEGF and its receptors. Furthermore, the detail of VEGF signal pathways will be introduced comprehensively and methodically. In addition, some up-to-date clinical or approved anticancer agents will be clearly tabulated. The binding modes of different kinase inhibitors will be used to explain the SAR of the small molecule inhibitors. Finally, in order to make the readers master VEGF signal system completely, some novel targets and inhibitors block the downstream signal pathways of VEGF are plainly stated.
Full-text · Article · Sep 2013 · Current Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: A novel series of 4-amino-2-(thio)phenol derivatives were well synthesized. The preliminary biological test revealed that several compounds displayed high specific protein kinase and angiogenesis inhibitory activities compared with previous work mainly because of the substitution of sulfonamide structure for amide fragment. Among which, compound 5i was identified to inhibit protein kinase B/AKT (IC50 = 1.26 μM) and ABL tyrosine kinase (IC50 = 1.50 μM) effectively. Meanwhile, compound 5i demonstrated competitive in vitro antiangiogenic activities to Pazopanib in both human umbilical vein endothelial cell (HUVEC) tube formation assay and the rat thoracic aorta rings test.
No preview · Article · Aug 2013 · European Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Apr 2013 · European Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: A novel class of L-lysine derivatives as aminopeptidase N (APN) inhibitors was designed and synthesized. Activity evaluation showed that compound C7 (IC(50) = 9.6 +/-1.3 microM) and C20 (IC(50) = 13.6 +/- 1.9 microM) were equivalent to the positive control Bestatin (IC(50) = 11.3 +/- 1.6 microM).
No preview · Article · Feb 2010 · Protein and Peptide Letters