1-Benzyl-3-(5‘-hydroxymethyl-2‘-furyl)indazole (YC-1) Derivatives as Novel Inhibitors Against Sodium Nitroprusside-Induced Apoptosis

Antiapoptotic agents based on 1-benzyl-3-(5‘-hydroxymethyl-2‘-furyl)indazole (22, YC-1) derivatives were explored for effective treatment of sepsis and septic shock. We found that compound 22, 1-benzyl-3-(5‘-methoxymethyl-2‘-furyl)indazole (27), and 1-phenyl-3-(5‘-hydroxymethyl-2‘-furyl)indazole (23) were the most effective inhibitors of sodium nitroprusside-induced vascular smooth muscle cell apoptosis. These three compounds are proposed as potential therapeutic agents for the treatment of sepsis

Synthesis and Cytotoxicity of 1,2-Disubstituted Naphth[2,3-<i>d</i>]imidazole-4,9-diones and Related Compounds

As part of our continuing search for potential anticancer drug candidates that are selective against slowly growing solid tumors, we have synthesized several series of 1- and 2-substituted derivatives of the lead structure, 1-ethyl-2-methylnaphth[2,3-d]imidazole-4,9-dione (5). Their cytotoxic activity in the National Cancer Institute's in vitro cancer cell line panel is reported. In general, substitution of various alkyl, phenyl, or benzyl moieties did not improve activity, and compound 5 remains the most active naphth[2,3-d]imidazole-4,9-dione derivative. However, high levels of activity and selectivity were found with several related 2-(acylamino)-3-chloro-1,4-naphthoquinones (2f−j). Compound 2i, 2-[(2-fluorophenyl)acetamido]-3-chloro-1,4-naphthoquinone, has been selected for further in vivo testing and as an additional lead compound for further structural modification

Synthesis of 1-Benzyl-3-(5‘-hydroxymethyl-2‘-furyl)indazole Analogues as Novel Antiplatelet Agents

1-Benzyl-3-(5‘-hydroxymethyl-2‘-furyl)indazole (28, YC-1) was selected as the lead compound for systemic structural modification. After screening for antiplatelet activity, SARs of YC-1 analogues were established. Among these potent active derivatives, compounds 29, 30, 31, 44, and 45 functioned as potent activators of sGC and inhibitors of PDE5 with potency comparable to that of YC-1. In addition, compound 58 was found to be a selective and potent inhibitor of protease-activated receptor type 4 (PAR4)-dependent platelet activation

DataSheet_1_Anti-Angiogenetic and Anti-Lymphangiogenic Effects of a Novel 2-Aminobenzimidazole Derivative, MFB.doc

Background and PurposeBenzimidazoles have attracted much attention over the last few decades due to their broad-spectrum pharmacological properties. Increasing evidence is showing the potential use of benzimidazoles as anti-angiogenic agents, although the mechanisms that impact angiogenesis remain to be fully defined. In this study, we aim to investigate the anti-angiogenic mechanisms of MFB, a novel 2-aminobenzimidazole derivative, to develop a novel angiogenesis inhibitor.Experimental ApproachMTT, BrdU, migration and invasion assays, and immunoblotting were employed to examine MFB’s effects on vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration, invasion, as well as signaling molecules activation. The anti-angiogenic effects of MFB were analyzed by tube formation, aorta ring sprouting, and matrigel plug assays. We also used a mouse model of lung metastasis to determine the MFB’s anti-metastatic effects.Key ResultsMFB suppressed cell proliferation, migration, invasion, and endothelial tube formation of VEGF-A-stimulated human umbilical vascular endothelial cells (HUVECs) or VEGF-C-stimulated lymphatic endothelial cells (LECs). MFB suppressed VEGF-A and VEGF-C signaling in HUVECs or LECs. In addition, MFB reduced VEGF-A- or tumor cells-induced neovascularization in vivo. MFB also diminished B16F10 melanoma lung metastasis. The molecular docking results further showed that MFB may bind to VEGFR-2 rather than VEGF-A with high affinity.Conclusions and ImplicationsThese observations indicated that MFB may target VEGF/VEGFR signaling to suppress angiogenesis and lymphangiogenesis. It also supports the role of MFB as a potential lead in developing novel agents for the treatment of angiogenesis- or lymphangiogenesis-associated diseases and cancer.</p